Expert Discusses Durvalumab and Future of Immunotherapy in NSCLC

Neil Morganstein, MD

Following the encouraging overall survival (OS) data with durvalumab (Imfinzi) in patients with unresectable stage III non—small cell lung cancer (NSCLC) who did not have disease progression after concurrent chemoradiotherapy, the next steps include biomarker research and moving the agent into earlier treatment settings, according to Neil Morganstein, MD.

In updated findings of the phase III PACIFIC trial, which was the basis for the FDA approval of durvalumab in this setting, the 2-year OS rate in the durvalumab group was 66.3% compared with 55.6% for placebo.

Updated analyses regarding progression-free survival (PFS) were similar to those previously reported, with a median duration of 17.2 months in the durvalumab arm and 5.6 months in the placebo group. Median time to death or distant metastasis was 28.3 months for patients treated with the PD-1 inhibitor versus 16.2 months for those who received placebo.

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In an interview at the 2018 OncLive State of the Science Summit on Advanced Non—Small Cell Lung Cancer, Morganstein, assistant medical director of the Cancer Center at Overlook Medical Center, discussed the intriguing PACIFIC results and the future role of immunotherapy in NSCLC.Morganstein: The PACIFIC trial looked at more than 700 patients with stage III NSCLC. They had to receive chemotherapy and radiation therapy. This was an international trial that randomized patients to either durvalumab or placebo. The initial endpoint was PFS, and we saw dramatic results here. There was over a 1-year difference in PFS.

Are there any planned or ongoing trials seeking to answer remaining questions with durvalumab?

More recently, there was an updated analysis published in the New England Journal of Medicine that showed a clear OS benefit was seen across most tumor types. The question of PACIFIC is now well-answered. In patients with stage III NSCLC who have received chemotherapy and radiation therapy, the standard of care has become adjuvant durvalumab. An interesting question that is currently being asked is, "How about durvalumab or other PD-1/L1 antibodies in earlier settings?"

Could other immunotherapies be slotted in for durvalumab?

If a patient progresses on durvalumab, what happens next?

Is there a potential for immunotherapy in patients who progress on concurrent chemotherapy?

What neoadjuvant therapy trials are currently ongoing?

Where would you like to see research moving forward?

This is being looked at in the ALCHEMIST trial. In my opinion, the much more interesting area will be the neoadjuvant approach to the utilization of PD-1/PD-L1 antibodies. This is particularly interesting because you have a higher tumor mutational burden, so maybe you should introduce a higher immune response prior to taking out the tumor. Durvalumab was the drug studied. Given the extremely exciting results, I don't think a different drug would be recommended at this time.If patients progress on durvalumab or immunotherapy, we have to step back and look at their mutational analysis. Are there any targeted options for the patients? It all depends on the timing and the type of relapse they have. In those patients who progress on chemoimmunotherapy and become metastatic, that's essentially what would happen. You would then treat them like any other patient with metastatic disease. I'm not sure durvalumab would be the first-line therapy in that case. Certainly, it could be considered, but you would use chemotherapy with or without immunotherapy or targeted therapies. There are published data looking at early, small phase II trials that are more proof-of-concept studies and are looking at immunotherapies prior to surgery. They are looking at the pathologic complete response rates on the surgical specimens. In other tumor types, we are seeing that this holds a lot of promise. We'll get a better idea of the efficacy of these treatments [in lung cancer] as we move forward.Although we're doing better—and PACIFIC was an immense step forward—at least half of these patients had recurrent disease. The next step has to be identifying the patients who will benefit from immunotherapy. How do we characterize them based on molecular phenotypes? We then would try to hone in our drugs based off of that. We know there are different markers for many different tumor types that can predict response to immunotherapy.

What is the biggest challenge in treating patients with NSCLC?

By looking at something like PD-L1 expression, we originally thought it was beneficial; however, now it appears to be a poor biomarker. There needs to be more out there that can differentiate patients. Hopefully, we could also distinguish the patients who will get severe side effects from immunotherapies. The biggest challenge in treating patients with lung cancer in general is that the vast majority still relapse and become metastatic. The vast majority of patients still pass away from the disease. Although we've made tremendous strides, it's still very fatal, unfortunately, in stage IV disease. To move these advances further, we need to be able to predict ahead of time the patients that will derive the most benefit.

The concept of dual immunotherapies is out there. Immunotherapy, in general, is still in its infancy. It's an emerging field.

Antonia S, Villegas A, Daniel D, et all. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC [published online September 25, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1809697