Cabozantinib plus durvalumab shows efficacy in subset of patients with colorectal cancer
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The combination of cabozantinib and durvalumab appeared safe and demonstrated efficacy among a small cohort of patients with advanced mismatch repair-proficient/microsatellite-stable colorectal cancer, according to study results.
The findings from cohort two of the phase 2 CAMILLA trial, presented at ASCO Gastrointestinal Cancers Symposium, also showed an association of wild-type RAS with improvements in PFS, OS and objective response rate.
“These encouraging results warrant further evaluation of this regimen in a randomized setting as salvage therapy in this patient population,” Anwaar Saeed, MD, associate professor of medicine in the division of medical oncology and associate director of the Early Phase Program at The University of Kansas Cancer Center, told Healio.
Rationale
“Preclinical published data supported the synergistic effect when combining VEGF targeted therapy with PD-1 immune checkpoint inhibitors. There is also growing clinical evidence that supports the efficacy of cabozantinib-immunotherapy combinations in other disease settings, such as renal cell carcinoma, hepatocellular carcinoma and others,” Saeed said. “Considering the known activity of VEGF-targeted therapy in gastrointestinal malignancies, we have proposed that combining the VEGFR multi-tyrosine kinase inhibitor cabozantinib with PD-L1 inhibitor durvalumab will lead to clinical synergy in this patient population.”
After phase 1b results of the gastrointestinal basket CAMILLA trial demonstrated favorable safety and efficacy with cabozantinib (Cabometyx, Exelixis) plus durvalumab (Imfinzi, AstraZeneca), the study expanded to a phase 2, multicohort, multicenter trial of 117 patients.
Methods
Cohort 2 of the phase 2 trial included 36 patients who had progressed on two or more lines of prior therapy and received 40 mg cabozantinib daily plus 1,500 mg IV durvalumab every 4 weeks.
“Eligible patients had failed on at least two prior lines of standard therapy and had microsatellite-stable or proficient mismatch-repair tumor phenotype. Among those with RAS wild type tumors, a documentation of prior exposure or failure of EGFR targeted therapy was required for eligibility,” Saeed said.
Investigator-assessed ORR served as the primary outcome. Secondary outcomes included the rate of treatment-associated adverse events, investigator-assessed disease control rate, PFS and OS.
Key findings
The 29 patients evaluable for the efficacy analysis had an ORR of 27.6%, confirmed partial response rate of 20.7% and disease control rate of 86.2%.
Researchers reported median PFS of 3.8 months (95% CI, 3.4-6.3) and median OS of 9.1 months (95% CI, 5.8-21.8), as well as a 6-month PFS rate of 34.5% (95% CI, 17.9-54.3).
The most common grade 1 and grade 2 treatment-associated adverse events included fatigue (53%), nausea (42%), diarrhea (36%), anorexia (31%) and palmar-plantar erythrodysesthesia syndrome (25%). Thirty-one percent of patients experienced grade 3 or higher treatment-associated adverse events and 16.6% experienced grade 3 or higher immune-related adverse events. One patient discontinued treatment with durvalumab only.
In a subgroup of patients with wild-type RAS (n = 12), researchers observed an ORR of 50% and a disease control rate of 83.3%. Additionally, analysis showed median PFS of 6.3 months (95% CI, 1.8-not estimable) and median OS of 21.8 months (95% CI, 4.5-not estimable).
“A post-hoc analysis of results from cohort 16 of the COSMIC-021 trial examining cabozantinib plus the PD-L1 inhibitor atezolizumab [Genentech, Roche] in patients with advanced pretreated colorectal cancer revealed similar differential advantage in the RAS wild-type colorectal cancer subgroup, with a reported median PFS of around 6 months, which was also presented during this meeting,” Saeed said.
Implications
“The combination of cabozantinib plus the PD-L1 inhibitor is not yet indicated or FDA-approved for this patient population. While the results will not change how we practice in oncology clinics today, the data highlight the potential for this combination to change the current practice if the same positive outcome is validated in future pivotal trials,” Saeed said.
Next steps will include a randomized clinical trial comparing this or a similar combination with standard of care therapy in the third-line setting among patients with mismatch repair-proficient/microsatellite-stable colorectal cancer, Saeed added.
“We look forward to the launch of the STELLAR 303 trial later this year,” she said. “This trial will examine XL092, a next generation multi-tyrosine kinase inhibitor, with a similar target profile as cabozantinib, in combination with atezolizumab vs. regorafenib [Stivarga, Bayer] in this patient population.”
References:
Abrams TA, et al. Abstract 121. Presented at: ASCO Gastrointestinal Cancers Symposium; Jan. 20-22, 2022; San Francisco.
Saeed A, et al. Abstract 135. Presented at: ASCO Gastrointestinal Cancers Symposium; Jan. 20-22, 2022; San Francisco.
For more information:
Anwaar Saeed, MD, can be reached at The University of Kansas Cancer Center, 4350 Shawnee Mission Parkway, Fairway, KS 66205; email: asaeed@kumc.edu.
Perspective
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Afsaneh Barzi, MD, PhD
This is the first cohort of the combination of tyrosine kinase inhibitor and immune checkpoint inhibitors in the U.S. that had generated results on par with the REGONIVO trial in the Japanese population. Although these results are promising, it is notable that the sample size of this study is much smaller than the two reported regorafenib (Stivarga, Bayer) combination studies with immune checkpoint inhibitors in the U.S. presented by Barzi and Fakih. More importantly, cabozantinib as a single agent and durvalumab combined with tremelimumab (MedImmune/AstraZeneca) in colorectal cancer are not associated with significant response. Therefore, it is likely that the results of this study would not be reproducible.
Given the dilemma of efficacy of tyrosine kinase inhibitors in combination with immune checkpoint inhibitors and contradictory results, it is time to dig deep into the potential patients who can benefit from these treatments and focus efforts in targeted drug development.
Barzi A, et al. Abstract 15. Presented at: ASCO Gastrointestinal Cancers Symposium; Jan. 20-22, 2022; San Francisco.
References:
Chen EX, et al. JAMA Oncol. 2020;doi:10.1001/jamaoncol.2020.0910.
Fukuoka S, et al. J Clin Oncol. 2020;doi:10.1200/JCO.19.03296.
Scott AJ, et al. J Clin Oncol. 2020;doi:10.1200/JCO.2020.38.4_suppl.103.
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Saeed A, et al. Abstract 135. Presented at: ASCO Gastrointestinal Cancers Symposium; Jan. 20-22, 2022; San Francisco.
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