key: cord-0067440-gnf6wkkz
authors: nan
title: A GLOBAL CONGRESS DIGEST ON SOLID TUMORS. Report from the ASCO Virtual Congress, 4th –8th June 2021
date: 2021-09-09
journal: Memo
DOI: 10.1007/s12254-021-00754-w
sha: 230c4488a0e8aa3824108f6bff4aa8710318bdaf
doc_id: 67440
cord_uid: gnf6wkkz

nan

Preface

Novel approaches in gastric cancer

Checkpoint inhibition: predictors, resistance and immunogenomic features S98 PARP-and anti-PD-1-based strategies in breast and cervical cancer S102 Anti-PD-1 compounds targeting MSI-H/ dMMR tumors S106 Early insights for CPI combinations in solid tumors S111 Esophageal cancer: taking immunotherapy one step further Preface Dear Colleagues,

Because of the ongoing COVID-19 pandemic, this year's ASCO scientific meeting took place for the second time virtually from Friday, June 04, through Monday, June 08. During these five-day world's largest oncology conference, approximately 30,000 professionals attended online at least one of the 150 ondemand and broadcast sessions featuring over almost 5,000 abstracts, more than 2,000 poster presentations, 19 oral and 16 educational sessions, as well as opening and plenary sessions, award lectures, cancer-specific highlights sessions, and several clinical cancer symposia. This shows the urge interest of the global oncology community to get information about advances in cancer research, treatments, and patient care through both scientific and educational sessions.

Next to indication-specific oral sessions dedicated to solid and hematologic malignancies, multiple general cross-thematic sessions dealt with developmental therapeutics, either molecular targeted agents and tumor biology, or immunotherapy. A large part of this publication is concerning new therapeutic options to overcome resistance to immune checkpoint inhibitors; especially, innovative strategies combining immunotherapy and targeted agents led to encouraging results in the treatment of patients with advanced or metastatic solid malignancies. The identification of predictive biomarkers to anticipate patients' susceptibility to immune-related adverse events was certainly also a main point of interest.

Novel combination approaches are currently being investigated in a wide range of solid tumors, including gastric cancers, breast cancer, cervical cancers, as well as esophageal cancers. Significant progress was communicated in breast cancer regarding PARP inhibitors, while a new potential synergetic treatment combination was reported in patients with advanced cervical cancer. More generally, new therapeutic strategies are now being explored in advanced solid tumors as combination between an anti-PD-1 antibody and different potential targets, including VEGF/Ang2, TIGIT, LAG3, PVRIG, TGF-β or HER2. Dual immunotherapy regimen or immunotherapy associated with chemotherapy are potential new standards of care in difficult-to-treat advanced or metastatic esophageal cancer. In addition, the clinical benefit of immune checkpoint inhibitors in MSI-H/dMMR solid tumors was confirmed and several innovative tissue-agnostic treatment options are currently under clinical investigation. Additionally, the effect of immunotherapy in terms of tumor elimination and pathologic response led to a better understanding of the dynamic changes in the immune microenvironment of the tumor.

Therefore, ASCO 2021 met once more its primary goal of sharing information between participants to ensure that all patients have access to the best knowledge in the field and benefit from latest therapeutic advances.

Novel approaches in gastric cancer LEAP-005: lenvatinib plus pembrolizumab in gastric cancer With more than 1 million newly diagnosed cases in 2020, gastric cancer was at the fifth place (5.6 %) of the most frequent malignant diseases and accounted for nearly 8 % of cancer deaths worldwide [1] .

The multicohort, non-randomized, open-label, phase II LEAP-005 study (NCT03797326) was designed to evaluate the safety and efficacy of a combinationthe anti-angiogenic multikinase inhibitor lenvatinib plus the anti-PD-1 antibody pembrolizumab -in patients with previ-ously treated advanced solid tumors. Among the seven different cohorts, the results of the gastric cohort have been presented at the virtual scientific ASCO 2021 meeting [2] . The eligibility criteria were adults with confirmed metastatic and/or unresectable gastric cancer (GC), who received at least two prior lines of therapy, had measurable disease per RECIST v1.1, had a good performance status (ECOG PS 0-1) and provided a tissue sample evaluable for PD-L1 (programmed cell death-ligand 1) expres sion. For up to 35 cycles (approximately 2 years) or until confirmed disease progression, unacceptable toxicity, or withdrawal of consent, len-vatinib was administered daily (20 mg, orally), while patients received pembrolizumab (200 mg, IV) every three weeks; if patients experienced a clinical benefit, lenvatinib could be continued beyond two years. Objective response rate (ORR) according to RECIST v1.1 criteria assessed by a blinded independent central review (BICR) and safety were the co-primary endpoints. Secondary endpoints included disease control rate (DCR), duration of response (DOR), PFS (progression-free survival), and OS (overall survival).

Among the 31 eligible patients recruited, the mean age was 62 years memo S92 (range, , most of them (87 %) were male and 71 % had a combined PD-L1 positive score (CPS) ≥ 1. At the time of the analysis (April 10, 2020), patients were for 7.0 months (range, 1.9-11.9) on treatment. An ORR of 10 % (95 % CI, 2-26) and a DCR of 48 % (95 % CI, were achieved by the study population; in total, one patient (3 %) experienced a complete response (CR), while two patients (6 %) experienced a partial response (PR) and twelve patients (39 %) a stable disease. Median DOR was not reached yet. A median PFS of 2.5 months (range, 1.8-4.2; 6-month rate, 22 %) and a median OS of 5.9 months (range, 2.6-8.7; 6-month rate, 46 %) were attained (Figure 1) . The most common treatment-related adverse events (TRAEs) observed in ≥ 20 % of patients were diarrhea (26 %) and fatigue (26 %) . Immune-mediated AEs, which were experienced by seven patients (22 %), included hypothyroidism (n = 5) and hyperthyroidism (n = 2). In total, twelve patients (39 %) experienced grade 3 AEs, while no AE of grade 4 severity was seen; one patient died due to a gastrointestinal hemorrhage considered to be tumor-related by the investigator.

According to these data, the combination of lenvatinib plus pembrolizumab demonstrated promising antitumor activity and a manageable safety profile; therefore, the enrollment in the gastric cohort has been extended to 100 patients.

PARALLEL 303: pamiparib as maintenance monotherapy in GC Some gastric cancer present platinum sensitivity, as well as genomic instability (HRD, homologous recombination deficiency). Considering that cells with HRD are sensitive to poly (ADP-ribose) polymerase protein (PARP) inhibition [3] , the use of PARP inhibitors as maintenance following platinum-based chemotherapy might be an efficient therapeutic strategy. The efficacy of PARP inhibitors in other cancer showing platinum sensitivity and higher levels of HRD has been already described, inclusive as maintenance therapy [4] [5] [6] . Pamiparib is an investigational PARP inhibitor showing sensitivity to HRD cells, which demonstrated its efficacy and tol-erability in early-phase clinical study in advanced solid tumors [7, 8] .

The double-blind, randomized, global, phase II PARALLEL 303 study (NCT03427814) compared the efficacy, safety, and tolerability of pamiparib against placebo as maintenance treatment in responders, who were defined as having a PR for ≥ 4 weeks or a CR after platinum-based fist-line chemotherapy [9] . Eligible patients had histologically confirmed inoperable locally advanced or metastatic GC (adenocarcinoma of the stomach or gastroesophageal junction) and were enrolled in 128 Overall, 136 patients were randomized 1:1 to receive either pamiparib (60 mg orally, twice daily) or placebo (twice daily) in 28-day cycles. At the time of analysis, 51.5 % of patients remained on study and 16.9 % remained on treatment. After a median follow-up of approximately 8.0 months in both arms, median PFS was longer with the investigational drug than with placebo, also not significantly different (3.7 vs 2.1 months; HR, 0.799; p = 0.1428). No significant clinical benefit was observed for median OS (10.2 with pamiparib vs 12.0 months with placebo) or ORR (7.7 vs 6.3, respectively) between both arms. Anemia (36.6 %) and nausea (32.4 %) among pamiparib-treated patients, as well as abdominal pain (18.5 %) in the control arm were the most frequently observed treatment-emergent adverse events (TEAEs). TEAEs led to treatment discontinuation in 11.3 % (n = 8) of patients in investigational arm and 3.1 % (n = 2) in placebo arm. Although pami-parib did not meet its primary endpoint in this study, it showed a manageable safety profile consistent with that of other PARP inhibitors and no new safety signals were detected.

In the phase III GOLD study, the combination olaparib plus paclitaxel missed its primary endpoint -improvement of OS -compared to paclitaxel alone for the treatment of patients with gastric and gastroesophageal junction tumors, who progressed following the frontline therapy [10] . The PARP inhibitor olaparib not only induce DNA damage and cell death but is also involved in the upregulation of PD-L1. Based on these findings, the authors hypothesize that the combination of a cytotoxic chemotherapy (paclitaxel) plus a PARP inhibitor (olaparib) plus an immune checkpoint inhibitor (durvalumab) might potentiate the antitumor activity in gastric cancer [11] . Therefore, a biomarkeroriented study was designed to explore the changes of tumor environment and to evaluate if the anti-PD-L1 addition might enhance the antitumor activity.

An ongoing phase II trial (NCT03579784) is enrolling patients with measurable lesions and histologically confirmed unresectable GC, who have failed to one prior chemotherapy. Patients previously exposed to anti-PD(L1)-1 or PARP inhibitors are excluded. Following the administration schema described on Figure 2 , patients receive olaparib (150 mg twice daily on Day 1-28) plus paclitaxel (80 mg/m 2 intravenously, IV, on Day 1/8/15) for four cycles, with the addition of durvalumab (1.5g IV on Day 1) on cycles 2 to 4. At the time of progression, biopsy is mandatory; additionally, blood samples for biomarker analysis are collected at each treatment cycle. The DCR per RECIST v1.1 is the primary study endpoint, while the key secondary endpoints include ORR, PFS, OS, quality of life (QoL) and safety. This trial is intended to recruit 40 patients in Korea.

Esophageal cancer is the sixth most common cause of cancer mortality globally; together, gastric and esophageal cancers were responsible for more than 1.3 million deaths in 2020 [1] . In patients with resectable gastroesophageal carcinoma (GEA), ESMO guidelines recommend a neoadjuvant chemotherapy as standard of care [12, 13] , which might also be further administered after surgery; however, this regimen leads to suboptimal outcomes. In the CheckMate 577 study, adjuvant immunotherapy with nivolumab -an anti-PD-1 (programmed cell death protein 1) -has proven to be efficient in poor risk patients with GEA treated with neoadjuvant chemotherapy [14] . Moreover, nivolumab and ipilimumab -a CTLA-4 inhibitor -combined therapy showed antitumoral activity in advanced GEA. High risk patients with GEA are defined as those presenting metastatic lymph nodes or a microscopically incomplete surgical resection (R1). According to the data previously presented, high risk GEA patients treated with this dual adjuvant immunotherapy post-resection might have a better disease-free survival (DFS) than those who received standard post-operative chemotherapy [15] .

In the international, open-label, randomized, phase II EORTC VESTIGE 

Immune checkpoints, such as cytotoxic T-lymphocyte associated protein-4 (CTLA-4) or programmed cell death protein 1 (PD-1), downregulate T-cell responses and are crucial for self-tolerance, which protects the body against attacking cells indiscriminately [1] . Tumor cells hijack this mechanism to evade the immune system through the activation of immune checkpoints and inhibition of the T-cell response [1] . Immune checkpoint inhibitors (CPIs) block these pathways, thus enhancing the anticancer immunity [1, 2] . CPIs have changed the treatment landscape across various tumor entities due to durable clinical response [3] . However, specific immune-related adverse events study (NCT03443856), nivolumab plus ipilimumab versus chemotherapy are currently investigated as adjuvant therapy in high-risk GEA patients [16] . After a post-surgery recovery period of two months, eligible patients are rand-omized 1:1 to receive for a year either nivolumab (3 mg/kg IV, biweekly) plus ipilimumab (1 mg/kg IV, every six weeks) or the same chemotherapy regimen as pre-operatively (Figure 3 ). DFS will be primarily analyzed, and OS, safety, toxicity, and QoL secondarily evaluated. Checkpoint inhibition: predictors, resistance and immunogenomic features (irAEs) have been described in various clinical trials [2, 4] . There is an unmet need to identify predictive biomarkers to anticipate patients' susceptibility to irAEs [5] . So far, data specifically linking the tumor immune response to the risk of experiencing irAEs are scarce [6] . The analyzed population included 472 patients with various cancer entities who had tumor immune profiling performed on paraffin embedded formalin fixed archival tumor samples using the omniseq immune report card [6] . The patients subsequently underwent CPI therapy. The immune report card enclosed the enumeration of tumor infiltrating lymphocytes (TILs) by immunohistochemistry (IHC) and TIL-associated genes by RNA-sequencing, programmed cell death 1 ligand 1 (PD-L1) expression via IHC, and tumor mutational burden (TMB) via DNA-sequencing. The irAEs (type and grade) were investigated based on retrospective patient chart review, and their association with immune biomarkers analyzed statistically.

More than half of the patients had lung cancer (55 %), 9 % ovarian cancer, and 6 % melanoma. The median age of the patients was 61 (range, 53-70) and 56 % were women. Most of the patients received an anti-PD-1/PD-L1 treatment (94 %), while 6 % had a combination therapy. Among the 37 % of patients who developed irAEs, 3 % had grade ≥3 irAEs. The most affected organs were the skin (11 %), thyroid gland (10 %), and gastrointestinal tract (9 % The study demonstrated a correlation between the tumor immune environment and the immune toxicity, as increased TILs and a high PD-L1 expression were associated with an elevated risk for irAEs in patients receiving immunotherapy.

NBTXR3: Overcoming resistance to anti-PD-1 therapy

The success of CPIs has been largely driven by unprecedented durability of responses, which can last for years even in absence of continuous treatment [7] . However, resistance to CPIs, which has been described in more than 80 % of treated patients, is challenging [8] . Radiotherapy (RT) combined to immunotherapy has been previously shown to improve CPI response rates [9, 10] .

NBTXR3 is a novel radioenhancer which is administered via a single intratumoral injection and activated by RT. NBTXR3 was designed to enhance the ionizing energy deposit inside tumor cells -without increasing the toxicity in the surrounding healthy tissue -to trigger tumor cell death and to prime an adaptive immune response. In preclinical settings, this radioenhancer showed antitumor efficacy in various tumors; especially in the combination NBTXR3 plus radiation therapy, a local and a systemic control, as well as an induction of the immune response, were observed in mice [11] [12] [13] . Moreover, in in vivo tumor models, activated NBTXR3 increased the local efficacy of PD-1 therapy compared to RT alone and improved distant tumor control via an abscopal effect [14] . In April 2019, NBTXR3 received CE Mark in Europe for the treatment of locally advanced soft tissue sarcoma, and FDA fast track designation in 2020 for patients with locally advanced head and neck squamous cell carcinoma (HN-SCC) who are not eligible for a platinum-based chemotherapy [15] [16] [17] . New data recently presented at ASCO 2021 showed that NBTXR3 activated through radiation acts synergistically with anti-PD-1 therapy to enhance the therapeutic index of the RT and to overcome PD-1 resistance [14, 18] .

An ongoing multicenter, open-label, non-randomized, phase I, first-in-human study evaluates the safety and tolerability of RT-activated NBTXR3 in combination with anti-PD-1 in three cohorts. The first cohort includes patients with locoregional recurrent (LRR) or recurrent and metastatic (R/M) HNSCC at the target lesion in a previously irradi- 

ated field. In cohort 2 and 3, patients with respectively lung or liver metastases from any primary cancer eligible for anti-PD-1 treatment are enrolled [14, 18] . About 60 patients will receive RTactivated NBTXR3 in combination with an approved anti-PD-1 therapy (NCT03589339). Primary endpoints enclose the determination of the recommended phase 2 dose, dose limiting toxicities and maximum tolerated dose. Secondary objectives include antitumor response (objective response rate by RECIST 1.1), safety, and feasibility of the NBTXR3 injection. First results demonstrated tumor regression in 10 out of 13 patients evaluable for tumor responses, regardless of prior anti-PD-1 exposure [14] . Four out of five anti-PD-1 naïve patients experienced a regression; ORR reached 60 %, including one complete response (CR) (Figure 2A) . In anti-PD-1 non-responders, 78 % (n = 6) had posttreatment tumor regression and ORR was 50 % (1 CR and 2 partial responses) ( Figure 2B) . Altogether, among 16 serious adverse events (SAE) observed, four were related to NBTXR3 or injection related, and included hyperglycemia, pneumonitis, and soft tissue necrosis. Taken together, this data underline the immune modulation effect of radiotherapy-activated NBTXR3, not only as single agent, but also in combination with an anti-PD-1 treatment.

In patients with resectable esophageal or gastroesophageal junction (E/GEJ) cancer, the standard-of-care neoadjuvant chemoradiation is associated with a high recurrence rate [20] . In the CheckMate 577 trial, the treatment with the CPI nivolumab as adjuvant therapy following neoadjuvant chemoradiation and surgery significantly increased disease-free survival in patients with stage II/III esophagogastric cancer [21] . In a study reported at ASCO 2021, multi-omics analyses were performed to determine the immune and genomic landscape contributing to pathologic response in patients with E/GEJ cancer treated with an immune checkpoint blockade therapy [22, 23] . This phase IB study assessed the safety of two cycles anti-PD-1 nivolumab alone or nivolumab plus the anti-LAG3 relatlimab with chemoradiation in the preoperative setting (NCT03044613). Serial tumor samples from 23 patients were collected prior to therapy, after two cycles of CPI induction, and at resection (Figure 3) . Pathologic response was measured by tumor regression at resection. Median follow up was 23 months post-surgery. Overall, 48 serial tumor samples were analyzed via bulk RNA sequencing (RNAseq), while 22 baseline tumor and normal DNA pairs were ana-lyzed by whole exome sequencing (WES) to find somatic mutations and generate tumor mutation burden (TMB) estimates.

After immunotherapy induction, a significant upregulation of interferonalpha (IFN-α), interferon-gamma (IFN-γ), tumor-necrosis factor-α (TNF-α) and antigen presentation related genes were detected compared to baseline (p<0.0001). On the other hand, E2F targets (p = 0.002), G2M checkpoint genes (p = 0.005) and DNA damage repair genes (p = 0.004) were significantly downregulated following CPI neoadjuvant treatment. Patients who reached a pathologic complete response (pCR) were those whose tumors harbored a high number of expressed mutations (p = 0.026). A significantly higher density of intratumoral activated M1 macrophages was observed post-induction with CPI in patients with pCR (p = 0.0034). Additionally, TMB was not a predictive marker of a pathologic response (p = 0.22).

In summary, CPI neoadjuvant therapy induced an inflammatory immune response in the tumor microenvironment which was associated with tumor elimination and pathologic response. n 

Talazoparib in germline BRCA1/2-mutated breast cancer …

Breast cancer (BC) is the most diagnosed cancer in women and the leading cause of cancer death in females [1] . It has been recently shown that approximately 38 % of female patients younger than 40 years presenting with triplenegative breast carcinomas (TNBC) harbored a germline mutation in breast cancer (BC) susceptibility genes 1 or 2 (gBRCA1/2m) [2] . Treatment options are limited for patients with gBRCA1/2m BC, and the presence of these genetic alterations is associated with younger age at diagnosis, aggressive disease, dismal prognosis and higher risk of recurrence [3] . The enzyme poly (adenosine diphosphate-ribose) polymerase (PARP) plays an important role in the regulation of single-strand DNA breaks and PARP inhibitors induce tumor cell death due to accumulation of irreparable DNA damages [4] . Moreover, PARP inhibitors are well tolerated, oral targeted therapies [3] . Therefore, PARP inhibitors such as talazoparib are a welcome addition to the treatment arsenal for patients with gBRCA1/2m human epidermal growth factor receptor 2-negative (HER2-) locally advanced or metastatic BC [5] . Based on the findings of the pivotal phase III EMBRACA trial (NCT01945775), talazoparib received approval in October 2018 in the USA and in June 2019 in Europe for the treatment of adult patients with gBRCA1/2m, HER2-negative locally advanced or metastatic BC [5] [6] [7] . In this trial, talazoparib met its primary endpoint by show-ing a significantly better median progression-free survival (PFS) versus physician's choice of chemotherapy (PCT) in this population (8.6 vs 5.6 months; HR, 0.54; 95 % CI, 0.41-0.71; p<0.001) [5] . A previous analysis of the EMBRACA trial investigating biomarkers associated with LONG and SHORT responders revealed that a tumor MYC amplification was associated with shorter overall survival (OS) in TNBC patients treated with talazoparib [8] .

At ASCO virtual scientific meeting 2021, Ettl et al. reported about a retrospective post hoc analysis describing the clinical characteristics of LONG and SHORT responders following treatment with talazoparib or PCT in the EMB-RACA study [9] . Patients in the intendto-treat (ITT) population were mapped into two groups based on their response: LONG responders included patients with an OS ≥ 30 months and a duration of response (DOR) ≥ 24 months in the talazoparib arm (n=37) and an OS ≥ 30 months in the PCT arm (n=34); SHORT responders included patients in either arm with a PFS event ≤ 12 weeks (talazoparib arm, n=40; PCT arm, n=32). At the data cutoff date of September 30, 2019, a higher proportion of LONG responders with hormone receptor-positive (HR+) BC and no prior chemotherapy (CT) for locally advanced or metastatic BC was observed; additionally, a greater proportion of SHORT responders had TNBC and received ≥2 prior CT regimens for locally advanced or metastatic BC or platinum therapy. Approximately half of the LONG responders receiving talazoparib (51.4 %) and 91.2 % of the LONG responders treated with PCT had subsequent antineoplastic treatment. Moreover, at data cut off, more LONG responders (43.2 %) under talazoparib were still on treatment compared to the PCT arm (2.9 %). The median treatment duration for LONG responders was 33.5 months in the experimental arm and 7.6 months in the control arm, whereas patients from the SHORT group responded only 2.0 months in the talazoparib arm and 1.4 months in the PCT arm. As these findings were based on a limited data set, further investigations with a larger number of patients in this setting might be warranted.

International guidelines recommend the use of PARP inhibitors for patients with metastatic HER2-negative BC with gBRCA1/2m, who were pretreated with chemotherapy in the neoadjuvant, adjuvant or metastatic stetting [10] . Only 5-10 % of BC are presenting gBRCA1/2 mutations and the current clinical usability of PARP inhibitors is limited so far to this population [11] . This raises the question whether PARP inhibitors are similarly effective in patients with somatic BRCA1/2m HER2-negative locally advanced or metastatic BC. Somatic BRCA1/2m were detected in circulating cell-free DNA (cfDNA) in 13.5 % of patients with metastatic BC and preclinical models have shown that pathogenic somatic BRCA1/2 mutations are sensitive to the PARP inhibitor talazoparib [12] .

An ongoing multicenter, single-arm, phase II study (NCT03990896) has been memo S98 initiated with the aim of evaluating the efficacy of talazoparib in patients with somatic BRCA1/2m metastatic BC detectable in cfDNA [13] . Eligible patients may have TNBC (with ≥ 1 prior CT) or HR+/HER2-BC (with ≥ 1 prior hormone therapy). Patients who received platinum therapy as neoadjuvant or adjuvant treatment, will have to observe at least a 6-month interval before being eligible for this trial. Patients must have adequate organ function, ECOG performance status ≤ 2 and should be PARP inhibitor naive. Patients receive talazoparib (1mg daily) until disease progression or intolerability; additionally, they undergo serial imaging using chest/abdomen/pelvis CT and bone scan at baseline and every twelve weeks, and as well as cfDNA analysis every four weeks. PFS by RECIST v1.1 was defined as the primary endpoint, while secondary endpoints include objective response rate (ORR) and safety assessed according to NCI CTCAE v5.0. Currently, two patients are completing screening at Massachusetts General Hospital (USA), where the study is already open; six more academic US centers will follow soon.

Pamiparib is an orally administered investigational selective PARP1/2 inhibitor, which demonstrated antitumor activity and was generally well tolerated in patients with advanced solid tumors [2, 4] . Preclinical models showed a good bio availability and blood-brain pene-tration [14] . A single-arm, open-label, multi-center Chinese phase II study (NCT03575065) was designed to assess the efficacy and safety of pamiparib in patients diagnosed with locally advanced or metastatic HER2-negative BC, with deleterious or suspected deleterious gBRCA1/2m TNBC or HR+/ HER2-, who received ≤ 2 prior line of chemotherapy [15] . Patients received pamiparib 60 mg orally twice daily in 28-day cycles. The primary endpoint of the trial was ORR per RECIST v1.1 assessed by an independent review committee (IRC); secondary endpoints included investigator-assessed OR (INV-ORR), DOR, best overall response (BOR), PFS, clinical benefit rate (CBR), disease control rate (DCR) and OS, as well as safety and tolerability.

Out of 88 patients enrolled, 76 cases (55 in TNBC cohort and 21 in HR+ cohort) had measurable disease at baseline. The median age of patients was 46 years (range 27-67); 48 % were previously treated with platinum. The median study follow-up was 13.8 months (TNBC cohort: 10.9 months, HR+ cohort: 18.5 months). In the TNBC cohort, treatment with pamiparib demonstrated a confirmed ORR of 38.2 % (95 % CI: 25.4-52.3) and responses lasted for a median of seven months (95 % CI: 3.9not estimable), while median PFS reached 5.5 months (95 % CI: 3.7-7.3) and median OS 17.1 months (95 % CI: 13.7-not estimable) ( Figure 1A) .

In the HR+ cohort, median ORR amounted to 61.9% (95 % CI: 38.4-81.9), median DOR was 7.5 months (95 % CI: 5.6-14.8), median PFS attained 9.2 months (95 % CI: 7.4-11.9) and survival data had not reached maturity at the time of the analysis (not reached; 95 % CI 18.1-not estimable) ( Figure 1B) . Four patients achieved a complete response (CR), including three in the TNBC cohort and one patient in the HR+ cohort. Overall, 18 patients in the TNBC cohort and twelve patients in the HR+ cohort experienced a partial response (PR). As assessed by IRC, 72.7 % of patients (95 % CI: 59.0-83.9) in the TNBC cohort and 90.5 % (95 % CI: 69.6-98.8) in the HR+ cohort achieved disease control. Additionally, a CBR of 43.6 % (95 % CI: 30.3-57.7) and of 71.4 % (95 % CI: 47.8-88.7) was reached in the TNBC-and HR+ cohorts, respectively.

Pamiparib was generally well tolerated, with treatment-emergent adverse event (TEAEs) leading to dose interruption in two patients (2.3 %) and to reduction in 57 patients (64.8 %). The most common ≥ grade 3 TEAEs were hematologic events, including anemia (in 39.8 % of patients), decreased neutrophil count (29.5 %) and decreased white blood cell count (21.6 %). The encouraging data obtained in this phase 2 study suggested that pamiparib might be a feasible and tolerable treatment strategy for this population.

TBCRC 050: niraparib combined with trastuzumab HER2 is overexpressed in around 20-30 % of BC tumors [16] . In addition to its role in DNA damage repair, PARP1 has also been implicated in other cellular functions including co-activation of 4 5 6 7 8 9 10 11 0 12 13 14 15 16 17 18 19 20 21 22 23 1 2 3 4 5 6 7 8 9 10 11 0 12 13 14 15 16 17 18 19 20 21 22 genes such as NF-κB, which regulate tumor proliferation and HER2 drug resistance. It has been shown previously that the sensitivity against PARP inhibitors observed in HER2-positive BC cells may be due to elevated PARP1 expression [17] . In preclinical models, through the inhibition of NF-kB signaling, PARP inhibitors induced apoptosis independently of a DNA repair deficiency. The TBCRC 050 trial is a multicenter, single-arm, phase Ib/II clinical study currently investigating the maximum tolerated dose and efficacy of the PARP inhibitor niraparib (200 mg orally) in combination with the anti-HER2 monoclonal antibody trastuzumab (6mg/kg, cycle 1 loading dose of 8 mg/kg) in patients diagnosed with locally advanced or metastatic unresectable HER2-positive BC (Figure 2 ) [18] . Eligible patients must have a measurable disease per RE-CIST v1.1 criterion, have already progressed under at least one prior HER2-targeted therapy, present a good performance status (ECOG PS 0-1) and a LVEF (left ventricular ejection fraction) ≥ 50 % by ECHO or MUGA, and have adequate bone-marrow, renal and liver functions. Patients initially treated with PARP inhibitors or having a concurrent endocrine therapy (for ER+/ HER2+ patients) or having a known gBRCA1/2 BC are not eligible. The recruitment of patients with stable disease as well as treated CNS (central nervous system) metastases and/or carcinomatous meningitis is allowed. The primary objectives are to assess the dose-limiting toxicity (DLT) of this combined therapy, as well as the ORR. Blood and tissue biomarkers are collected to assess clinical benefit and to predict therapy response. Enrollment started in February 2021; this trial intends to recruit 40 patients in seven participating US sites.

Cervical cancer is the fourth most common malignant disease in women with over 600,000 new diagnoses (6.5 %) per year worldwide and accounting for approximately 340.000 deaths (4 th place) because of cancer yearly in this population [19] . Locally advanced or metastatic cervical cancer are associated with a higher risk of recurrence [20] . Standard of care for patients with metastatic, recurrent, or persistent cervical cancer in the first-line stetting is platinum-based chemotherapy with the option of adding the antiangiogenic agent bevacizumab; few treatment options exist in case of failure of this standard regimen [21] . As most cervical cancers have a viral etiology, which impairs the immune system, immune checkpoint inhibitors (CPIs) combined to other agents appears to be a promising strategy [20] . At the virtual ASCO 2021 meeting, Xu et al. presented the results of a new therapy combining anlotinib -a multi-target tyrosine kinase inhibitor inhibiting tumor angiogenesis and proliferative signalingwith sintilimab -a monoclonal antibody against programmed cell death-1 (PD-1) [22] . This single-arm, phase II Chinese study (ChiCTR1900023015) was conducted in patients with recurrent advanced cervical cancer to investigate the efficacy and safety of anlotinib plus sintilimab. Eligible patients should have received at least one prior platinum-based chemotherapy, have a good performance status (ECOG 0-1) and their tumor should show more than 1 % PD-L1 expression. Anlotinib was administered orally (10mg/day, d1-14, 21 days per cycle) and sintilimab intravenously (200mg once every 3 weeks). The primary endpoint was ORR, while DCR, PFS, OS and safety were the secondary endpoints.

In total, 42 patients with a median age of 52 years (range, 47-58) were recruited. Among the 39 evaluable patients, objective response occurred in 61.5 % of patients (95 % CI, 44.9-75.9) and DCR was 94.9 % (95 % CI, 80.7-98.8). At the time of the analysis, the median PFS had not been reached yet. Three patients (8 %) achieved a CR and 21 (54 %) a PR, while 13 patients (33 %) had a stable disease (SD) (Figure 3) . The most common adverse events (AEs) experienced by the patients were grade 1 or 2. Grade 3 AEs were hypertension (in 4.8 % of patients), hyponatremia (4.8 %), immune pneumonia (2.4 %) and immune myocarditis (2.4 %); no AEs grade 4 were observed. The authors pointed out that, according to the presented data, anlotinib plus sintilimab might represent a potential new treatment option with manageable safety profile in patients with recurrent ad-vanced cervical cancer; they announced more data to be presented in the future.

Considering the elevated rate of PD-L1 expression in up to 80 % of cervical cancers [23] , immune CPIs such as PD-1/ PD-L1 inhibitors might be a novel therapeutic choice to improve clinical outcomes of patients with recurrent and/or metastatic cervical cancer. However, recent studies showed only moderate efficacy in this population [24] [25] [26] . Dual targeting of tumors with anti-TIGIT and anti-PD1 monoclonal antibodies might be an effective strategy to improve the clinical benefit of checkpoint inhibition. TIGIT (T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain) is an co-inhibitory, immune checkpoint Safety and survival follow-up memo S101 receptor, which is upregulated on Tcells and natural killer (NK) cells in various tumor cells [27] . Ociperlimab is a novel investigational anti-TIGIT monoclonal antibody. Tislelizumab -a human IgG4 monoclonal antibody binding to and blocking PD-1 receptor expressed on activated immune cellshas been approved in China in December 2019 and is involved in a broad clinical program combining various anti-cancer agents [28] .

The multicenter, open-label, randomized, phase II study AdvanTIG-202 (NCT04693234) aim to investigate the clinical benefit of the addition of ociperlimab to tislelizumab. This trial will enroll in around 100 centers in Asia approximately 167 patients with cervical cancer (squamous cell carcinoma, adenosquamous carcinoma or adenocarcinoma) who progressed after at least one prior line of chemotherapy for recurrent or metastatic disease [22] . In Part 1, 80 patients will be randomized (1:1) to receive either ociperlimab (900 mg intravenously [IV]) in combination with tislelizumab (200 mg IV) threeweekly, or tislelizumab monotherapy (same dose) in Arm 2, until disease progression, unacceptable toxicity, or withdrawal of consent (Figure 4) . In Part 2, Arm 1 will be expanded by 87 additional patients whose tumors are evaluable for PD-L1 expression. ORR per RECIST v1.1 according to IRC constitutes the primary endpoint, while secondary endpoints include investigatorassessed ORR, DOR, DCR, PFS, time to response (TTR), CBR, OS, safety, and tolerability; the exploratory endpoints are health-related quality of life (HR-QoL), as well as the association of biomarkers with patient prognosis and response, or tumor resistance. [8] . MSI-H/dMMR status was evaluated locally from a tumor tissue sample and defined as ≥ 1 of 4 MMR proteins absent by immunohistochemmemo S102 istry (IHC) or as ≥ 2 allelic loci size shifts of 5 microsatellite markers by polymerase chain reaction (PCR). Eligible patients received pembrolizumab (200 mg once every three weeks) for up to two years or until disease progression, unacceptable toxicity, investigator decision, or withdrawal of consent. Secondary endpoints included duration of response (DoR), PFS, OS, safety, and tolerability.

The cohort K included multiple tumor types, like endometrial ( (Figure 1) .

The safety profile was consistent with previous analyses. Treatment-related adverse events (TRAEs) occurred in 64.7 % of patients; 12.0 % experienced TRAEs grade ≥ 3. The most common AEs in 5 % or more of patients were pruritus (14.5 %), fatigue (12.3 %), and diarrhea (11.7 %). Immune mediated AEs and infusion reactions occurred in 20.2 % of patients (in 4.8 % with grade ≥ 3) and led to death in two patients be-cause of myocarditis and Guillain-Barré syndrome.

Pembrolizumab demonstrated a maintained clinical benefit and a manageable safety profile in a heavily pretreated study population with advanced MSI-H/dMMR non-colorectal cancer.

Tislelizumab is a uniquely designed humanized immunoglobulin G4 (IgG4) monoclonal antibody with high affinity and binding specificity for PD-1 [9] as well as high antitumor activity in patients with solid tumors, including MSI-H/dMMR solid tumors. This anti-PD-1 antibody was engineered to minimize the binding to the Fcγ receptor (FcγR) on macrophages, which might be a potential strategy to circumvent resistance to anti-PD-1 therapy through the abrogation of the antibody-dependent cellular phagocytosis (ADCP) [9] . In early phase studies, Tislelizumab showed a good tolerability and antitumor activity against multiple solid tumors [10] [11] [12] . In 2019, tislelizumab was approved in China for patients with relapsed or refractory Hodgkin´s lymphoma after at least a second-line chemotherapy [13] . Tislelizumab is being currently evaluated in several global pivotal trials in a wide range of tumors, including esophageal squamous cell carcinoma, hepatocellular carcinoma, and non-small cell lung cancer [13] .

This single-arm, non-randomized, open-label, multicenter, phase II study investigated the efficacy and safety of ti-slelizumab in patients with previously treated, locally advanced unresectable or metastatic MSI-H/dMMR solid tumors, including colorectal cancer (CRC) (NCT03736889) [14] . Adult patients with at least one measurable lesion according to RECIST v1.1, who received or refused prior cancer therapy regimen(s) for advanced disease, were treated with tislelizumab (200 mg intravenously three-weekly) until disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was ORR as assessed by independent review committee (IRC); optionally, patients were able to continue tislelizumab monotherapy after an investigator-assessed radiological progression. Time to response (TTR), disease control rate (DCR), DoR, as well as safety and tolerability, were the secondary study endpoints.

Among the 80 patients enrolled, 74 (median age, 53 years; range, 19-75) were included in the primary efficacy analysis set. In total, 56.8 % of them were male and almost all patients had metastatic disease. Overall, 62.2 % of patients suffered from CRC, while 17.6% had endometrial cancer, 10.8 % gastric/ gastroesophageal junction (GI/GEJ) cancer, 4.1 % small bowel adenocarcinoma and 5.4 % another type of cancer. The median number of prior therapy regimens was two (range, 0-7). Among all tumor types, tislelizumab monotherapy resulted in an ORR of 45.9 % (95 % CI, 34.3-57.9; p<0.0001) after a median follow-up of 11.8 months. A high rate of disease control (DCR, 71.6 %) was shown with tislelizumab treatment across all tumor entities (4 CRs, 30 PRs In the safety population (n = 80), treatment-emergent adverse events (TEAEs) grade ≥ 3 occurred in 47.5% of patients, including laboratory abnormalities in 21.3 % of them. Immunemediated TEAEs grade ≥ 3 occurred in 5 % of patients.

Overall, Tislelizumab monotherapy showed a clinically meaningful and durable efficacy across several tumor types. This treatment was well tolerated, and no new safety signals were detected. From the researchers' point of view, tislelizumab might be a potential new treatment option for MSI-H/dMMR solid tumors.

Whereas MSI-H/dMMR advanced solid tumors have a poor prognosis when treated with conventional chemotherapy, they usually reach a high response to immune checkpoint inhibitors [6, 15, 16] . The investigational anti-PD-1 monoclonal antibody HLX10 -also known as serplulimab -has shown antitumor activity and a favorable safety and tolerability profile in preclinical and early clinical studies [17] . The ongoing singlearm, open-label, multicenter, phase II study (NCT03941574) evaluates the efficacy and safety of HLX10 monotherapy for the treatment of patients with histologically or cytologically confirmed unresectable or metastatic MSI-H/dMMR solid tumors who had progressed on or been intolerant to at least one prior standard therapy [18] . The patients receive an intravenous infusion of HLX10 (3 mg/kg) every two weeks for up to two years until disease progression, unacceptable toxicity, or withdrawal of informed consent. By the time of the analysis (January 9, 2021), 108 patients were enrolled and 68 subjects with confirmed MSI-H were included in the main efficacy analysis. Median age of the patients was 53 years (range, 23-72). MSI-H tumor types included CRC (77.9 %), endometrial cancer (7.4 %), and gastric cancer (5.9 %).

The most common prior treatments were oxaliplatin (83.8 %) and capecitabine (70.6 %). About 44.1 % patients were positive for programmed death-ligand 1 (PD-L1) at baseline.

After a median follow-up of 7.7 months, ORR per RECIST v1.1 -as assessed by an independent radiological review committee (IRRC) -and defined in the study protocol as the primary endpoint -achieved 38.2 % (95 % CI, 26.7-50.8; 2 CRs, 24 PRs and 20 SDs) and IRRC-DCR reached 67.6 % (95 % CI, 55.2-78.5). The ORR in the PD-L1 negative population (n = 29) and PD-L1 positive population (n = 30) amounted to 34.5 % and 46.7 %, respectively. Concerning the secondary endpoints reported, median DoR, PFS and OS were not attained, but a 12-month IRRC-assessed PFS and OS of 61.9 % (95 % CI, 49.0-72.5) and 81.2 % (95 % CI, 67.8-89.4) were respectively observed.

About half of the study population (49.1 %) experienced grade ≥ 3 TEAEs, primarily anemia (8.3 %), progressive disease (PD) (6.5 %), increased γglutamyltransferase (5.6 %) and intestinal obstruction (5.6 %). Immune-related adverse events (irAEs) appeared in 48.1 % of patients (grade ≥ 3 in 9.3 % of them). Altogether, three fatal cases (2.8 %; 2 PDs and 1 intestinal obstruction) possibly related to the investigational drug were reported.

The authors concluded that through its antitumor activity and its managea- memo S104 ble safety profile, HLX10 has the potential to improve patients' clinical outcomes as an effective and safe tissue-agnostic treatment.

Endometrial cancers (ECs) -the most commonly diagnosed gynecologic malignancy -is usually detected in early stages of the disease [19] . However, in 21 % of cases, EC has already spread to regional lymph nodes, and distant metastases are present at initial presentation in 9 % of patients [20] . Chemotherapy remains the standard treatment, despite modest efficacy; therefore, there is a high unmet therapeutic need in advanced EC [20] .

Dostarlimab is a novel humanized anti-PD-1 monoclonal antibody developed for the treatment of various tumor types. Based on preliminary results of the GARNET trial (NCT02715284), dostarlimab has been recently approved in the EU and USA as monotherapy for the treatment of adult patients with dMMR recurrent or advanced EC which were progressive on or after a platinumbased regimen [20, 21] .

The open-label, multicenter, singlearm phase I, ongoing GARNET study evaluates dostarlimab in patients with advanced solid malignant entities in several cohorts. Preliminary data showed a meaningful and durable clin- [18, 20] . At ASCO 2021, an interim analysis presented the results from cohort A1 (patients with advanced or recurrent dMMR/MSI-H EC) and cohort F (patients with dMMR or POLEmutated non-EC solid tumors) individually and combined [22] . Dostarlimab was administered at 500 mg every three weeks for the first four cycles, and thereafter at 1000 mg every six weeks until disease progression or discontinuation. For this interim analysis, an efficacy analysis was performed for the patients who had baseline measurable disease and ≥ 6 months of follow-up in the study. Among those 209 patients in cohorts A1 + F, the median age of the patients was 63 years (A1, n = 103; F, n = 106 Dostarlimab was well tolerated. In cohorts A1 + F, the most common grade ≥3 TEAEs were anemia (10.8 %), abdominal pain (4.1 %), hyponatremia (3.5 %) and sepsis (3.2 %), while immune-related TEAEs grade ≥3 experienced by 2.5 % of patients were increased alanine aminotransferase (ALT) lipase (2.2 %), respectively (Table) . No deaths related to dostarlimab occurred.

In their conclusions, the authors reported an antitumor activity of dostarlimab in patients with different dMMR advanced or recurrent solid malignant entities, especially here in EC and non-EC cases. With mostly low-grade TREAS observed, dostarlimab showed a good tolerable safety profile across different tumor types. n

Ezabenlimab combined with anti-VEGF/Ang2 inhibitor Immunotherapy using anti-PD-1 immune checkpoint inhibitors (CPIs), which is a major therapeutic option in oncology, can potentially achieve synergistic effects once combined with targeted therapies [1] . Drugs targeting proangiogenic factors, such as VEGF and angiopoietin 2 (ANG2), can improve therapeutic responsiveness through their immunosuppressive activity in the tumor environment [1] . Combining antiangiogenic agents with CPIs may improve patient outcomes [2] . In an ongoing phase IB trial (NCT03468426), this therapeutic approach led to a manageable safety and preliminary anti-tumor activity [3] . At the virtual ASCO 2021 meeting, Hussein et al. presented data from Module C of an ongoing open-label, phase II platform trial (NCT03697304) evaluating ezabenlimab -an anti-PD-1 antibodyin combination with BI 836880 -a humanized bispecific nanobody targeting VEGF and Ang2 -in previously treated advanced solid tumors [4] . The multico-hort study already enrolled 150 patients into five patient cohorts (Figure 1) . The patients received intravenously (IV) ezabenlimab (240 mg) and BI 836880 (720 mg) ever three weeks (Q3W). The objective response rate (ORR) per RE-CIST v1.1 is the primary study endpoint.

Among 60 treated patients as of April 2021, 62 % of them were male (median age, 62 years) and median duration of treatment was 70 days. Overall, 77 % of patients (n = 46) experienced any adverse events (AEs), most of them being mild or moderate; nausea (27 %), fatigue (23 %) and hypertension (20 %) were the most commonly reported AEs. Treatment-related adverse events (TRAEs) were observed in 47 % of patients, none of them being grade 4 or 5. Immune-related adverse events (irAEs) occurred in 7 % of patients and included rash and arthralgia (both of grade 1/G1), hypothyroidism (G2) and increased blood creatine phosphokinase (G3). Two patients had AEs that led to treatment discontinuation (G3 bile duct stone and G2 pain). Out of 33 patients with evaluable response, one had confirmed partial response (PR), 21 had stable disease and nine experienced progressive disease (PD). 

The authors concluded that the combination of ezabenlimab with BI 836880 showed a manageable safety profile in this population. The study is currently recruiting in USA, Canada, and UK.

The dual targeting of ociperlimab -an anti-TIGIT inhibitor -and tislelizumab -an inhibitor of PD-1 -induced a synergistic immune cell activation and an enhanced antitumor activity in preclinical studies. This combination has been evaluated in a first-in-human phase I study AdvanTIG-105 in three Australian centers among 26 patients with advanced, metastatic unresectable solid tumors, for which standard therapy was ineffective, intolerable, or unavailable (NCT04047862). In this trial, the pharmacokinetics, the safety and the antitumoral activity of tislelizumab (200 mg, IV) combined with ociperlimab (IV, dose escalation between 50 and 900 mg, every three weeks) were investigated [5] .

The median age of study participants was 56 years and 42 % were male. Two patients had a partial response (PR) (one with 900 mg ociperlimab, whose treatment is still ongoing and another with 450 mg, who unfortunately showed progression of disease after several months). The longest duration of stable disease was 54 weeks in one patient with 150 mg ociperlimab. A reduction in target lesions of more than 30 % was observed in three patients.

Overall, 96 % of patients (n = 25) experienced at least one treatment-emergent AE (TEAE) and 58 % of them (n = 15) had one immune-related TEAE or more. In the investigational group which received 900 mg of ociperlimab, three irAEs grade ≥ 3 occurred (colitis, decreased cortisol, and diabetic ketoacidosis). No dose-limiting toxicities (DLTs) were reported.

The authors concluded that this dual therapy showed a preliminary antitumoral activity and was well tolerated in patients with advanced solid tumors. The recommended phase II dose is therefore 900 mg ociperlimab IV combined with 200 mg tislelizumab IV three-weekly (Q3W).

Lymphocyte-activation gene 3 (LAG-3) is a CPI involved in the response, activation and growth of T-cells [6] . The addition of anti-LAG-3 to an anti-PD-1 inhibitor might improve synergistically the antitumoral activity. This hypothesis was tested in a phase Ia/Ib dose-escalation study (NCT04085185) evaluating IBI110 (anti-LAG-3) and sintilimab (anti-PD-1) in patients with locally advanced, recurrent or metastatic solid tumors and presented at ASCO 2021 [7] .

The dose-escalation of IBI110 alone was investigated in the phase Ia among 22 patients, while the phase Ib evaluated IBI110 plus sintilimab (200 mg, IV, Q3W) in 18 patients; a cross-over from IBI110 monotherapy to the combination group was allowed at disease progression. The study objectives were safety and tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of IBI110 according to RECIST v1.1. The median age was 61 years in both phases; both groups enrolled in majority male patients (63.6 vs 72.2 %, respectively) and the lung was the primary tumor location (54.5 vs 66.7 %, respectively). A PR was seen in three patients (1 patient with ovarian cancer in phase 1a, as well as 2 patients with small cell lung cancer and endometrial cancer in phase 1b). Five progressive patients under IBI110 monotherapy had a stable disease (SD) with the dual therapy after crossing over.

In the phase Ia, treatment-related adverse events (TRAEs) all grades were experienced by 40.9 % of patients, while grade ≥ 3 TREAs (anemia) occurred in 4.5 % of them. In the phase Ib with the combined therapy, a higher incidence of TRAEs any grade (66.7 %) and grade ≥ 3 (22.2 %); increased bilirubin conjugated, abnormal hepatic function and hypertension, 5.6 % each) were observed. Additionally, irAE (hyperglycemia) was experienced by one patient (5.6 %) (Table) . No DLT was reported, and no adverse event led to discontinuation of the treatment in both groups. IBI110 alone or combined with sintilimab showed a preliminary antitumor activity and an acceptable toxicity.

Eftilagimod alpha (efti) is a soluble LAG-3 and an MHC class II antagonist involved in the activation of the antigenpresenting cells after CD8 T-call activation. In combination with the anti-PD-1 CPI pembrolizumab, it showed already an encouraging antitumor activity by Listed TRAEs occured in more than 20 % subjects, any TRAE ≥ Grade 3 and all irAEs memo S107 good tolerability in patients with metastatic melanoma [8] . Efti is currently under investigation in a phase II study in addition to paclitaxel to treat metastatic breast cancer [9] .

In the stratum D of the INSIGHT investigator-initiated (IIT) platform trial (NCT03252938), the combination of efti plus avelumab -an anti-PD-L1 inhibitor -has been evaluated in patients with histologically confirmed locally advanced or metastatic solid tumors who did not receive more than three prior lines of therapy. The twelve enrolled patients received avelumab (800 mg, IV) plus efti (6 to 30 mg, SC) Q2W for a maximum of six months, followed by avelumab maintenance therapy Q2W for a maximum of a half year further [10] .

With data-cut-off of January 22, 2021, a PR as best response was obtained in five patients, one SD with clinical progression, five disease progression according to RECIST v1.1 and one clinical progression. Moreover, the disease control rate (DCR) reached 50 %. Concerning the safety, among ten serious adverse events (SAEs) reported, none of them was related to the treatment. The most frequently observed grade ≥ 3 AEs were ileus (grade 3), nausea/vomiting (3), pain (3), hypokalemia (3), dysphagia (3), impaired hearing (4), sepsis (4), acute renal insufficiency (5), diffuse myocardial fibrosis (5) and urinary tract infection (3, related to avelumab).

As no unexpected AEs occurred, the researchers concluded that the combination of efti plus avelumab is feasible and safe.

COM701 is a novel first-in-class monoclonal antibody designed to block through a high affinity binding the interaction between the poliovirus receptor related immunoglobulin domain containing (PVRIG) and its ligand -PVRL2 [11] . The blockade of PVRIG induces an enhanced activation of T-and natural killer (NK) cells. At ASCO meeting 2021, Vaena et al. reported about results of an ongoing phase I study (NCT03667716) concerning the safety and tolerability, pharmacokinetics, and antitumor activity in patients with histologically confirmed locally advanced or metastatic solid tumors [12] .

So far, 36 patients in monotherapy arm (A) received COM701 (0.01-20 mg/kg dose escalation, IV, Q3/ Q4W). In arm B, 15 patients were administered additionally nivolumab (360 mg or 480 mg) to COM701 (0.3-20 mg/kg dose escalation) Q3/Q4W until the data-cut-off date (April 15, 2021). In the monotherapy group, the ORR was 3 % and the DCR 47 %, while in the combination group, these parameters amounted respectively to 13 % and 67 %. The Spider plot is showing the response in patients with a measurable disease (Figure 2) . Overall, a CR, PR or SD was reached as best response in 52 % (n = 11/21) of patients with prior treatment refractory disease and in 72 % (n = 13/18) of those previously treated with a CPI.

At the maximal administered dose evaluated and chosen for the expansion cohorts (20 mg/kg COM701 alone or with 480 mg nivolumab), no DLTs were observed in both arms. Grade 3 TEAEs were experienced by 29 % (n = 11/38) of patients in arm A and in 44 % (n = 7/16) of those in the combination arm; they were concerning mostly ascites (8 %), dyspnea (5 %), nausea (3 %), diarrhea (3 %), vomiting (3 %) and abdominal pain (3 %) in arm A, as well as anemia (13 %), nausea (6 %) and back pain (6 %) in arm B. No TEAE grade 4 was reported, but one malignant neoplasm progression (breast cancer, TEAE grade 5) was observed in arm B.

The combination of COM701 plus nivolumab had an acceptable safety profile, was well tolerated, and showed a durable antitumor activity in extensively pretreated patients.

The transforming growth factor beta (TGF-β) pathway signaling is involved in the immune regulation and plays especially a role in T-cell exhaustion, immune escape and resistance to immune checkpoint blockade [13] . Therefore, there is a scientific rationale to combine CPI with TGF-β inhibitor to improve the efficacy of the immunotherapy [14] . NIS793 is a novel anti-TGF-β monoclonal antibody and spartalizumab an anti-PD-1 inhibitor, whose safety has been already demonstrated in a first-in-human phase I study in patients with advanced solid tumors [15] .

The results of a dose escalation and dose expansion first-in-man phase Ib (NCT02947165) of NIS793 first alone, than combined with spartalizumab by proven good safety have been recently presented at ASCO 2021 [16] . The safety and tolerability, as well as the determination of the recommended dose for expansion. Patients received initially NIS793 (0.3 to 1 mg/kg, Q3W) monotherapy; dose escalation continued then with NIS793 (0.3 to 30 mg/kg, Q3W) plus spartalizumab (300 mg, Q3W) or NIS793 (20 to 30 mg/kg, Q2W) plus spartalizumab (400 mg, Q4W).

In total, 60 patients were treated in the dose escalation phase and 60 more (11 in monotherapy arm and 49 in the memo S108 combination arm) in the dose expansion phase with the recommended dose (NIS793 2100 mg + spartalizumab 300 mg, Q3W) at the time of the analysis (December 1, 2020). The population was heavily pretreated, as nearly half of them had at least four prior therapies. Best response obtained were four PRs (3 %) and 28 SDs (23 %) -including twelve which lasted for more than four months -and 71 PDs (59 %). The duration of response (DoR) attained by MSS-CRC (microsatellite stable colorectal cancer) cases (40.8 % of all patients) and NSCLC (non-small cell lung cancer) cases (18.3 %) is shown in Figure 3 . Moreover, gene expression and protein analyses in tumoral tissues suggested a modulation of the TGF-β pathway.

No DLTs were observed. Most of toxicities reported were grade 1 or 2, with dermatological ones being the most common (rash and pruritus); 13 patients (11 %) experienced grade 3 TRAEs, including rash (3 %), hyponatremia (2 %), as well as elevated lipase or amylase, adrenal insufficiency, and diarrhea (1 % each). No TRAEs grade 4 or 5 were observed. Treatment-related serious adverse events were observed in 7 % of patients.

The authors concluded that a preliminary antimoral activity was shown with this dual therapy, which was well tolerated in the recommended dose in patients with advanced malignant entities.

Cold tumors are usually not responding to immunotherapy, as they are surrounded by cells able to suppress the immune response and keep T cells at distance. Therefore ORRs < 10 % were obtained in clinical trials with combined CPIs in this kind of tumors [17] . At ASCO 2021, an analysis performed in CPI-naïve patients with cold tumors treated between 2015 and 2021 with immune combinations was presented [18] . Clinicopathological data and antitumor activity were extracted from a prospective database.

Among the 97 patients analyzed, median age was 62 years; the most represented tumor types were microsatellite stable (MSS) colorectal cancer (61 %) or ovarian cancer (14 %). In total, 69 % of patients received as combined treatment an anti-PD-1/L1 plus another CPI (most frequently anti-LAG3 and CD40 antagonist) (Figure 4) . No patient achieved a response; the clinical benefit rate -defined as complete response (CR) + PR + SD for at least 4 monthswas 15.3 %, with 58 patients (60 %) reaching a PD. Additionally, 20 patients (21 %) had a hyperprogressive disease (HPD) per RECIST v1.1 as previously defined by Matos et al. [19] . The median progression-free survival (PFS) was 1.9 months (95 % CI, 1.7-2.0) for the overall population and 5.9 months (95 % CI, 5.4-NR) for the CBR group. The median overall survival (OS) for the overall population was 7.6 months (range, 5.9-9.5), with a benefit for patients presenting a good LIPI (lung immune prognostic index) score (12.6 vs. 6.2 months; HR, 1.9; 95 % CI, 1.1-3.3; p = 0.02).

Out of 33 patients (34 %) who experienced immune-mediated toxicities, four patients (12 %) had grade 3 irAE (dry mouth, hypertransaminasemia, myocarditis and decreased neutrophil count) and 1 patient (3 %) grade 4 irAE (hyperglycemia). Overall, 33 % of patients who had PD developed irAEs.

The researchers concluded that CPI combinations showed only very limited activity in patients with unselected cold tumors and are associated with substantial risk for irAE and HPD.

Patients with HER2 tumors tend to develop resistance and/or relapse towards HER2-targeted therapies; therefore, those patients are characterized by a poor survival and a lack of therapeutic responses [20, 21] . Zanidatamab is a novel anti-HER2 bispecific antibody that lead to enhanced tumor cell binding [22] ; in a previously published early phase trial, Zanidatamab was well tolerated and showed antitumor activity in advanced HER2-positive tumors [23, 24] . The combination of HER2-targeting agents with chemotherapy led to improved survival [25] . Tislelizumab, which has been designed to overcome resistance to CPI, demonstrated good tolerability and antitumoral activity as monotherapy or combined with chemotherapy in advanced solid malignancies [26, 27] .

At the ASCO Annual Meeting 2021, the design of a currently ongoing phase Ib/II trial was presented (NCT02892123) [28] . In cohort 1, zanidatamab (30mg/kg or 1800 mg, IV, Q3W) plus docetaxel (75 mg/m 2, IV, Q3W) is evaluated as first-line therapy of patients with HER2+ metastatic breast cancer; in cohort 2, zanidatamab plus chemotherapy (Q3W) is combined to tislelizumab (200 mg, IV) in treatment-naïve patients with HER2+ advanced gastric/gastroesophageal junction adenocarcinoma (GC/ GEJC). The co-primary study endpoints are safety and ORR per RECIST v1.1, while secondary endpoints include DoR, time to response, PFS, DCR, and OS. The study is intended to be conducted in twelve centers in Asia and to enroll approximately 50 patients. n memo S110

In 2020, more than 604,000 new cases of esophageal cancer (EC) were diagnosed; EC was the sixth leading cause of cancer-related death worldwide [1] . Especially in Asia, the incidence of EC is high; for instance in China, its mortality rate reaches the fourth place of all deaths caused by cancer [2] . Esophageal squamous cell carcinoma (ESCC) accounted globally for approximately 85 % of all EC affected patients [3] , with more than half of all ESCC cases worldwide are observed in China [4] . As most patients with ESCC are diagnosed in an advanced stage of the disease, their prognosis is poor, with an estimated 5-year survival rate of approximately 5 % [5] . Paclitaxel plus cisplatin or 5-FU plus cisplatin were the standard firstline therapy of advanced ESCC for almost two decades [6] . Considering that 1L chemotherapy leads to suboptimal overall survival (OS), alternative treatment options for this difficult-to-treat cancer with high related mortality (90 %) are scarce [1, 7] . In ESCC, PD-L1 overexpression (up to 62 %) is significantly associated with poor prognosis [8] . In previous clinical trials, the combination of an immune checkpoint inhibitor (CPI) and chemotherapy has demonstrated synergistic antitumoral activity [9] . However, only moderate improvements in terms of ORR and OS have been obtained so far with anti-PD-1 CPI versus chemotherapy as first-line treatment in patients with advanced ESCC [10] , as well as for 2L therapy in patients with recurrent, locally advanced or metastatic ESCC who progressed on or after one prior line of systemic treatment [11, 12] .

In the phase III ATTRACTION-3 trial, the anti-PD-1 CPI nivolumab used as monotherapy has proven to be superior to chemotherapy in terms of OS in patients with ESCC that was refractory or intolerant to previous chemotherapy [11] . Additionally, nivolumab plus ipilimumab already showed significant antitumoral efficacy across several tumor types [13] .

In the randomized, phase III Check-Mate 648 study (NCT03143153), the efficacy and safety of nivolumab as frontline treatment were evaluated in patients with unresectable, advanced, recurrent, or metastatic ESCC following a 3-arm design (1:1:1) nivolumab plus chemotherapy (CT), nivolumab plus anti-CTLA-4 CPI ipilimumab, or chemotherapy alone. The treatment administered was either nivolumab (240 mg every other week [Q2W]) plus chemotherapy (fluorouracil + cisplatin Q4W), or nivolumab (3 mg/kg Q2W) plus ipili-mumab (1 mg/kg Q6W), or chemotherapy alone until disease progression, discontinuation due to toxicity, withdrawal of consent or study end. OS and progression-fee survival (PFS) according to a blinded independent central review (BICR) in patients whose tumor cells expressed at least 1 % PD-L1 were the dual primary endpoints.

The primary analysis presented at ASCO 2021 included 970 enrolled patients [14] . After a minimum of 12.9 months follow-up, compared to chemotherapy alone, the regimen nivolumab plus chemotherapy showed a significant OS benefit compared to chemotherapy (15.4 vs 9.1 months; HR, 0.54; 99.5 % CI, 0.37-0.80; p < 0.0001) (Figure 1A) and a meaningful PFS advantage (6.9 vs 4.4 months; HR, 0.65; 98.5 % CI, 0.46-0.92; p<0.0023) in patients with tumor cells PD-L1 ≥ 1%. Similarly, median OS was significantly better in the nivolumab + ipilimumab arm compared to chemotherapy alone (13.7 vs 9.1 months; HR, 0.64; 99.5 % CI, 0.46-0.90; p < 0.001) (Figure 1B) , but no PFS benefit was observed. Among patients with PD-L1 expressing tumors, the ORR reached 53 % in the nivolumab + chemo therapy arm versus 35 % in the nivolumab + ipilimumab arm versus 20 % with chemotherapy alone, while median DoR amounted to 8.4 versus 11.8 versus 5.7 months, respectively. Esophageal cancer: taking immunotherapy one step further memo S111 Similar findings were observed regardless of PD-L1 expression.

In terms of safety, most common any-grade treatment-related adverse events (TRAEs) (≥ 10 %) included nausea, decreased appetite and stomatitis in the nivolumab plus chemotherapy arm (96 %), as well as in the chemotherapy (90 %) arm, whereas rash, pruritus and hypothyroidism were reported with nivolumab plus ipilimumab (80 %). Most selected side effects with potential immunologic etiology that require frequent monitoring/intervention experienced by study participants were grade 1 or 2; grades 3 and 4 TRAEs occurred in ≤ 6 % of patients across several organ categories. In comparison to previous studies with those CPIs, no new safety signals were detected.

The authors concluded that both nivolumab plus chemotherapy and the dual immunotherapy regimen are potential new 1L standards of care for patients with advanced ESCC, particularly for those with PD-L1 positive tumors.

Tislelizumab is an IgG4 monoclonal antibody against PD-1, which might avoid the development of resistance to anti-PD-1 therapy [15] . In early phase studies, the antitumoral activity of tislelizumab monotherapy was already shown in several solid tumors including ESCC [16] . Therefore, the authors hypothesized that tislelizumab might be an alternative treatment to the current chemotherapy standard.

RATIONALE 302 was a global, phase III trial (NCT03430843) that investigated the efficacy and safety of tislelizumab compared to chemotherapy in patients with histologically confirmed advanced/unresectable or metastatic ESCC, who progressed during or after a prior systemic therapy. Tislelizumab was administered at 200 mg intravenously (IV) every three weeks; the investigator-chosen therapy consisted of paclitaxel or docetaxel or irinotecan. The primary analysis of the data was presented at ASCO 2021 [17] .

In total, 512 patients from 132 sites across 10 countries in Asia, Europe and North America, were randomized 1:1. The study met its primary endpoint as a significantly better median OS was ob-served with tislelizumab compared to the chemotherapy arm (8.6 vs 6.3 months; HR, 0.70; 95 % CI, 0.57-0.85; p = 0.0001). In patients with PD-L1 expression ≥ 10 % by vCPS, tislelizumab showed a clinically meaningful OS improvement -the key secondary endpoint -over chemotherapy with a 46 % reduction in the risk of death (10.3 vs 6.8 months; HR, 0.54; 95 % CI, 0.36-0.79; p = 0.0006) An OS benefit was consistently observed across all pre-defined subgroups. Compared to chemotherapy, a higher response rate was obtained with tislelizumab (ORR, 20.3 vs 9.8 %) and the responders showed a more durable DoR (7.1 vs 4.0 months; HR, 0.42; 95 % CI, 0.23-0.75).

Overall, 19 % of tislelizumab-treated patients experienced grade ≥ 3 TRAEs versus 56 % in the group who received chemotherapy. TRAEs leading to treatment discontinuation amounted to 7 % with tislelizumab and 14% with chemotherapy. No new safety signals were detected.

As tislelizumab showed a statistically significant and clinically meaningful improvement in OS compared to chemotherapy, as well as a better safety profile, the researchers concluded that it might be a potential new standard second-line therapy option for patients with advanced/unresectable or metastatic ESCC.

During a presentation at ASCO 2021 [18] , the first author Rui-hua Xu spoke about a potential synergistic effect between immunotherapy and chemotherapy in patients with advanced or metastatic ESCC. The efficacy and safety of camrelizumab -an anti-PD-1 monoclonal antibody that already showed promising antitumoral activity in 2L ESCC (ESCORT trial) [19] -was thus evaluated in the phase III ESCORT-1st study (NCT03691090) as first-line therapy for advanced or metastatic ESCC patients. Study patients received either camrelizumab (200 mg) plus chemotherapy (paclitaxel and cisplatin for up to 6 cycles) or only the chemotherapy doublet IV Q3W. The co-primary endpoints were PFS assessed per IRC (independent review committee) and OS.

The first interim analysis presented the data of 596 eligible patients (median age of 62 years; mostly male patients) from 60 Chinese hospitals, who were randomized 1:1 to each arm. With a median follow-up of 10.8 months, a statistically significant median OS improvement was observed when camrelizumab was added to the dual chemotherapy regimen ( Based on those findings, the author concluded that camrelizumab combined with paclitaxel plus cisplatin might be a new promising 1L therapy option for those patients; he also revealed that a new drug application dossier was already submitted to the China National Medical Products Administration for the approval of the combined immunochemotherapy in this setting.

For patients with advanced or metastatic HER2-negative gastric cancer (GC) or gastroesophageal junction cancer (GEJC), 1L chemotherapy led to limited outcome, with a median OS of less than a year [20] . In the randomized, phase III CheckMate 649 study (NCT02872116), the efficacy and safety of first-line nivolumab plus chemotherapy versus chemotherapy alone was evaluated in advanced GC/GEJC/EAC (esophageal adenocarcinoma). In this trial, eligible patients with previously memo S112 untreated, unresectable advanced or metastatic GC/GEJC/EAC -except those HER2-positive -were randomized 1:1:1 to receive either nivolumab (360 mg, Q3W or 240 mg, Q2W) plus chemotherapy (Xelox, Q3W or Folfox, Q2W) or nivolumab plus ipilimumab (Q3W x 4, then nivolumab 240 mg, Q2W) or only the chemotherapy regimen.

The first data of this trial were presented at ESMO 2020 [21] ; the immunochemotherapy combination showed an OS superiority and a PFS benefit compared to chemotherapy alone. Based on those findings, nivolumab plus chemotherapy received FDA approval as 1L therapy for GC/GEJC/EAC in April 2021.

At this year's ASCO meeting, an expanded analysis of the CheckMate 649 was presented [22] .

In this updated analysis, the OS (13.8 vs 11.6 months; HR, 0.80; 95 % CI, 0.68-0.94; p = 0.0002) and PFS (7.7 vs 6.9 months; HR, 0.77; 95 % CI, 0.68-0.87) benefits of the immunochemotherapy combination over chemotherapy in all randomized patients were confirmed. To note, OS advantage was observed across multiple prespecified subgroups. A higher response was obtained in the investigational arm compared to the control arm (ORR, 58 vs 46 %; CRs, 10 vs 6; PRs, 48 vs 40; SDs, 28 vs 33); this ORR benefit was observed regardless of the PD-L1 expression status and was more durable (DoR, 8.5 vs 6.9 months, respectively).

In total, TRAEs grade 3-4 were experienced by 59 % of patients in the nivolumab plus chemotherapy group and in 44 % of those in the chemotherapy group. Concerning the HR-QoL, patients in the investigational arm showed a decreased risk of symptom deterioration on treatment compared to the patients in the control group (HR, 0.77; 95 % CI, 0.63-0.95; p = 0.0129).

These updated data further support this immunochemotherapy as firstline standard treatment in patients with advanced HER2-negative GC/ GEJC/EAC.

In patients with resectable EC or GEJC, neoadjuvant chemoradiotherapy (CRT) has been shown to improve survival [23] . Recently, adjuvant anti-PD-1 nivolumab treatment following neoadjuvant CRT has been demonstrated to be beneficial in resected EC/GEJC patients with residual disease (CheckMate 577 trial) [24] . In the Keynote-590 study, the efficacy of anti-PD-1 pembrolizumab plus chemotherapy has been proven as efficient and safe 1L treatment of EC/GEJC patients [25] . Therefore, one might hypothesize that the addition of pembrolizumab to CRT in the neoadjuvant setting may further improve the outcome of locally advanced EAC patients.

In a randomized, phase II study, patients with T2-4 or N+ non-metastatic, resectable EAC or GEJC were randomized 1:1 to receive either full-dose paclitaxel (T)/ carboplatin (C) or T/C + pembrolizumab as preoperative therapy (NCT02998268). All study patients got neoadjuvant CRT, consisting in weekly dual chemotherapy with 41.4 Gy in 23 radiotherapy fractions; in the investigational arm, pembrolizumab was additionally administered every 3rd week. Following resection, all patients received pembrolizumab for one year. The rate of major pathologic response (MPR, defined as pathologic CR or near CR [< 10 % residual disease]) was primary assessed [26] .

Among the 39 enrolled patients ( . This might be explained by a different tumor immune microenvironment in those tumor entities; indeed, EAC or GEJC type I tumors presented a greater infiltration of activated dendritic cells (p = 0.12), whereas GEJ tumors showed a significantly higher infiltration of activated B cells (p = 0.02).

Pembrolizumab plus CRT was well tolerated. Post-surgery, typical post-operative AEs -including wound dehis-cence, infections, atrial fibrillation, and cardiac toxicities -were reported, while the most common toxicities of interest grade 3-4 observed were elevated liver enzymes (13.9 %), pneumonitis (11.1 %), elevated blood sugar (8.3 %) and adrenal insufficiency (2.8 %).

In resectable EC or GEJC patients, the combination of pembrolizumab plus CRT as neoadjuvant therapy, followed by pembrolizumab adjuvant treatment, was safe and more efficient than CRT alone in terms of MPR, DFS and OS. Two follow-up clinical studies are currently investigating the benefit of the addition of pembrolizumab (Keynote-975) or nivolumab (EA2174) to CRT in the neoadjuvant setting.

KN046 is the first dual CPI which has been designed to block both PD-1/PD-L1 and CTLA-4 pathways simultaneously. Its efficacy and safety as monotherapy or in combination with chemotherapy is currently under evaluation in a phase II study in China. Patients with histologically or cytologically confirmed unresectable, locally advanced, recurrent, or metastatic ESCC are included in the study cohort (NCT03925870).

The preliminary results of the cohort 3 (1L therapy) were recently presented at ASCO 2021 [27] . Eligible patients are receiving KN046 (5 mg/kg) plus paclitaxel (135-175 mg/m 2 ) and cisplatin (75 mg/m 2 ) intravenously Q3W for four to six cycles; additionally, in patients without progressive disease, a maintenance therapy with KN046 monotherapy (Q2W) is administered until progression or unacceptable toxicity. Investigator-assessed ORR per RECIST v1.1 is the primary endpoint.

At the time of analysis, among 15 male patients (median age, 63 years; 80 % stage IV) already enrolled, twelve, who had at least one tumor assessment, entered the evaluable analysis set (EAS). The ORR was 58.3 % (95 % CI, 21.1-78.9), while the DCR amounted to 91.7 % (95 % CI, 61.5-99.8; 4 PRs, 3 unconfirmed PRs and 4 SDs). One patient had a progressive disease (PD).

The incidence of KN046-associated AEs was 80.0 %, 13.3 % of them being grade ≥ 3 TRAEs. Immune-related AEs (irAEs) of any grade were observed in memo S113 53.3 % of patients; most common grade ≥ 3 irAEs experienced by 13.3 % of patients were nausea (n = 1, 6.7 %) and rash (n = 1, 6.7 %).

The study group concluded that KN046 combined to the dual chemotherapy paclitaxel plus cisplatin is an efficient and safe first-line treatment, and therefore a potential new therapeutic option for patients with advanced ESCC.

Because of resistance mechanism, a durable outcome remains an unmet need in patients with recurrent, locally advanced, or metastatic ESCC who progressed on or after one prior line of systemic treatment. TIGIT is a co-inhibitory immune checkpoint receptor expressed on immune cells in multiple solid tumors [28] . Ociperlimab is a humanized, monoclonal antibody targeting TIGIT with a highly specific binding activity; thereby, it activates the antitumoral immune response through T-cells and natural killer cells [29] . The anti-PD-1 ti-slelizumab has been designed to have a minimal binding to Fcy receptor on macrophages to abolish the antibodydependent phagocytosis, a mechanism involved in resistance to anti-PD-1 treatment [15] . The OS superiority of tislelizumab over chemotherapy in the 2L treatment of patients with advanced or metastatic ESCC was presented at this year's ASCO meeting [17] . Moreover, a dual targeting of tumors with an anti-TIGIT and anti-PD-1 has been already shown to result in a synergistic immune cell activation in early phase studies [30] .

At ASCO 2021, the design of a new randomized, double-blind, phase II study named AdvanTIG-203 (NCT04732494) -which aims to evaluate the efficacy and safety of ociperlimab plus tislelizumab -was presented. This trial is currently enrolling patients with histologically confirmed unresectable, locally advanced, recurrent or metastatic ESCC, who are progressive following first-line systemic therapy and whose tumors express PD-L1 (CPS ≥ 10) [31] . This trial intends to randomize 140 patients in each study arms: in arm A, patients receive IV Q3W ociperlimab (900 mg) plus tislelizumab (200 mg), while patients in arm B receive tislelizumab plus placebo. The OS and ORR are the co-primary study endpoints; the multiple secondary and exploratory endpoints are described in the Table. Concerning the safety assessments, AEs, serious AEs (SAEs) and irAEs will be reported.

In 2020, gastric cancer (GC) was the sixth more common cause of cancer worldwide and responsible of more than 760, 000 deaths (mortality rate of 71 %) [1] . In Western countries, neoadjuvant-adjuvant FLOT (5-fluorouracil + leucovorin + oxaliplatin + docetaxel) chemotherapy is the standard of care of resectable GC/GEJC [32] ; in East Asian countries, surgery -followed by adjuvant chemotherapy and eventually preceded by perioperative chemotherapyis the current treatment in this setting [33] . Despite improved OS outcome thanks to new treatment advances, patients with GC/GEJC have a poor prognosis, mostly due to a high recurrence rate [34] . Previous evidence suggested that the combination of an anti-PD-1 CPI and cytotoxic chemotherapy as neoadjuvant-adjuvant treatment may result in increased efficacy [35] .

The randomized, double-blind, ongoing, global, multicenter, phase III MATTERHORN study (NCT04592913) evaluates FLOT chemotherapy plus neoadjuvant-adjuvant anti-PD-1 durvalumab or placebo -followed respectively by adjuvant durvalumab or placebo -in patients with histologically confirmed (stage II or higher) resecta- ble GC/GEJC [36] . This trial is open for enrolment and intend to enroll 900 anticancer therapy-naïve patients equally either in the investigational group (arm A) or in the control group (arm B) following the design described in Figure 2. The key inclusion criteria include a complete surgical resection of the primary tumor, as well as a performance status ≤ 1. Patients who received any prior immune-mediated therapy, as well as those who have peritoneal dissemination or distant metastasis, (adeno)squamous cell carcinoma or gastrointestinal stromal tumor, will be excluded. The primary endpoint is event-free survival (EFS) assessed by BICR and/or pathology testing; the secondary endpoints enclose OS, pathological complete response (pCR) rate, safety, and tolerability profile.

In this ongoing, global, randomized, double-blind, placebo-controlled, phase III study (NCT03615326), the addition of the anti-PD-1 pembrolizumab (200 mg IV Q3W) to the standard-of-care (SOC) 1L therapy (trastuzumab plus chemotherapy) was evaluated in unresectable or metastatic HER2+ G/GEJ cancer [37] . From the first 264 enrolled patients, the confirmed ORR was higher with the in-vestigational combination compared to SOC (74.4 vs 51.9 %; 95 % CI, 11.2-33.7; p = 0.00006), with a CR rate of 11.3 vs 3.1 %. The addition of pembrolizumab to SOC led to a longer median DoR (10.6 vs 9.5 months with SOC). Grade 3-5 AEs were experienced by 57.1 % of patients in pembrolizumab + SOC arm versus 57.4 % with SOC; discontinuation rate was 24.4 vs 25.9 %, respectively. Based on these results showing a durable response and a manageable safety, the triple regimen was approved by the FDA for this patient population in May 2021.

n

Microsatellite instability and immune checkpoint inhibitors: toward precision medicine against gastrointestinal and hepatobiliary cancers

Novel Therapeutics for Recurrent Cervical Cancer: Moving Towards Personalized Therapy

Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study

Immune checkpoint blockade therapy for cancer: An overview of FDA-approved immune checkpoint inhibitors

PD-1 Blockade in Tumors with Mismatch-Repair Deficiency

First FDA Approval Agnostic of Cancer Site -When a Biomarker Defines the Indication

Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study

Pembrolizumab in microsatellite instability high (MSI-H)/mismatch repair deficient (dMMR) cancers: Updated analysis from phase 2 KEYNOTE-158 study

The binding of an anti-PD-1 antibody to FcγRΙ has a profound impact on its biological functions

Phase IA/IB study of singleagent tislelizumab, an investigational anti-PD-1 antibody, in solid tumors

Tislelizumab in Chinese patients with advanced solid tumors: an open-label, noncomparative, phase 1/2 study

Treatment of relapsed or refractory classical Hodgkin lymphoma with the anti-PD-1, tislelizumab: results of a phase 2, singlearm, multicenter study

A phase 2 study of tislelizumab monotherapy in patients with previously treated, locally advanced unresectable or metastatic microsatellite instability-high/mismatch repair deficient solid tumors

Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade

Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study

A novel anti-PD-1 antibody HLX10 study led to the initiation of combination immunotherapy

Efficacy and safety of HLX10, a novel anti-PD-1 antibody, in patients with previously treated unresectable or metastatic microsatellite instability-high or mismatch repair-deficient solid tumors: A single-arm, multicenter, phase 2 study

Cancer statistics

Dostarlimab in the treatment of recurrent or primary advanced endometrial cancer

Antitumor activity of dostarlimab in patients with mismatch repair-deficient/microsatellite instability-high tumors: A combined analysis of two cohorts in the GARNET study

Phase I INSIGHT platform trial: Advanced safety and effcacy data from stra-tumD evaluating feasibility and safety of eftilagimod alpha (soluble LAG-3 protein)combined with avelumab in advanced solid tumors

Blockade of checkpoint receptor PVRIG unleashes anti-tumor immunity of NK cells in murine and human solid tumors

COM701 with or without nivolumab: Results of an ongoing phase 1 study of safety, tolerability and preliminary antitumor activity in patients with advancedsolid malignancies

Blocking TGF-β Signaling To Enhance The Efficacy Of Immune Checkpoint Inhibitor

TGFβ-blockade uncovers stromal plasticity in tumors by revealing the existence of a subset of interferon-licensed fibroblasts

A first-in-human phase 1 dose escalation study of spartalizumab (PDR001), an anti-PD-1 antibody, in patients with advanced solid tumors

Phase Ib study of the anti-TGF-β monoclonal antibody (mAb) NIS793 combinedwith spartalizumab (PDR001), a PD-1 inhibitor, in patients (pts) with advancedsolid tumors

Approaches to treat immune hot, altered and cold tumours with combination immunotherapies

Evaluating the role of immune-checkpoint inhibitor (ICI) combinations in patients (pts) with unselected "cold" tumors enrolled in early clinical trials (CT)

Capturing Hyperprogressive Disease with Immune-Checkpoint Inhibitors Using RECIST 1.1 Criteria

Targeted therapeutic options and future perspectives for HER2-positive breast cancer

Immunotherapy for HER2-positive breast cancer: recent advances and combination therapeutic approaches. Breast Cancer

The Bispecific Antibody Zanidatamab (ZW25) Has Unique Mechanisms of Action and Durable Anti-Tumor Activity in HER2-Expressing Cancers

Safety, anti-tumour activity, and biomarker results of the HER2-targeted bispecific antibody ZW25 in HER2-expressing solid tumors

Zanidatamab (ZW25) in HER2-positive biliary tract cancers (BTCs): Results from a phase I study

HER2-positive breast cancer: new therapeutic frontiers and overcoming resistance

The binding of an anti-PD-1 antibody to FcγRΙ has a profound impact on its biological functions

Zanidatamab, an anti-HER2 bispecific antibody, plus chemotherapy with/withouttislelizumab as first-line treatment for patients with advanced HER2-positivebreast cancer or gastric/gastroesophageal junction adenocarcinoma: A phase1B/2 trial-in-progress

GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

Global burden of oesophageal and gastric cancer by histology and subsite in 2018

Survival of Esophageal Cancer in China: A Pooled Analysis on Hospital-Based Studies From

Oesophageal cancer: ESMO clinical practice guidelines

Cisplatin and 5-fluorouracil with or without epidermal growth factor receptor inhibition panitumumab for patients with non-resectable, advanced or metastatic oesophageal squamous cell cancer: a prospective, open-label, randomised phase III AIO/EORTC trial (POWER)

PD-L1 Expression On tumor Cells Was Associated With Unfavorable Prognosis In Esophageal Squamous Cell Carcinoma

Tumor immune microenvironment and immune checkpoint inhibitors in esophageal squamous cell carcinoma

Pembrolizumab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced esophageal cancer: The phase 3 KEYNOTE-590 study

Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial

Immune Checkpoint Inhibitors in Esophageal Cancers: are we Finally Finding the Right Path in the Mist?

Immunotherapy of Ipilimumab and Nivolumab in Patients with Advanced Neuroendocrine Tumors: A Subgroup Analysis of the CA209

Clinical Trial for Rare Cancers

Nivolumab (NIVO) plus ipilimumab (IPI) or NIVO plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): First re-REFERENCES sults of the CheckMate 648 study

The binding of an anti-PD-1 antibody to FcγRΙ has a profound impact on its biological functions

Tislelizumab in Chinese patients with advanced solid tumors: an open-label, noncomparative, phase 1/2 study

Randomized, phase 3 study of tislelizumab versus chemotherapy as second-line treatment for advanced unresectable/metastatic esophageal squamous cell carcinoma

ESCORT-1st: A randomized, doubleblind, placebo-controlled, phase 3 trial of camrelizumab plus chemotherapy versus chemotherapy in patients with untreated advanced or metastatic esophageal squamous cell carcinoma (ESCC)

Camrelizumab versus investigator's choice of chemotherapy as second-line therapy for advanced or metastatic oesophageal squamous cell carcinoma (ESCORT): a multicentre, randomised, open-label, phase 3 study

Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): a double-blind, randomised, placebo-controlled, phase 3 trial

nivo) plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC)/esophageal adenocarcinoma (EAC): First results of the CheckMate 649 study

First-line (1L) nivolumab (NIVO) plus chemotherapy (chemo) versus chemo in advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/ EAC): Expanded efficacy and safety data from CheckMate 649

Preoperative chemoradiotherapy for esophageal or junctional cancer

Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer

KEYNOTE-590: Phase III study of first-line chemotherapy with or without pembrolizumab for advanced esophageal cancer

Multicenter, randomized phase II study of neoadjuvant pembrolizumab plus chemotherapy and chemoradiotherapy in esophageal adenocarcinoma (EAC)

Efficacy and safety of KN046 plus paclitaxel/cisplatin as first-line treatment for unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC)

TIGIT as an emerging immune checkpoint

ADVANTIG-105: Phase 1 dose-escalation study of anti-TIGIT monoclonal antibody ociperlimab (BGB-A1217) in combination with tislelizumab in patients with advanced solid tumors

Primary analysis of a randomized, double-blind, phase II study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected NSCLC (CITYSCAPE)

AdvanTIG-203: A randomized phase 2 study comparing anti-TIGIT ociperlimabplus tislelizumab versus tislelizumab plus placebo as secondline treatment inpatients with advanced or recurrent esophageal squamous cell carcinoma(ESCC) expressing programmed death-ligand 1 (PD-L1)

Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial

Perioperative chemotherapy for locally advanced gastric cancer in Japan: current and future perspectives

Gastric cancer: a comprehensive review of current and future treatment strategies

Mechanisms and therapeutic potentials of cancer immunotherapy in combination with radiotherapy and/or chemotherapy

MATTERHORN: Efficacy and safety of neoadjuvant-adjuvant durvalumab and FLOT chemotherapy in resectable gastric and gastroesophageal junction cancer-A randomized, double-blind, placebo-controlled, phase 3 study

Pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction (G/GEJ) cancer: Initial findings of the global phase 3 KEY-NOTE-811 study

The editors of "memo, magazine of european medical oncology" assume no responsibility for this supplement. The Publisher does not assume any legal liability or responsibility for the accuracy, completeness, or usefulness of the information supplied herein, nor for any opinion expressed. The Publisher, its agent, and employees will not be liable for any loss or damage arising directly or indirectly from possession, publication, use of, or reliance on information obtained from this report. It is provided in good faith without express of implied warranty.Reference to any specific commercial product or service does not imply endorsement or recommendation by the Publisher. All articles are peer-reviewed and protected from any commercial influence.This issue is intended only for healthcare professionals outside the US, the UK and Australia. This special issue will be offering a synopsis from the ESMO 2021 that will be held in September 2021. The report promises to make for stimulating reading, as the ESMO Congress itself draws on the input from a number of partner organizations, representing a multidisciplinary approach to cancer treatment and care. Again, solid tumors will be at the heart of this special issue.

Annual Meeting

Robe rto Pazo-Cid outline s recen t insigh ts gained in terms of anti-P D-1 treatm ent in the setting of esoph ageal squam ous cell carcinoma , talks about the practi ce-ch anging results obtain ed in the Check Mate 649 trial and the impac t of PD-1 inhibit ion on the realworld progn osis of patien ts with gastric and esoph ageal adeno carcin oma as well as further develo pmen ts regard ing immu ne check point inhibit ion.

Peter R. Galle overvi ews the role of immunothe rapy in the setting of hepat ocellu lar carcin oma as well as bioma rker-b ased patient select ion and discus ses which novel comb ination s of immu ne check point inhibitors with other drug classe s are most promising at prese nt and how those novel strategies impac t the treatm ent landsc ape. Sign up for the mem o inOnc ology News letter on mem oinon colog y.com to keep yourself updat ed on all exciti ng news and developme nts in lung cance r.