Joel W. Neal, MD, PhD Highlights Promise of Cabozantinib ± Atezolizumab in Advanced NSCLC, But Cites Need for More Research


Findings from the phase 3 COSMIC-021 trial, comparing the effect of cabozantinib alone or in combination with atezolizumab vs docetaxel for advanced non–small cell lung cancer previously treated with immunotherapy, though promising, highlighted further need for randomized data to confirm the regimen’s benefit in the second-line setting, according to Joel W. Neal, MD, PhD.

Joel W. Neal, MD, PhD, Associate Professor of Medicine (Oncology) Stanford Medicine

Joel W. Neal, MD, PhD, Associate Professor of Medicine (Oncology) Stanford Medicine

Results from the phase 3 COSMIC-021 study (NCT03170960), which read out at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, indicated that cabozantinib (Cabometyx) plus atezolizumab (Tecentriq) demonstrated encouraging clinical activity when used as treatment for patients with stage IV non-squamous advanced non-small lung cancer (NSCLC) previously treated prior immune checkpoint inhibitors, according to Joel W. Neal, MD, PhD.

The cabozantinib and atezolizumab regimen yielded an overall response rate (ORR) of 19% (n = 15/81) in the overall population while the cabozantinib monotherapy regimen demonstrated an ORR of 6% (n = 2/31). Moreover, the ORR in the population with a PD-L1 expression of 1% or less was 11% (n = 2/19). Additionally, the ORR was 20% (n = 8/41) for those with a PD-L1 expression of 1% or more. Although the combination regimen demonstrated promise, Neal cautioned that it may be too soon to incorporate the agents into the treatment paradigm.

“The takeaway from this is that even though cabozantinib might be available for routine use and can be prescribed off label, I wouldn't personally use it off label in this context,” Neal said. “These data points were not randomized [and] they were not compared to each other. I think we need to wait for phase 3 data [before we] start using cabozantinib, except for special circumstances [such as] targeted alterations which can be found in the guidelines. But I think I'm encouraged to think about options in the second-line setting where patients may be able to avoid chemotherapy. Stay tuned, and hopefully we'll provide more data soon.”

Neal, an associate professor of Medicine (Oncology) at Stanford Medicine, spoke with CancerNetwork® about the efficacy of the regimens based on PD-L1 status and where future research efforts with the agents are being focused.

CancerNetwork®: What was the rationale for assessing cabozantinib plus or minus atezolizumab in patients with previously treated advanced NSCLC?

Neal: Patients with NSCLC have the first-line therapy option of immunotherapy, often [in combination] with chemotherapy. But in the second-line setting, the only FDA-approved therapy is docetaxel, which is an old chemotherapy with a lot of toxicities such as hair loss. We're investigating new regimens to try and see what can move into that second-line setting that may be more tolerable and more effective. The background for this study was that we decided to [combine] the immunotherapy [with] cabozantinib—which is a tyrosine kinase inhibitor active against VEGF, MET, RET, ROS1, and the TAM family of kinases—that theoretically is very tolerable together with atezolizumab and also may synergize this activity or show better response rates in the second-line setting.

Were there any other findings that really stood out to you in this research?

One interesting thing was that we looked at the response rates. The response rates of the combination of cabozantinib and atezolizumab was 19% of the 81 patients. Then, if we look at tumor control, 76% of tumors actually had some degree of tumor shrinkage. We saw these as very encouraging signs of clinical activity from the combination regimen. One interesting thing is that even though we didn't have PD-L1 status on all the tumors that were collected, of the PD-L1–negative tumors, there were lower response rates in the 10% range vs PD-L1 positive. And most interesting to me was the PD-L1 unknown [cohort]—the ones that hadn't been tested or for which we don’t have central tissue to retest. Those [tumors] actually had a slightly higher response rate and seem to have better outcomes. I thought that was interesting because I would have thought that the first line use of immunotherapy would have minimized any effect from the PD-L1 being high or low.

Beyond the response rates that were higher in the combination group of cabozantinib and atezolizumab compared to cabozantinib alone, we did see that median progression-free survival looked modestly higher at 4.5 months vs around 3.4 months in the cabozantinib alone [group]. Again, these weren't designed to be directly compared. I also thought it was interesting and hypothesis-provoking that cabozantinib plus atezolizumab might have some sort of synergistic activity. The overall survival data showed that patients lived 13.8 months vs 9.4 months with cabozantinib alone. Again, not meant for direct comparison. There was a little bit of randomization and I think the phase 3 trial will really help tease this out.

Did anything surprise you with the safety profile?

We looked at safety with regard to usual treatment-emergent adverse effects [TEAEs], which are regardless of relationship or attribution, then we also looked at immune-related AEs or AEs of special interest that we thought might be related to immunotherapy. For the most part, both in the cabozantinib and atezolizumab group, as well as the cabozantinib alone group, it looked like the AEs were much in line with what we expect from cabozantinib alone. Interestingly, the dose of cabozantinib was 60 mg in the cabozantinib alone group, which is the usual FDA-approved dose in tumor types like thyroid cancer, hepatocellular carcinoma, and renal cell cancer. But in combination with immunotherapy, it's a slightly lower dose of 40 mg daily with the atezolizumab.

We saw diarrhea, hypertension and liver function test abnormalities. [There were] 3 grade 5 events, 1 grade 5 event of pneumonitis as well as a grade 4 event of myocarditis, that was probably immune related in the combination group. In the cabozantinib alone group, 1 patient did die of gastric hemorrhage. Overall, I don't think that these were surprising compared to what we expect from cabozantinib alone, which is, by itself, already an FDA-approved drug for multiple different tumor types, including an approval in combination with nivolumab [Opdivo] for renal cell cancer.


Neal JW, Santoro A, Viteri A, et al. Cabozantinib (C) plus atezolizumab (A) or C alone in patients (pts) with advanced non–small cell lung cancer (aNSCLC) previously treated with an immune checkpoint inhibitor (ICI): Results from Cohorts 7 and 20 of the COSMIC-021 study. J Clin Oncol. 2022;40(suppl 16):9005. doi:10.1200/JCO.2022.40.16_suppl.9005

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