Navigating New Immune-Based Combinations in Advanced NSCLC

Joshua K. Sabari, MD, discusses a number of immunotherapy regimens that have emerged in the frontline setting for patients with driver-negative advanced non–small cell lung cancer; however, for many patients, the decision comes down to pembrolizumab monotherapy or pembrolizumab in combination with platinum-doublet chemotherapy.

A number of immunotherapy regimens have emerged in the frontline setting for patients with driver-negative advanced non–small cell lung cancer (NSCLC). However, for many patients, the decision comes down to pembrolizumab (Keytruda) monotherapy or pembrolizumab in combination with platinum-doublet chemotherapy, said Joshua K. Sabari, MD.

“In patients who have PD-L1 expression greater than or equal to 50%, we recommend pembrolizumab monotherapy in the frontline setting,” said Sabari. “For patients who have PD-L1 expression less than 50%, we recommend the combination of carboplatin, pemetrexed, and pembrolizumab,” said Sabari.

The combination of atezolizumab (Tecentriq), bevacizumab (Avastin), carboplatin, and paclitaxel, as well as the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) are also approved for frontline use. However, the level of evidence and the lack of a robust biomarker of response has made it challenging to integrate the regimens into practice.

“We definitely need more research [regarding biomarkers of response] in order to move immunotherapeutics forward,” Sabari added. “For regimens like ipilimumab and nivolumab or potentially carboplatin, paclitaxel, bevacizumab, and atezolizumab, if we had a specific biomarker to select the correct population for versus the KEYNOTE-189 regimen or the KEYNOTE-024 regimen, I think you would see increased uses of those regimens.”

Moreover, the combination of nivolumab and ipilimumab plus platinum-doublet chemotherapy received regulatory approval in May 2020 for the frontline treatment of patients with metastatic or recurrent NSCLC without EGFR or ALK alterations, based on findings from the phase 3 CheckMate-9LA trial. 

Although the interim analysis demonstrated a 3.4-month improvement in overall survival (OS) with the triplet versus chemotherapy alone, Sabari explained that more data, specifically with regard to OS, are needed before the regimen is incorporated into practice. 

In an interview with OncLive® during the Institutional Perspectives in Cancer webinar on Lung Cancer,Sabari, assistant professor, Department of Medicine, NYU Langone’s Perlmutter Cancer Center, discussed the current management of patients with newly diagnosed stage IV NSCLC, the impact of osimertinib’s (Tagrisso) entrance into the adjuvant setting, and ongoing research efforts evaluating combination regimens and biomarkers of response to therapy.

OncLive®: Could you discuss some of the pivotal immunotherapy trials in the frontline setting?

Sabari: One of the critical things to think about is the stage of disease. Once you confirm that a patient has stage IV disease, you have to understand the molecular status of the patient, including EGFR, ALK, and ROS1 status, as well as PD-L1 expression. In the driver-negative population, we're looking at PD-L1 expression to help guide therapy.

KEYNOTE-024 was the first study to move immunotherapy into the frontline setting. The study evaluated pembrolizumab versus chemotherapy in the frontline setting in patients with PD-L1 expression greater than 50%. This was a major study, the results of which led to the FDA approval of pembrolizumab in 2016. Now we have 3- or even 4-year OS data showing a significant [improvement in] OS.

From that point on, the question became: How do we improve on this? The KEYNOTE-189 trial evaluated the combination of pembrolizumab and platinum-doublet chemotherapy versus platinum-doublet chemotherapy alone in all-comers. The results were published in 2018, showing a significant improvement in OS in patients who received the combination. This regimen became the standard of care.

There are a few caveats to that. If a patient has a prior history of autoimmune disease, we caution against the use of immunotherapy. Co-alterations or driver alterations might steer us away from using pembrolizumab monotherapy. For example, for my KRAS patient population with co-alterations in SDK11 or KEAP1, even if their PD-L1 expression is high, I tend to still use the KEYNOTE-189 regimen because we know that the response rate and the durability of response for patients with those alterations who receive single-agent PD-1 inhibition is relatively low.

There’s also the IMpower150 trial, which was a large phase 3 study looking at carboplatin, paclitaxel, bevacizumab—a VEGF inhibitor—and atezolizumab, a PD-L1 inhibitor. The study was positive, but the results were not as robust as the KEYNOTE-189 regimen. The IMpower150 regimen is FDA approved, but I don't use it in my patient population. There is some rationale for its use in the EGFR and ALK patient population, according to the post-hoc analysis. After those patients have exhausted all targeted therapeutics, there is some rationale for VEGF inhibition with the IMpower150 regimen.

Finally, the CheckMate-227 trial evaluated ipilimumab and nivolumab in the frontline setting. Here too, the data was positive compared with chemotherapy. The results of the trial led to May 2020 approval of the combination in the frontline setting. I don't have a great patient population to use the combination in the frontline setting. There is no real biomarker to select patients for that regimen. It is a chemotherapy-free regimen, but there is increased toxicity to using a CTLA-4 inhibitor in combination with a PD-1 inhibitor.

The post-hoc analysis from IMpower150 showed the potential benefit of using immunotherapy following EGFR-targeted therapy. With the results of the ADAURA trial, is there any data to suggest that patients who receive adjuvant osimertinib could receive immunotherapy in the metastatic setting as their first-line therapy?

That’s a very controversial topic. We have retrospective data looking at patients who received immunotherapy first and then go on to get osimertinib with high levels of immune-related adverse effects (irAEs), such as colitis and hepatitis. The question is: In the reverse, is that true as well if you received osimertinib first and then went on to get immunotherapy in the frontline setting at the time of recurrence or metastatic disease? The answer is: We don't have the data.

We do know that combinations of those drugs are toxic. The concern there is all the irAEs. It does however open up a strategy for a patient who has an early-stage lung cancer, stage II/III disease who goes on osimertinib in the adjuvant setting, post-chemotherapy, which is standard of care, and is stable on therapy for 2 to 4 years and then has progression of disease. The question is going to be: What is the correct first-line regimen?

I hope we’ll have a better therapy than osimertinib at that time, one that targets MET amplification, or C797S resistance mechanisms. I would prefer to use that approach over an immunotherapeutic approach in the frontline setting. If we don't have those drugs available at that time, using a combination strategy of immunotherapy and chemotherapy might be an option, but I worry about toxicity.

How will the results of the CITYSCAPE and CheckMate-9LA trials affect the current landscape in the frontline setting?

The CheckMate-9LA trial tested the combination of ipilimumab and nivolumab plus chemotherapy. Everyone worries about potential toxicity, but the addition of chemotherapy didn't seem to add significant toxicity to what we already know of ipilimumab. The study was positive. I have to see more data, specifically OS data in order to integrate that regimen into my clinical practice. However, you can imagine a patient population that is very fit, very young, has very good performance; that is where you would consider using that regimen in the frontline setting.

The CITYSCAPE study was a very interesting study looking at atezolizumab in combination with a TIGIT monoclonal antibody. We've seen prior data with TIGIT antibodies from Merck, and other companies that did not look that impressive. However, in a subset of patients with high PD-L1 expression, the response rate and the progression-free survival seemed to be pretty robust. The ongoing phase 3 SKYSCRAPER study is looking at this in a randomized fashion. It will be very interesting to see how the data play out.

We have PD-L1 as a biomarker of response to immunotherapy. Is there any insight into other potential biomarkers of response?

This is sort of the Achilles heel of the immunotherapeutics world right now is that we don't have any great biomarkers outside of PD-L1. We know that the higher PD-L1 expression patients have, the better they do with immunotherapy. We thought that tumor mutational burden (TMB) might be a potential biomarker. However, in 2018, the data from CheckMate-227 indicated that TMB was a prognostic but not a predictive biomarker of response to a particular therapeutic. TMB has really lost a lot of momentum.

Other companies have made signatures. For example, atezolizumab has a T-effector gene signature. Other approaches are looking at conglomerate biomarkers. To date, we don't have any great prospective data to support one biomarker over another outside of PD-L1 expression. PD-L1 expression remains the one sort of verified biomarker that we have.

Would you like to highlight anything else from your presentation?

Other trials are ongoing at NYU Langone Health, in particular the KRAS G12C study with AMG 510 as well as with MRTX849. That's a really exciting space right now. These are patients who are pretreated with chemotherapy and immunotherapy or immunotherapy who have a KRAS G12C alteration. Broadly, we've seen about a 50% response rate.

We're also looking at potential combination strategies. We have a cohort study open, looking at SHIP2 inhibition in combination with KRAS G12C inhibition. [KRAS] was thought to be undruggable in the past, but we’re seeing really robust responses [with some of these agents].

What is your take-home message for your colleagues?

Molecular testing in all patients is critical. Testing is going to help guide first-line therapy, improve quality of life and OS. If you know a patient has a driver alteration, it is critical to match that patient with that targeted therapeutic either on trial or off trial. If the patient does not have a targeted alteration, you should look at PD-L1 expression to help guide whether to use immunotherapy alone, which potentially has a lower adverse effect profile than immunotherapy in combination with chemotherapy.


Reck M, Ciuleanu TE, Cobo Dols M, et al. Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment (tx) for stage IV/recurrent non-small cell lung cancer (NSCLC): CheckMate 9LA. J Clin Oncol. 2020;38 (suppl; abstr 9501). doi:10.1200/JCO.2020.38.15_suppl.9501