CHRONOS, an open-label, single-arm, multicentre, phase II study was designed to evaluate the efficacy of panitumumab rechallenge in a population of patients with RAS/BRAF wild-type metastatic colorectal cancer (mCRC) selected on the basis of absence of RAS, BRAF and EGFR extracellular domain (ECD) resistance mutations in circulating tumour (ct)DNA at the actual moment of treatment initiation. The study findings demonstrate for the first time prospectively that genotyping tumour DNA in the blood can be safely, effectively and conveniently incorporated in the management of patients with mCRC. The results are published by Prof. Alberto Bardelli of the Candiolo Cancer Institute, FPO-IRCCS in Turin, Italy and colleagues on 1 August 2022 in the Nature Medicine.
The authors explained in the background that treatment of patients with mCRC who initially respond and then progress after cetuximab or panitumumab remains an unmet clinical need. The molecular bases of relapse are patient specific and difficult to define, as tissue biopsies at the time of progression cannot be systematically performed in clinical practice and have intrinsic risks. KRAS, NRAS and EGFR ECD acquired mutations, which occur in about 40% of the cases, are often highly heterogeneous, and the corresponding mutant proteins are difficult to target. Late-line standard treatment options beyond second-line in patients with mCRC are poorly effective. Upon failure of upfront anti-EGFR blockade, patients with RAS and BRAF wild-type mCRC and no targetable alterations, such as ERBB2 amplification or NTRK fusions, usually undergo additional lines of standard cytotoxic regimens and/or anti-angiogenic drugs. None of the latter options is currently based on a diagnostic molecular testing.
In this setting, retreatment with anti-EGFR monoclonal antibodies may be used as late-line treatment. In this context, rechallenge is defined as retreatment with an agent to which the tumour has responded and then progressed upon. Empirical anti-EGFR rechallenge has 8–20% response rate and manageable side effects. Despite much promising retrospective data, liquid biopsies have never been used to time and tailor anti-EGFR rechallenge in patients with mCRC which prompted the CHRONOS investigators to use for the first-time liquid biopsies prospectively to define chemotherapy-free anti-EGFR rechallenge with panitumumab in patients with mCRC.
The study primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), safety and tolerability. In CHRONOS, patients with tissue-RAS wild-type tumours after a previous treatment with anti-EGFR-based regimens underwent an interventional ctDNA-based screening. The study team found that 13 of 52 patients (25%) had KRAS, 4 of 52 had NRAS (8%), 1 of 52 had BRAF (2%), and 3 of 52 had EGFR (6%) ECD mutations in their ctDNA. Multiple mutations co-occurred in 5 of the 16 patients, whereas, in 2 patients, BRAF and EGFR ECD were the only resistance-conferring mutations, confirming that the addition of these 2 to the RAS panel optimised patient selection. The variant allele frequency varied between 0.28% and 46.20%. Codon 61 RAS mutations were among the most frequently identified RAS alleles, with a prevalence of 8 of 16 patients (50%).
According to the ‘zero mutation ctDNA triage’, 36 patients were molecularly eligible for panitumumab rechallenge. Of these, 27 received the drug as per study protocol, 6 did not meet clinical inclusion criteria, and 3 were treated otherwise as per physician choice. The median time interval between the screening liquid biopsy and the first dose of panitumumab rechallenge was 21 days (range, 9–44 days).
The primary endpoint of the study was met, with 8 partial responses (PRs) of which 6 confirmed plus 2 unconfirmed according to RECIST v1.1, defining an ORR of 30% (95% confidence interval (CI) 12–47%). The median duration of response was 17 weeks. Stable disease (SD) was achieved in 11 of 27 patients (40%) and lasted more than 4 months in 9 of 11 patients (82%). A disease control rate (defined as PR plus SD >4 months) was obtained in 17 patients (63%, 95% CI 41–78%). Objective responses occurred also in patients with right-sided primary tumours and in those with heavily pretreated disease. A 16-week PFS further corroborates the response findings. The median OS was 55 weeks.
The study team calculated for each patient the screening time interval (STI), defined as the time intercurred between the dates of the last dose of previous anti-EGFR and that of the CHRONOS screening. The median STI was 11.5 months. A specific time threshold differentiating patients with wild-type ctDNA from patients with mutated ctDNA was not present. There was no correlation between length of STI and probability of response, further suggesting that ‘zero mutation ctDNA’ status is the main predictive factor for anti-EGFR rechallenge efficacy.
The anti-EGFR rechallenge was overall well-tolerated with manageable side effects. The safety analysis included all patients who received at least one dose of panitumumab. There were no permanent treatment interruptions due to adverse events nor treatment withdraws requested by patients. No grade 5 adverse events were reported; grade 3/4 toxicities were recorded in 7 of 32 patients (22%). The most common severe adverse events were skin rash (9%), folliculitis (6%), paronychia (3%) and dermatitis (3%). Dose reduction and treatment delay was required in 3 of 32 patients (9%) due to grade 3 skin rash, folliculitis and skin rash and dermatitis. A total of 12 of 32 patients (37%) had primary prophylaxis with tetracycline antibiotics as per clinical choice, but the number of cutaneous events did not differ from those who did not receive such treatment.
The authors commented that future studies should consider screening of a larger panel of resistant variants in ctDNA to increase the therapeutic index of anti-EGFR monoclonal antibodies. For example, assessment of MAPK alterations or ERBB2/MET amplification should also be considered, as these are similarly known to confer resistance to EGFR blockade, although at lower prevalence in mCRC.
The study team concluded that their results indicate that selecting patients based on ctDNA improves the therapeutic index of anti-EGFR rechallenge by excluding resistant cases otherwise neglected by clinical criteria and by adopting a less toxic, chemotherapy-free panitumumab monotherapy.
The research leading to these results received funding from FONDAZIONE AIRC, European Research Council under the European Union’s Horizon 2020 research and innovation programme, IMI, International Accelerator Award, ACRCelerate, jointly funded by Cancer Research UK, FC AECC and AIRC, BiLiGeCT, Ministero della Salute, and Fondazione Oncologia Niguarda ONLUS. Amgen donated panitumumab for clinical use.
Sartore-Bianchi A, Pietrantonio F, Lonardi S, et al. Circulating tumor DNA to guide rechallenge with panitumumab in metastatic colorectal cancer: the phase 2 CHRONOS trial. Nature Medicine; Published online 1 August 2022. DOI: https://doi.org/10.1038/s41591-022-01886-0