Simon Says Immunotherapy Combo Regimens on Horizon in NSCLC

Danielle Bucco

George R. Simon, MD
George R. Simon, MD
Immunotherapy continues to show single-agent efficacy in non–small cell lung cancer (NSCLC) and is now being investigated in combination regimens to further improve patient outcomes.

Frontline treatment with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) is currently being assessed in the phase III CheckMate-227 study (NCT02477826). This 4-arm study is comparing nivolumab versus nivolumab plus ipilimumab versus nivolumab plus platinum-doublet chemotherapy versus platinum-doublet chemotherapy alone. This trial is currently accruing patients with stage IV NSCLC and will be completed in 2020.

“This combination is being investigated in multiple other diseases across the board, including small cell lung cancer (SCLC) and mesothelioma and other non-thoracic diseases,” said George R. Simon, MD.

In another realm of the lung cancer spectrum, the addition of osimertinib (Tagrisso) to the EGFR–positive armamentarium has garnered excitement among physicians, most recently with the phase III results of the FLAURA trial. Here, osimertinib’s benefit in the frontline setting was showcased in comparison to the first-generation EGFR inhibitors gefitinib (Iressa) and erlotinib (Tarceva). The agent is currently FDA approved in the second-line setting for patients who harbor the T790M resistance mutation, but now has a breakthrough therapy designation with the FDA to be used as a frontline agent for EGFR-positive patients.

In an interview during the 2017 OncLive® State of the Science SummitTM on Advanced NSCLC, Simon, a professor in the Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discussed advancements being made with immunotherapy for the treatment of NSCLC.

OncLive: Immunotherapy has had a significant impact on the NSCLC paradigm. What did you highlight in your talk?

Simon: We discussed targets beyond PD-1, PD-L1, and CTLA-4. There are newer emerging targets, including some of the novel checkpoint inhibitors that various investigators are working on in early-phase studies. Now, these newer targets are being incorporated in combination studies with existing checkpoint inhibitors. In my presentation, I also discussed how PD-1 and other checkpoint inhibitors will be combined with vaccines and cytokine therapy in various combination clinical trials.

What are some combination trials that are showing promise?

The farthest along is a PD-1 plus CTLA-4 combination. That has already been studied in melanoma. It is extensively being studied in NSCLC and SCLC, as well as mesothelioma. Another combination that is being evaluated is an OX40 agonist in combination with a PD-1 inhibitor. There are some other combinations that are still in early stages of development. We are looking for their phase I dose and, once we know that, then researchers will proceed to phase II studies and combination studies. 

How could we incorporate durvalumab (Imfinzi) more into this paradigm?

Durvalumab is a PD-L1 inhibitor that, in the recent PACIFIC trial, demonstrated improved progression-free survival (PFS) after definitive concurrent chemoradiation in patients with stage III NSCLC. Although durvalumab demonstrated statistical improvements in PFS, it is not currently FDA approved for this indication. However, the FDA approval is in process and is awaited. 

If durvalumab were to be approved, how would it impact the treatment landscape?

The approval of durvalumab would radically change the treatment landscape. The current standard of care is giving concurrent chemoradiation for patients with stage III NSCLC and that is it. Now, based on the PACIFIC data, after completing concurrent chemoradiation, we would proceed to 1 year of consolidation durvalumab, with durvalumab being given every 2 weeks.

What other immunotherapy regimens are coming down the pipeline worth mentioning?

Immunotherapy is being combined with chemotherapy. There is a combination that has already been approved, which is pembrolizumab in combination with carboplatin and pemetrexed. As we said before, nivolumab and a CTLA-4 inhibitor, ipilimumab, is being studied in the first-line setting in NSCLC. This is the CheckMate-227 trial that currently is enrolling and we have not seen the data from that yet. This combination is being investigated in multiple diseases across the board, including SCLC, mesothelioma, and other non-thoracic diseases. 

What does the future of immunotherapy in NSCLC look like to you?

The landscape is going to change, as we are just seeing the tip of the iceberg. We will be working with the new novel checkpoint inhibitors and novel combinations for the currently existing checkpoint inhibitors. We may have to learn their resistance mechanism to the checkpoint inhibitors as many responding patients will eventually progress. We are attempting to understand what those resistance mechanisms are and trying to understand how to best mitigate those resistance mechanisms. Many of these studies will be ongoing and will shed light in future studies.

You also discussed EGFR-mutated lung cancer at this meeting. What is the biggest unmet need for these patients?

EGFR has essentially been impacted by the FLAURA study with osimertinib (Tagrisso), showing a dramatic improvement in PFS compared with the existing standard gefitinib or erlotinib. Eventually, all the patients will progress on osimertinib. We will have to identify the resistance mechanism to osimertinib. We may have to [develop] new drugs to combat those resistance mechanisms once we have identified them. That is the first obstacle to tackle.

There is a second layer of EGFR mutations that are not the classic immune EGFR mutations, such as exon 19 deletions. We do not have good drugs for those—particularly EGFR duplications for which currently we are using afatinib (Gilotrif). For patients with EGFR insertions, we do not have good [agents]. Those patients would benefit from any available clinical trials. 

The last couple of years have significantly changed lung cancer treatment with the explosion of immunotherapy and targeted agents. What’s next?

There is room for significant optimism in the current lung cancer therapeutic landscape. Newer drugs are showing improvements to PFS over older, existing drugs, which is a dramatic improvement. We are now seeing PFS pushing 2 years, and overall survival is now pushing 3 to 5 years. The lung cancer landscape has dramatically changed over the last decade or so and we are still scratching the surface. There are new data to come and more studies to be conducted, which will increase our understanding to optimally treat patients with advanced NSCLC.
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