key: cord-1017356-c5wy1iyp
authors: Weiss, Lukas
title: ESMO 2021—highlights in colorectal cancer
date: 2022-04-28
journal: Memo
DOI: 10.1007/s12254-022-00808-7
sha: 2705281ec7b92bd3468270a1caecf4e5af8da773
doc_id: 1017356
cord_uid: c5wy1iyp

This short review reflects on a personal selection of three abstracts on colorectal cancer (CRC) presented at the 2021 ESMO Congress: (1) KRASG12C as a new therapeutic target in metastatic CRC, supported by data from the KRYSTAL‑1 and CodeBreaK101 trials, (2) positive phase 3 data on the possible role of selective internal radiotherapy (SIRT) in the second-line treatment of liver-limited metastatic CRC, and (3) the impact of the coronavirus disease 2019 (COVID-19) pandemic on CRC screening, management and mortality, now and in the upcoming years.

Although KRAS is one of the most frequently mutated genes in colorectal cancer (CRC), only 3-4% of all patients with metastatic CRC exhibit a KRAS G12C mutation [1] . KRAS G12C is a point mutation in the KRAS gene resulting in a glycine-to-cysteine amino acid substitution at codon 12, thereby, leading to constitutive activation and oncogenesis. These patients show a worse prognosis when compared to patients with non-KRAS G12C mutated disease.

Adagrasib is a covalent inhibitor of KRAS G12C which irreversibly and selectively binds to KRAS G12C [2] . In the KRYSTAL-1 phase 1/2 trial, adagrasib was investigated as monotherapy (n = 46) or in combination with the anti-EGFR antibody cetuximab (n = 32) L. Weiss, MD, PhD ( ) IIIrd Medical Department, Paracelsus Medical University, Muellner Hauptstr. 48, 5020 Salzburg, Austria lu.weiss@salk.at in heavily pretreated KRAS G12C-mutated metastatic CRC [3] . This combination is based on the rationale that EGFR signaling has been identified as the dominant mechanism of CRC resistance to KRAS G12C inhibitors [4] .

Adagrasib alone resulted in an overall response rate (ORR) of 22% and disease control rate (DCR) of 87% among 45 evaluable patients. Median progressionfree survival (PFS) for monotherapy was 5.6 months (95% confidence interval [CI] 4.1-8.3). The addition of cetuximab could increase clinical efficacy to an ORR of 43% and DCR of 100% among 28 evaluable patients. Here, median time to response was 1.3 months and 71% of patients remained on treatment at the time of analysis. Grade 3/4 adverse events for combination therapy could be observed in 16% of patients, with diarrhea, acneiform rash, stomatitis and QTc prolongation being the most frequent (each 3%).

Based on these results, adagrasib and cetuximab is compared to standard chemotherapy plus/minus antiangiogenic agent in the KRYSTAL-10 trial, a phase 3 randomized trial in patients with KRAS G12C mutated metastatic CRC who have progressed after first-line treatment (NCT04793958).

These data are supported by another trial: in the phase Ib CodeBreaK101 trial, sotorasib, another KRAS G12C inhibitor, was investigated in combination with the anti-EGFR antibody panitumumab in 31 chemorefractory patients [5] . The investigators reported a confirmed plus unconfirmed ORR of 27% and a DCR of 81%.

Sotorasib is already approved by the European Medicines Agency for the treatment of patients with advanced non-small cell lung cancer whose tumors harbor a KRAS G12C mutation and who have progressed after at least one prior line of systemic therapy [6] .

K ESMO 2021-highlights in colorectal cancer

The combination of sotorasib and panitumumab will be investigated in the CodeBreak300 trial, a phase 3 randomized trial in patients with KRAS G12C mutated metastatic CRC in the third-line setting (NCT04793958).

Selective internal radiotherapy (SIRT) or radioembolization describes the transarterial delivery of microscopic glass beads containing radioactive yttrium (Y-90) to liver metastases through hepatic tumorfeeding arteries.

The EPOCH trial investigated the role of SIRT when added to standard second-line chemotherapy in patients with metastatic CRC limited to the liver [7] .

In this phase 3 study, 428 patients were randomized to either chemotherapy alone or the combination with SIRT applied in a single setting, before or after the first cycle of chemotherapy. Both primary endpoints were met, with a slight increase in median PFS (8.0 vs 7.2 months, hazard ratio [HR] 0.69; 95% CI, 0.54-0.88; p = 0.0013) as well as in median hepatic PFS (9.1 vs 7.2 months, HR 0.59, p = 0.0019) when adding SIRT. Moreover, ORR was also higher in the combination arm with 34.0% compared to 21.1% with chemotherapy alone. However, this did not translate into an increased median overall survival (14.0 vs 14.4 months, HR 1.07, p = 0.7229).

Grade 3 adverse events-especially neutropenia-were reported more frequently with SIRT (68.4% vs 49.3%) but not leading to dose reductions in chemotherapy.

So after failing to show an improvement in PFS or OS in the first-line setting [8] , adding SIRT to standard chemotherapy to liver-limited metastatic CRC may be beneficial in the second-line setting.

Due to the immense challenges posed by the coronavirus disease 2019 (COVID-19) pandemic to health care systems worldwide, cancer screening programs had to be scaled back or were not sought by patients out of fear of COVID-19 infection.

At ESMO 2021, Tehfe M et al. presented their analysis of data of the Canadian province of Quebec regarding fecal occult blood test and colonoscopy for CRC screening, as well as CRC surgery [9] . When compar- ing the 4-month period during the first wave of the pandemic (April-July 2020) to the same time period in the preceding year (April-July 2019), the researchers could observe a dramatic drop in CRC screening but also CRC surgeries (Table 1) . Although prior to the second wave (August-October 2020) many health care services could be resumed, CRC screening was still less than in the previous year (fecal occult blood test: -5%, colonoscopy: -11.4%) as were CRC surgeries (-28%).

These data are in line with other reports [10] and exemplify how the COVID-19 pandemic is impacting CRC management. Since CRC survival is closely linked to stage of disease [11] , the delays in diagnosis of CRC are expected to lead to a stage-shift at first diagnosis as well as in an increase in emergency admissions, both known to negatively affect prognosis in CRC [12] . Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Comprehensive clinical and molecular characterization of KRASG12C-mutant colorectal cancer

The KRAS G12C Inhibitor MRTX849 ProvidesInsighttowardTherapeuticSusceptibilityofKRAS-Mutant Cancers in Mouse Models and Patients

KRYSTAL-1: adagrasib (MRTX849) as monotherapy or combined with cetuximab (Cetux) in patients (Pts) with colorectal cancer (CRC) harboring a KRASG12C mutation

EGFR blockade reverts resistance to KRAS G12C inhibition in colorectal cancer

CodeBreaK 101 subprotocol H: phase Ib study evaluating combination of sotorasib (Soto), a KRASG12C inhibitor, and panitumumab (PMab), an EGFR inhibitor, in advanced KRAS p.G12C-mutated colorectal cancer (CRC)

Sotorasib for lung cancers with KRASp.G12C mutation

Radioembolization with chemotherapy for colorectal liver metastases: A randomized, open-label, international, multicenter, phase III trial (EPOCH s

First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials

CRC) cancer screening anddiagnosis during the COVID-19 pandemic in Quebec

Impact of the COVID-19 pandemic on the detectionandmanagementofcolorectalcancerinEngland: a population-based study

Bowel cancer survival statistics | Cancer Research UK

Emergency presentation of cancer and short-term mortality

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