Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies are approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC), but the emergence of resistance mutations restricts their efficacy. We previously showed that RAS, BRAF and EGFR mutant alleles, which appear in circulating tumor DNA (ctDNA) during EGFR blockade, decline upon therapy withdrawal. We hypothesized that monitoring resistance mutations in blood could rationally guide subsequent therapy with anti-EGFR antibodies. We report here the results of CHRONOS, an open-label, single-arm phase 2 clinical trial exploiting blood-based identification of RAS/BRAF/EGFR mutations levels to tailor a chemotherapy-free anti-EGFR rechallenge with panitumumab (ClinicalTrials.gov: NCT03227926; EudraCT 2016-002597-12). The primary endpoint was objective response rate. Secondary endpoints were progression-free survival, overall survival, safety and tolerability of this strategy. In CHRONOS, patients with tissue-RAS WT tumors after a previous treatment with anti-EGFR-based regimens underwent an interventional ctDNA-based screening. Of 52 patients, 16 (31%) carried at least one mutation conferring resistance to anti-EGFR therapy and were excluded. The primary endpoint of the trial was met; and, of 27 enrolled patients, eight (30%) achieved partial response and 17 (63%) disease control, including two unconfirmed responses. These clinical results favorably compare with standard third-line treatments and show that interventional liquid biopsies can be effectively and safely exploited in a timely manner to guide anti-EGFR rechallenge therapy with panitumumab in patients with mCRC. Further larger and randomized trials are warranted to formally compare panitumumab rechallenge with standard-of-care therapies in this patient setting.
BackgroundDespite unprecedented benefit from immune checkpoint inhibitors (ICIs) in patients with mismatch repair deficient (dMMR)/microsatellite instability high (MSI-H) advanced gastrointestinal cancers, a relevant proportion of patients shows primary resistance or short-term disease control. Since malignant effusions represent an immune-suppressed niche, we investigated whether peritoneal involvement with or without ascites is a poor prognostic factor in patients with dMMR/MSI-H metastatic colorectal cancer (mCRC) and gastric cancer (mGC) receiving ICIs.MethodsWe conducted a global multicohort study at Tertiary Cancer Centers and collected clinic-pathological data from a cohort of patients with dMMR/MSI-H mCRC treated with anti-PD-(L)1 ±anti-CTLA-4 agents at 12 institutions (developing set). A cohort of patients with dMMR/MSI-high mGC treated with anti-PD-1 agents±chemotherapy at five institutions was used as validating dataset.ResultsThe mCRC cohort included 502 patients. After a median follow-up of 31.2 months, patients without peritoneal metastases and those with peritoneal metastases and no ascites had similar outcomes (adjusted HR (aHR) 1.15, 95% CI 0.85 to 1.56 for progression-free survival (PFS); aHR 0.96, 95% CI 0.65 to 1.42 for overall survival (OS)), whereas inferior outcomes were observed in patients with peritoneal metastases and ascites (aHR 2.90, 95% CI 1.70 to 4.94; aHR 3.33, 95% CI 1.88 to 5.91) compared with patients without peritoneal involvement. The mGC cohort included 59 patients. After a median follow-up of 17.4 months, inferior PFS and OS were reported in patients with peritoneal metastases and ascites (aHR 3.83, 95% CI 1.68 to 8.72; aHR 3.44, 95% CI 1.39 to 8.53, respectively), but not in patients with only peritoneal metastases (aHR 1.87, 95% CI 0.64 to 5.46; aHR 2.15, 95% CI 0.64 to 7.27) when compared with patients without peritoneal involvement.ConclusionsPatients with dMMR/MSI-H gastrointestinal cancers with peritoneal metastases and ascites should be considered as a peculiar subgroup with highly unfavorable outcomes to current ICI-based therapies. Novel strategies to target the immune-suppressive niche in malignant effusions should be investigated, as well as next-generation ICIs or intraperitoneal approaches.
Background: KRAS G12C mutations, which occur in 3%-4% of CRC, are a negative predictor of cetux efficacy. Adagrasib, an investigational agent, is a KRAS G12C inhibitor that irreversibly and selectively binds KRAS G12C , locking it in its inactive state; it was optimized for favorable PK properties, including a long half-life (w24 hours). Durable inhibition of KRAS G12C may be particularly important in CRC due to signaling pathways which create a susceptibility to feedback reactivation of KRAS. EGFR signaling is implicated in this reactivation, providing a rational co-targeting strategy for KRASmutant CRC.Methods: KRYSTAL-1 (NCT03785249) is a multicohort Phase 1/2 study evaluating adagrasib in pts with KRAS G12C -mutant advanced solid tumors. CRC cohorts include adagrasib 600 mg BID monotherapy (Phase 1/2) and adagrasib 600 mg BID + cetux 400 mg/m 2 followed by 250 mg/m 2 QW; or 500 mg/m 2 Q2W (Phase 1b). Endpoints include safety, PK, and clinical activity. Here we report preliminary monotherapy and cetux combination data.Results: As of 25 May 2021, 46 pts with CRC (50% female; median age 58 years; 3 median prior lines of therapy) had received adagrasib monotherapy (median followup 8.9 months). TRAEs of any grade (gr) occurred in 91% and gr 3/4 events in 30% of pts, with no gr 5 events. Among the 45 pts evaluable for clinical activity, the response rate was 22% (10/45, including 1 unconfirmed PR who remains on study) and DCR was 87% (39/45). Median DOR was 4.2 months; median PFS was 5.6 months. As of 9 July 2021, 32 pts with CRC (53% female; median age 60 years; 3 median prior lines of therapy) were treated with adagrasib + cetux (median follow-up 7 months). TRAEs of any gr occurred in 100% and gr 3/4 events in 16% of pts, with no gr 5 events. Among the 28 pts evaluable for clinical activity, the response rate was 43% (12/28, including 2
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