Advanced-Stage Non-Driver NSCLC: IMpower150 Trial

Benjamin P. Levy, MD:There’s lots of rationale to look at immunotherapy with antiangiogenesis. Preclinical data suggest that VEGF fosters an immunosuppressive environment by upregulating Tregs, which are immunosuppressive, and upregulating myeloid-derived suppressor cells, which are immunosuppressive. So, by targeting VEGF with an antiangiogenic drug, that may reverse the immunosuppression. That may allow immunotherapy drugs that you give with the antiangiogenic drug to work better.

And there was a lot of preclinical work on this, but certainly it has been, clinically, born out of the IMpower data. This was a trial looking at the synergy of immunotherapy with an antiangiogenic drug and chemotherapy, specifically looking at carboplatin/paclitaxel/bevacizumab/atezolizumab, and then the primary analysis comparing it with carboplatin/paclitaxel/bevacizumab. And the question being asked is, if we add immunotherapy to carboplatin/paclitaxel/bevacizumab, does that confer any benefit for the patient? And what we saw, impressively, was a significant improvement in response rate, a significant improvement in progression-free survival, and, importantly, a trend toward improvement in overall survival that’s immature at this time. But we hope to have updated analysis.

So, it’s hard to find a lung cancer trial, at least in the past 10 years, that shows overall survival advantages. And with the advent of immunotherapy, that’s changing. If you were to ask me, before this trial was designed, whether adding atezolizumab to 3 drugs would show a benefit, I would say probably not. But we’re seeing time and time again that no matter what the PD-L1 is—and we saw this in the trial—there was a benefit in the PD-L1—highs and in the PD-L1–negatives that adding atezolizumab to the 3-drug regimen of carboplatin/paclitaxel/bevacizumab led to meaningful improvements and outcome.

I look forward to the updated analysis to see what it shows. But to have response rates north of 50% and 60% with a 4-drug regimen—yes, it’s 4 drugs—for that patient who’s symptomatic and for what you want to give, you only have one shot on goal and you want to give your best drugs up front, I think this is going to be a consideration. I look forward to seeing more data with this regimen and seeing how the survival analysis comes out.

For this patient who’s a never-smoker, with a PD-L1—low level who does not have a driver mutation, who’s young and fit, this would be a patient who, if you’re trying to elicit a response, would be potentially a candidate for a 4-drug regimen. Now, would I use paclitaxel? I would love to use pemetrexed instead. I would love to see some data looking at carboplatin/pemetrexed/bevacizumab/atezolizumab, and I think that the outcomes would be similar, although we need to see that. But for a symptomatic patient who’s a never-smoker and doesn’t have a driver, even if their PD-L1 is low here, you’re covering your bases a) because you’re giving the bevacizumab and b) because the IMpower study showed that the benefit of atezolizumab was independent of their PD-L1 status. So, I think this is a consideration for a patient who’s younger and fitter, without a driver mutation, in which you need to elicit a response.

Transcript edited for clarity.

• A 55-year old female presented with chronic cough and 10-lb weight loss
• PMH: never smoker; no family history of cancer; no known exposure to chemicals or asbestos
• Chest x-ray showed a 5.0-cm lesion in the left lower lobe with bulky lymphadenopathy
• Chest CT scan confirmed the presence of a lung mass and enlargement of the right hilar lymph node and bilateral mediastinal lymph nodes
• EUS-guided biopsy was performed
• Pathology revealed adenocarcinoma
• Molecular testing:
  • FISH: negative for ALK translocation
  • NGS: negative for EGFR, ROS1, RET, BRAF, KRAS
  • IHC: PD-L1 expression in 0% of cells
• PET/CT imaging showed 18F-FDG uptake in the lung mass, right hilar lymph node, mediastinum, and left adrenal gland
• MRI of the brain was normal
• ECOG PS, 0
• The patient was started on therapy with carboplatin/pemetrexed and bevacizumab
• The regimen was well tolerated
• After 6 cycles, the patient had a good response
• She was continued on bevacizumab
• After 9 months on therapy, the patient developed cough and weight loss
• Follow-up imaging revealed multiple new lesions in the left adrenal gland and new liver metastases
• Patient was started on atezolizumab, planned for 12 months