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Vectibix, Bavencio Show Activity as 'Rechallenge' Therapy Strategy in Metastatic Colorectal Cancer

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NEW YORK – The combination of an anti-EGFR monoclonal antibody and an immune checkpoint inhibitor may be a beneficial "rechallenge" treatment strategy in previously treated RAS wild-type metastatic colorectal cancer patients who have become resistant to anti-EGFR treatment, researchers reported at the European Society for Medical Oncology's Virtual Congress on Saturday.

The single-arm CAVE study "provides the first clinical evidence" in a Phase II trial that avelumab (Pfizer/EMD Serono's Bavencio) plus cetuximab (Eli Lilly's Erbitux) is "effective, well-tolerated, and feasible" as a treatment for RAS wild-type metastatic colorectal cancer patients who have become resistant to first-line anti-EGFR monocolonal antibodies, are given a temporary reprieve from anti-EGFR treatment, and are challenged again with these drugs, said Erika Martinelli from the University of Campania in Naples, Italy, in a conference presentation.

The CAVE study met its prespecified endpoint of median overall survival, suggesting that a subset of chemo-refractory RAS wildtype colorectal cancer patients may benefit from receiving a checkpoint inhibitor alongside an anti-EGFR monoclonal antibody as a rechallenge strategy. However, Martinelli cautioned that the precise contribution of the two drugs in spurring immune responses cannot be definitively concluded in a single-arm trial, and that these Phase II findings need to be confirmed in a randomized Phase III trial.

Furthermore, she suggested that in a Phase III trial patients should be stratified based on circulating tumor DNA (ctDNA) analysis to identify best responders in this advanced and previously treated population.

The CAVE study enrolled 77 RAS wild-type, metastatic colorectal cancer patients who had previously received first-line treatment with chemotherapy and anti-EGFR drugs and then went onto receive subsequent lines of therapy that did not include an anti-EGFR therapy. In the study, most patients had received two lines of prior therapy and around a quarter of patients had previously received three or more treatments. After this, patients were given avelumab and cetuximab and followed until they progressed or had to stop treatment due to toxicities.

The benefit of immune checkpoint inhibitors is now well established as a treatment for patients with microsatellite-unstable metastatic colorectal cancer. However, the precise role of immunotherapy in microsatellite-stable colorectal cancer is still being explored. Some preclinical and single-arm early clinical studies have suggested that a checkpoint inhibitor and anti-EGFR monoclonal antibody may work together to activate NK cell-driven immune responses against cancer cells.

The CAVE study investigators set out to explore this combination specifically as a rechallenge treatment strategy in refractory, RAS wild-type metastatic colorectal cancer patients, for whom the standard of care in the first-line setting is anti-EGFR monoclonal antibodies, such as cetuximab and panitumumab (Amgen's Vectibix). The downside of this treatment is that patients eventually become resistant through the emergence of RAS mutant clones. "Circulating tumor DNA analysis has shown that at disease progression, a treatment break from antigen receptor drug is able to restore sensitivity" by suppressing RAS-mutant cancer cells, Martinelli explained.

In their study, Martinelli and colleagues prespecified their aim to demonstrate 11-month median overall survival, resulting in a three-month improvement over a median overall survival of 8 months, which is what is typically seen in this third-line setting with standard treatments. At data cutoff on July 13, seven patients had progressed on the avelumab-cetuximab regimen, 37 had died, 32 patients were still being followed for survival, seven patients were still on the treatment regimen, and one patient had been lost in follow up.

The study met its primary endpoint and demonstrated a median overall survival of 13.1 months and a median progression-free survival of 3.6 months. The objective response rate was 7 percent, and 57 percent had stable disease. The regimen appeared to be well-tolerated in this study, with 14 percent and 4 percent of patients experiencing grade 3 skin rash and diarrhea, respectively.

"This chemotherapy-free regimen compares favorably with concurrent standard third-line therapies with respect to safety and efficacy," Martinelli said. 

In the study, researchers collected plasma samples at baseline and conducted central ctDNA analysis in 56 patients for RAS, BRAF, and EGFR mutations. They found that after receiving a break from anti-EGFR antibody treatment, 41 had no mutations in RAS or BRAF but 15 patients still had mutations in these genes. The overall response rate to the avelumab-cetuximab combination was 9 percent in the wildtype population and there were no responders in the mutated population. The median progression-free survival was 4.3 months versus 3.2 months, and the median overall survival was 16.1 months and 11.5 months in the wildtype and mutated ctDNA groups, respectively.

"The evaluation of plasma ctDNA as assessed at baseline by liquid biopsy allowed [us] to further define the activity and the safety" of the combination, Martinelli said, noting that the findings need to be confirmed in a Phase III randomized trial. "Moreover, plasma DNA analysis before treatment should contribute to better selecting patients who may benefit from this treatment."

In reviewing the data, Chiara Cremolini, a colorectal cancer specialist from the University of Pisa recognized that stratifying patients based on ctDNA analysis certainly seems to have improved the identification of the population benefiting from the avelumab-cetuximab treatment, judging by the response rate increasing from an initial 7 percent to 9 percent and similar improvements in median progression-free and overall survival. 

The CAVE study, in her view, showed "a certain degree" of activity with this anti-EGFR treatment rechallenge strategy, though "not impressive" activity. However, she agreed that liquid biopsy may have a role in identifying best responders among previously treated, advanced colorectal cancer patients. She noted there are several other ongoing studies exploring an anti-EGFR rechallenge strategy in RAS wildtype metastatic colorectal cancer patients, and a few of them are even using ctDNA analysis to select patients.

Despite the activity seen in the CAVE study, there are still unanswered questions about the extent to which cetuximab is helping marshal NK cell-directed immune responses against cancer cells in parallel with avelumab, and about what benefit the checkpoint inhibitor is adding beyond cetuximab.

"The added value of avelumab is beyond the reach of this trial," Cremolini said, noting that six patients in the initial analysis responded to the avelumab-cetuximab regimen. However, the researchers didn't specify whether these patients were microsatellite stable or unstable. Patients with high microsatellite instability are predicted to respond particularly well to checkpoint inhibitors, and three patients in the study had high microsatellite instability.

"The results in the [microsatellite-stable] subgroup will be useful to properly assess the activity of this combination" and which patients are not responsive to immunotherapy, Cremolini said. "More research is needed to open the doors of [microsatellite-stable] tumors to checkpoint inhibitors."