Expert Highlights Next Steps With Chemoimmunotherapy in Nonsquamous NSCLC

Manish Patel, DO, discusses advances and remaining questions with chemoimmunotherapy combinations in nonsquamous metastatic non–small cell lung cancer.

Manish Patel, DO

The next steps following the FDA approvals of 2 frontline chemoimmunotherapy regimens for patients with metastatic nonsquamous non—small cell lung cancer (NSCLC) include comparisons of the combinations versus single-agent checkpoint inhibitors and understanding predictive factors of response, explained Manish Patel, DO.

One regimen, frontline pembrolizumab (Keytruda) plus platinum-based therapy and pemetrexed, was evaluated in the phase III KEYNOTE-189 study of patients with metastatic nonsquamous NSCLC without EGFR or ALK alterations. At a median follow-up of 18.7 months, results showed that patients in the pembrolizumab/chemotherapy arm had a median overall survival (OS) of 22.0 months versus 10.7 months for those who received placebo/chemotherapy (HR, 0.56; 95% CI, 0.45-0.70).1 In August 2018, the FDA granted a full approval to the combination of pembrolizumab plus chemotherapy in patients with metastatic nonsquamous NSCLC without EGFR or ALK alterations.

Secondly, the phase III IMpower150 study examined 3 regimens: the addition of atezolizumab (Tecentriq) to bevacizumab (Avastin), paclitaxel, and carboplatin (ABCP); bevacizumab/paclitaxel/carboplatin (BCP); and atezolizumab/paclitaxel/carboplatin (ACP) in patients with nonsquamous NSCLC.2 Median PFS was improved in ABCP at 8.5 months versus 7.0 months for BCP (HR, 0.71; 95% CI, 0.59-0.85; P <.0002), and the median OS was 19.2 months and 14.7 months, respectively (HR, 0.78; 95% CI, 0.64-0.96; P = .0164). Based on these data, the FDA approved the ACP combination in December 2018 as a first-line treatment for patients with metastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations.

“We have entered a new standard of care. We're using immunotherapy with chemotherapy for most patients,” said Patel, an associate professor in the Division of Hematology, Oncology and Transplantation at the University of Minnesota.

In an interview during the 2019 OncLive® State of the Science Summit™ on Non—Small Cell Lung Cancer, Patel discussed advances and remaining questions with chemoimmunotherapy combinations in nonsquamous metastatic NSCLC.

OncLive: What recent pivotal data have there been in metastatic nonsquamous NSCLC?

Patel: The KEYNOTE-189 study used platinum-based therapy and pemetrexed with pembrolizumab, which was a very positive study with a median survival that hasn't been reached, and a response rate [of 47%] that we haven't seen before in phase III trials of NSCLC. All subgroups of patients benefitted from that combination.

Similarly, the IMpower132 study used atezolizumab with a similar backbone of chemotherapy and was a very positive trial. If you compare the IMpower-132 and the KEYNOTE-189 trials, the outcomes are fairly similar. KEYNOTE-189 had a patient population that was much more likely to benefit from immunotherapy, with a higher proportion of patients with PD-L1—high tumors.

Additionally, if you look at the IMpower130 study, which used the backbone chemotherapy regimen of carboplatin/paclitaxel, there were very similar response rates and survival benefit.

Additionally, the IMpower150 study added atezolizumab and bevacizumab to the backbone of platinum-based therapy and paclitaxel. [There were even] better results with that 4-drug regimen versus platinum-based therapy and paclitaxel alone.

What are the next steps in this area of research?

There are several key questions. Right now, the 2 FDA-approved first-line chemoimmunotherapy regimens are platinum/pemetrexed with pembrolizumab and a 4-drug regimen using platinum, paclitaxel, bevacizumab, and atezolizumab. Between those 2 trials, it's very hard to know who might benefit from the addition of bevacizumab. [Also], patients with liver metastases seem to benefit from the [atezolizumab regimen], as well as patients with EGFR mutations who have failed TKIs.

To get more granular about the biologic basis of why bevacizumab might help with immunotherapy, we need to understand those things. We will be looking forward to getting more data about the immunologic effects of VEGF-directed therapy and trying to better understand which patients might benefit the most.

The other key question is regarding the patients with high PD-L1 expression. We know from the KEYNOTE-024 trial that patients with high PD-L1 expression benefit from pembrolizumab alone compared with chemotherapy. What we don't know is whether the combination of chemotherapy and immunotherapy are beneficial compared with immunotherapy alone in that patient population. Ongoing studies will help us answer those questions.

How are you currently determining whether patients should receive immunotherapy alone or in combination with chemotherapy?

This is a question that is still out in the unknown because, for patients with lower PD-L1 expression, we don't have a direct comparison between those two groups. We know from KEYNOTE-042 that patients with >20% PD-L1 expression benefit from pembrolizumab alone compared with chemotherapy alone. We have no information to know whether chemotherapy plus pembrolizumab is any better than pembrolizumab alone in that patient population. That is a key question going forward. Who can we safely treat with immunotherapy by itself?

What are the differences in efficacy and safety between these immunotherapy combinations? How do you choose which of the two regimens to give?

All of these immunotherapy drugs are virtually the same in terms of toxicity. If you look at the phase III trials that have been done with atezolizumab, nivolumab (Opdivo), and pembrolizumab, the rate of immune-related adverse events are virtually identical with few percentage point differences between them.

Similarly, the efficacy is very similar, with little differences based on PD-L1 expression versus tumor mutational burden. Virtually none of the drugs have off-target effects, so all of the adverse events are immune-related rather than other off-target toxicities. I view them as virtually the same, which makes it difficult to say one is better than the other. Perhaps we are in a place where we have too many immunotherapy drugs or more than we need.

What research is happening at your institution that you would like to highlight?

We are looking at [patients who fail on] first-line immunotherapy. We have an ongoing study using a medicine called sitravatinib, which is a VEGF TKI. We're seeing very impressive results with that combination in patients who failed prior immunotherapy.

Beyond that, we are looking at cellular therapy and have an ongoing trial using natural killer cells in combination with immune checkpoint blockade as the cellular therapy approach. We are also looking at oncolytic viruses using vesicular stomatitis virus in combination with avelumab (Bavencio), a different checkpoint blocker.

These are very early-phase studies, so they're not specifically for lung cancer. We're also looking at different combinations with immune checkpoint blockade, including hormonal therapy with exemestane for postmenopausal women. A large portion of women with lung cancer have estrogen receptor (ER) expression on their tumor cells, and some data suggest inhibiting the ER might have immunologic effects.

Finally, we have a study that is looking at replacing the gut bacteria in patients receiving immunotherapy, because there are intriguing data from the basic science world that showed replacing the gut bacteria may influence immunotherapy responses.


  1. Gadgeel SM, Garassino MC, Esteban E, et al. KEYNOTE-189: Updated OS and progression after the next line of therapy (PFS2) with pembrolizumab (pembro) plus chemo with pemetrexed and platinum vs placebo plus chemo for metastatic nonsquamous NSCLC. J Clin Oncol. 2019;37(suppl; abstr 9013). doi: 10.1200/JCO.2019.37.15_suppl.9013.
  2. Socinski M, Jotte RM, Cappuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288-2301. doi: 10.1056/NEJMo1716948.