Neoadjuvant Immunotherapy Has Potential in Stage IIIa NSCLC

Nisha A. Mohindra, MD

Although advancements have been made in the treatment of patients with stage IIIa non—small cell lung cancer (NSCLC), there is still debate what the optimal therapy is and when it should be administered, according to Nisha A. Mohindra, MD.

“As immunotherapy is coming into lung cancer so rapidly, one [approach] that is now a very hot topic is to use these agents before resection,” said Mohindra, an assistant professor of medicine in the Hematology/Oncology Division of Northwestern University’s Feinberg School of Medicine.

This idea is being explored further in clinical trials, such as the phase II NADIM trial, where investigators are evaluating the effectiveness of the PD-1 inhibitor nivolumab (Opdivo) combined with carboplatin/paclitaxel as neoadjuvant therapy in patients with stage IIIa resectable NSCLC.

Preliminary data of this phase II study, which were presented at the 19th World Conference on Lung Cancer, showed an unprecedented complete pathologic response rate. Eighteen patients (75.0%) achieved complete response, while 24 patients (80.0%) had a major pathologic response, defined as <10% viable tumor cells in the resection specimen. These findings, Mohindra said, are encouraging for what will come next in this space.

“This space is evolving quickly, and I think there’s a lot to look out for,” Mohindra added.

OncLive^®: What are the optimal treatment approaches for patients with stage IIIa NSCLC?

In an interview with OncLive^® during the 2018 State of the Science Summit™ on Advanced Non—Small Cell Lung Cancer, Mohindra discussed the current treatment landscape, challenges faced in this patient population, and what she believes will be a focus for further research over the next decade.Mohindra: When it comes to the disease of stage IIIa NSCLC, the question is, “Is this someone who is potentially resectable?” In such a patient, there’s still uncertainty as to whether the approach should be chemotherapy followed by surgery versus chemoradiation followed by surgery. As such, the best approach is to always discuss the patient at a tumor board and get a consensus as to what should be done up front before you start any treatment.

Could you focus on some historic trials in this area?

For patients who can’t go through surgery or their disease is too bulky, we will do chemoradiation, and the durvalumab (Imfinzi) data collected from the PACIFIC trial have been exciting for those patients who are treated with chemoradiation.A lot of the historic trials asked different questions. We know that if you’re going to consider surgery in the stage IIIa space, you should start with some type of preoperative therapy. There have been a lot of questions, such as, “Does that include radiation? Does that include chemotherapy? Does that include both?

What are some of the ongoing trials in this space? Could you share more insight on the NADIM trial?

The trials, historically—and even to date—haven’t yet told us if there is an optimal strategy, so either is acceptable. It comes down to discussing as a group, for your tumor board, which strategy makes the most sense.There are a number of trials in this space. There’s the use of immunotherapy with chemotherapy, the use of immunotherapy alone, and the use of dual immunotherapy, and there is even consideration for trials using immunotherapy with chemoradiation at the same time.

For the NADIM trial, investigators looked at patients specifically with stage IIIa disease; it was a multicenter, single-arm trial, and all patients received 3 cycles of nivolumab and carboplatin/paclitaxel followed by surgery. They reported the results of the patients who had received the treatment and undergone surgical resection at the 19th World Conference on Lung Cancer, and it was exciting to see that all patients had, at least on imaging, radiographic response.

They achieved complete pathologic response in 60% of patients and major pathologic response in 80% of patients. Almost all patients had a complete resection, and there were few postoperative complications.

How do you see treatment for patients with stage IIIa NSCLC evolving over the next 5 to 10 years?

What are some challenges to focus on moving forward?

What is your message to providers working with patients who have stage IIIa NSCLC?

The data show that this treatment is well tolerated; there were no patients in this small cohort who had primary progression—that’s one thing you worry about when you’re doing a trial like this, is to make sure you don’t lose the opportunity to take someone into surgery if they would have been a surgical candidate earlier—and now, we have an unprecedented major pathologic response that has been reported, so that’s exciting.Immunotherapy is going to be another big player in this field and the one thing that’s going to be interesting is getting the drugs in earlier. There is some rationale to consider using these drugs when there’s still a tumor in place. If you’re looking at how the immune system is going to react, it may be important to have gross tumor there. As the field expands, it would be nice to see how these neoadjuvant trials with immunotherapy pan out and then also to see if this major pathologic response truly correlates with how patients do longterm.One challenge, specifically for this group of patients, is how heterogeneous they are. We’re still trying to figure out at the individual level what makes sense for each patient, individually. They’ve been lumped together, but there is a very wide array of tumors [classified as] stage III. It can either be a big tumor or it can be a tumor that has lymph nodes in the center of the chest involved. Going forward, the challenge will be trying to pinpoint if we can better identify which tumors need which types of therapy. There is a lot of controversy as to what the right treatment is for these stage IIIa patients, but they are best managed with a multidisciplinary approach. We do believe that more than one modality is probably needed for these patients. The exciting areas of research are the use and application of immunotherapy in this space.

Provencio M, Nadal E, Insa A, et al. Phase II study of neo-adjuvant chemo/immunotherapy for resectable stages IIIa non-small cell lung cancer—NADIM study–SLCG. J Thorac Oncol. 2018;13(10):S320. doi: 10.1016/j.jtho.2018.08.236.