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We analyzed the antitumor activity of platinum-based chemotherapies and then immune checkpoint inhibitors (ICI) in all-comers patients with solid tumors having a somatic DNA damage repair gene alteration (DDR-GA) identified through a prospective precision medicine study (NCT02534649). Each DDR-GA was classified as pathogenic (Pa), probably pathogenic (PPa), and unknown pathogenicity (UPa) according to OncoKB and ClinVAR databases. Between January 2018 and May 2020, 662 patients were screened. One hundred ninety-nine tumors with DDR-GA were found in 121 (18.3%) patients. Ninety-six patients received platinum-based chemotherapy in the advanced setting. No difference in objective response rate (ORR) under platinum regimen was observed between the 3 DDR-GA groups. The only predictor of worse progression-free survival (PFS) in Cox regression was the existence of a Pa alteration compared to the UPa group: HR = 2.11 (95% CI = 1.2-3.7), P  = .009. Forty-eight patients received ICI alone or in combination. We observed a significant trend in better ORR to ICI according to the DDR-GA status: 1/11 (9%) patients in UPa, 5/17 (29.4%) patients in PPa, and 9/20 (45%) patients in Pa (P  = .003, Cochran-Armitage trend test), and an increased 6-month PFS probability of 11%, 44%, and 50% in the UPa, PPa, and Pa groups, respectively (P  = .37, log-rank test). Overall, somatic pathogenic DDR-GAs were not associated with ORR or PFS to platinum-based chemotherapy in patients with unselected advanced solid tumors. However, DDR-GA seemed to impact ORR and PFS to ICI, paving the way for a therapeutic combination with ICI and molecules targeting the DDR mechanisms, which are currently evaluated in ongoing clinical trials. [ABSTRACT FROM AUTHOR]

KRAS mutations are common in metastatic colorectal cancer and represent a contraindication to the use of anti-EGFR agents. KRAS pro-tumorigenic signaling is one of the main signaling axes for tumor cell proliferation and survival, making it a key therapeutic target. However, the structural configuration of the RAS protein has for many years made it a difficult target to reach. Among RAS mutations, the KRASG12C mutation is rare, occurring in 3-4% of colorectal cancers. Recently, several molecules targeting this KRASG12C mutation have been developed, including sotorasib and adagrasib. The efficacy of these oral molecules, when used as monotherapies, was initially shown to be rather limited, compared with that of other tumor localizations such as lung cancers. In order to overpass some resistances, combination strategies with anti-EGFR agents have been developed, and have significantly improved these results. After several phase I and II trials evaluating these combinations, the combination of sotorasib + panitumumab showed, for the first time in a phase III study, a survival benefit compared with standard treatment in 3rd line and beyond, consecrating a new therapeutic option for these patients. Other trials are still in progress with new molecules and innovative combinations. [ABSTRACT FROM AUTHOR]