Circulating tumor DNA to guide rechallenge with panitumumab in metastatic colorectal cancer: the phase 2 CHRONOS trial

Abstract

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.

Fig. 1

CONSORT diagram and molecular screening of the CHRONOS trial. Results of ctDNA ddPCR analysis and distribution of RAS, BRAF and EGFR ECD mutations in patients screened within the CHRONOS trial. Abbreviations: ctDNA, circulating tumor DNA; ddPCR, droplet digital PCR; ECD, ectodomain.

Fig. 2

Waterfall plot depicts best responses to panitumumab rechallenge within the CHRONOS trial according to RECIST 1.1 (a). Spider plot displays best responses according to RECIST 1.1 and duration of response to panitumumab rechallenge (b). Magenta, progressive disease; gray, stable disease; blue, partial response; black, unconfirmed partial response; * progressive disease exclusively due to the onset of a new metastatic lesion.

Fig. 3

Tree graph describing ctDNA RAS/BRAF/EGFR status of patients screened for CHRONOS enrollment according to the time interval between the end of the last anti-EGFR course and the date of the CHRONOS ctDNA screening. Top: patients with WT sample; color-coded objective response to rechallenge with panitumumab on a time scale displaying PFS. Bottom: patients with mutated sample and mutations retrieved leading to CHRONOS screening failure. αEGFR, anti-EGFR. Abbreviations: MT, mutant; WT, wild-type.

Fig. 4

Alterations identified by NGS on tissue samples collected before CHRONOS enrollment (upper panel), on ctDNA at baseline to panitumumab rechallenge (middle panel) and on ctDNA at progression to panitumumab rechallenge (lower panel). As per inclusion criteria, all patients enrolled achieved complete or partial response to prior anti-EGFR antibodies either as monotherapy or in combination with cytotoxic agents. Mutations in the genes (NRAS/KRAS/BRAF/EGFR) of the molecular screening panel and KRAS/EGFR amplifications are highlighted in yellow.

Extended Data Fig. 1. Schematic representation of the CHRONOS trial design (Amendment 3.0).

Schematic representation of the CHRONOS trial design (Amendment 3.0). Created with BioRender.com.

Extended Data Fig. 2. Molecular screening panel based on droplet-digital PCR implemented in the CHRONOS trial.

Molecular screening panel based on droplet-digital PCR implemented in the CHRONOS trial.

Extended Data Fig. 3. Outcome to panitumumab rechallenge in CHRONOS trial, according to (right) RECIST 1.1 response and progression-free survival and (left) the number and type of previous lines of treatments, type of previous anti-EGFR agent administered, and primary tumor sidedness.

Outcome to panitumumab rechallenge in CHRONOS trial, according to (right) RECIST 1.1 response and progression-free survival and (left) the number and type of previous lines of treatments, type of previous anti-EGFR agent administered, and primary tumor sidedness. Created with GraphPad Prism 9.

Extended Data Fig. 4. Progression-free survival (panel A) and overall survival (panel B) of the 27 patients enrolled in the CHRONOS trial.

Progression-free survival (panel A) and overall survival (panel B) of the 27 patients enrolled in the CHRONOS trial. Keys: EOTTIME = End of Treatment Time; SURTIME = Survival Time.