Neoadjuvant Immunotherapy Being Investigated in Early-Stage NSCLC

Jae Y. Kim, MD

Pivotal results from the phase III PACIFIC trial were practice-changing for patients with stage III non—small cell lung cancer (NSCLC) who received the PD-L1 inhibitor durvalumab (Imfinzi) following platinum-based chemoradiation. Now, investigators are exploring the effects of neoadjuvant immunotherapy regimens in early-stage patients.

“Checkpoint inhibition has been shown to be effective in patients with metastatic lung cancer, but its role in earlier-stage lung cancer, particularly for patients who were treated surgically, is really unknown at this point,” said Jae Y. Kim, MD.

In the multicenter, open-label, single-arm, phase II LCMC3 trial conducted by the Lung Cancer Mutation Consortium, researchers are evaluating the safety and efficacy of neoadjuvant and adjuvant treatment with atezolizumab (Tecentriq) in patients with resectable NSCLC (NCT02927301). In the study, neoadjuvant therapy will consist of two 21-day cycles of atezolizumab. Then, following surgery, adjuvant therapy will include up to 12 months of atezolizumab in those who demonstrate clinical benefit with neoadjuvant therapy. The primary endpoint will be major pathologic response.

OncLive: What type of data do we have thus far exploring immunotherapy in early-stage lung cancer?

Kim, chief of Thoracic Surgery, City of Hope, shed light on developments with checkpoint inhibition in patients with resectable NSCLC in an interview during the 2017 OncLive^® State of the Science Summit^TM on Advanced Non—Small Cell Lung Cancer.Kim: So far, there have been a couple of phase II trials that have looked at CTLA-4 blockade as well as PD-1 inhibition for patients who have gone on to surgery. These have been neoadjuvant trials; the information of the trials has shown that immune checkpoint inhibition is safe for surgical patients, so the patients have gone on to surgery without major complications. For the most part, the surgery was not delayed by the immunotherapy.

In 1 of the trials, 2 surgeries were delayed due to some toxicity from immunotherapy, but they were ultimately able to undergo surgery. Currently, the Lung Cancer Mutation Consortium, which City of Hope is part of, is conducting a trial looking at immune checkpoint inhibition as a neoadjuvant therapy. We're looking at atezolizumab, so patients are getting 2 cycles before surgery.

Can you provide some more detail on this patient population?

The main endpoint of the trial is major pathological response, which is kind of a new thing that we're looking at in neoadjuvant trials in lung cancer. Studies have shown that major pathologic response correlates well with overall survival (OS). It’s sort of a surrogate endpoint, and the nice thing about looking at this type of surrogate endpoint is that you can potentially detect a signal with fewer patients than if you were to look at the endpoint of OS. Also, you can get results a lot faster, particularly in a surgical population.These are, for the most part, resectable patients. Although one of the trials, which looked at ipilimumab (Yervoy) in a neoadjuvant setting, chose patients who were borderline resectable. In that trial, roughly half of the patients did not undergo surgery. But other trials, including ours, is looking at patients who have surgery planned. For the most part, these are patients in whom a surgeon has deemed resectable.

What are the current overarching challenges in this setting?

Therefore, for those patients who are receiving neoadjuvant immunotherapy, what we are doing is we are looking at clinical response radiographically, but then as long as the patients do not progress to the point where surgery is no longer possible or they haven’t had toxicities that prohibit surgery, we move forward with planned operation. There are a lot of unknowns. We know that immunotherapy is effective for a lot of patients in the metastatic setting, and it will be effective for a lot of patients in the perioperative or preoperative setting. However, exactly which drugs, which combination of therapies, and how best to deliver the therapies are all questions that need to be answered.

What immunotherapy combinations might have potential in this setting?

Whether immunotherapy alone should be used, immunotherapy combined with standard cytotoxic chemotherapy, whether you should continue immunotherapy postoperatively, for how long to continue the immunotherapy, and knowing what biomarkers can best predict which patients will benefit most from these therapies are all questions that need to be answered. What is exciting is this idea of using major pathologic response as a surrogate endpoint. It allows us to answer many of those questions in a way that, if you were looking at OS, would take a lot longer and may not even be feasible. In the metastatic setting, we are looking at pembrolizumab (Keytruda) with platinum-based chemotherapy. Looking at that combination, that would be one to naturally look at in the neoadjuvant setting, as well. However, there are other drugs that are also being investigated in combination with immunotherapy. The neoadjuvant setting really offers an opportunity to investigate novel combinations of drugs.

It is almost like a window-of-opportunity study where you can look at differences in major pathologic response, and determine whether you want to move forward with a large study. Even things such as PARP inhibitors have been looked at as ways to potentially potentiate the effects of immunotherapy. They might be drugs that could increase the neoantigen burden, because tumor mutation burden has been shown to correlate with response to certain immunotherapies. Therefore, if there are small molecular drugs, that could increase the tumor mutation burden and it could help immunotherapy work more effectively.

In your opinion, what have been the top advances in the field of lung cancer over the past year?

One interesting trial that is open at University of California, San Francisco, is a study looking at neoadjuvant immunotherapy in combination with stereotactic radiotherapy. This is something that is being looked at for patients who have stage III lung cancer—the combination immunotherapy with radiotherapy—but it is also looking at radiotherapy as a way to increase that tumor mutation burden—or at least the antigen burden. Obviously, the adoption of immunotherapy and the widespread implementation of immunotherapy as frontline treatment for metastatic disease has really been the main thing. For surgical patients, we are still conducting the ALCHEMIST trial, but the randomized trial in China that looked at gefitinib (Iressa) as adjuvant therapy for patients with EGFR-mutant lung cancer was the first positive trial of a biomarker-driven targeted therapy in earlier-stage patients. For surgical patients, having a trial that was positive is really exciting and gives us some optimism for the other arms of the ALCHEMIST trial.