The New Frontier in NSCLC: Immuno-Oncology Combinations - Episode 4
Mark A. Socinski, MD: The other standard that we had in practice was the FDA-approved regimen that came out of ECOG 4599: carboplatin/paclitaxel and bevacizumab. And we saw IMpower150, which is near and dear to my heart. I’m going to ask Ben to review it. But that was kind of the other standard FDA-approved platform in this nonsquamous, non—small cell space, and that kind of led to IMpower150.
Benjamin P. Levy, MD: Yes. First of all, there’s a lot of rationale to look at the synergy between PD-L1 and antiangiogenesis. There’s some preclinical work that has shown that VEGF upregulates regulatory T cells and myeloid-derived suppressor cells—both are immunosuppressive. And by giving an antiangiogenic drug, you can reverse that immunosuppression that may augment the PD-L1 drug. And so, IMpower150 looked at this synergy. It was a very large trial. It looked at more than 1200 advanced-age patients with nonsquamous, non—small cell lung cancer. They were randomized to 3 arms. Arm A was carboplatin, paclitaxel, and atezolizumab. Arm B was carboplatin, paclitaxel, bevacizumab, and atezolizumab—quadruplet therapy. And arm C was the ECOG 4599 backbone.
Mark A. Socinski, MD: C for control.
Benjamin P. Levy, MD: C for control. Impressively, in the intent-to-treat analysis, we saw an improvement in response rates between arms B and C. The primary analysis that we have, so far, is between arms B and C, answering the question regarding what atezolizumab does to the carboplatin/paclitaxel/bevacizumab backbone, that ECOG 4599 backbone. In the intent-to-treat analysis, response rates were higher in the quadruplet therapy in arm B. The response rate was 64% versus 48%. I would argue that outside of an actionable mutation, showing a response rate that high is quite impressive. There was a difference in the progression-free survival as well. The hazard ratio for progression-free survival was 0.62; 8.3 months versus 6.8.
Interestingly, in the subset analysis for the progression-free survival, there was a pronounced benefit for patients with liver metastases. The benefit, by the way, crossed all PD-L1 expressers, but there was a more pronounced benefit in liver metastases. I think there’s a lot of interest in looking at why that is and in going back, preclinically, to understand this. And then, importantly, this trial did allow for EGFR and ALK-rearranged lung cancer patients. I think there were about 100 patients who had a mutation.
Mark A. Socinski, MD: Actually, there were 150. There were about 50 in each arm.
Benjamin P. Levy, MD: And there was a benefit to adding atezolizumab to the backbone, which was surprising to see. I think this is one of the first trials we have with these particular genotypes, where we see a benefit by adding immunotherapy. We’ll receive an update on overall survival at this meeting.
Mark A. Socinski, MD: There was a press release in March that said that it reached significance for overall survival in the statistical design. Reaching overall survival superiority for arm B versus C allowed us to go look at arm A versus C. We’ll present that data at this meeting. I just want to make a comment on the liver metastases in the EGFR/ALK patients and explain the rationale for kind of looking at those as special populations. We’re all familiar with the Japanese trial in EGFR-mutant patients that added bevacizumab or erlotinib, and we’ll get an update on the overall survival for that. The progression-free survival was fairly impressive, so there was a rationale for thinking that this population may gain a benefit.
And then, going back to ECOG 4599, if you look at the Forest plots in patients who have liver metastases—liver metastases are negative for poor prognostic feature—there was a clear benefit in adding bevacizumab to carboplatin/paclitaxel in ECOG 4599. So, that was kind of the rationale for looking at those populations. Again, we saw some interesting data, particularly in the oncogenic driver subsets.
Corey J. Langer, MD, FACP: I want to add one other observation, and I don’t know if this is a bias on my part or if it’s real. When we look at the progression-free survival curves, the separation seems to get magnified over time after the chemotherapy is concluded. One wonders if that is evidence of a special synergy between angiogenesis inhibition and the immunotherapeutic agent. And certainly, that’s now born out by survival. The control arm pretty much matches the data that we observed in the original adenocarcinoma cohort. We’re going from 14 months to 19 months, overall.
Karen Kelly, MD: Nineteen months.
Corey J. Langer, MD, FACP: It’s another positive trial.
Transcript Edited for Clarity