Socinski Says Immunotherapy, Targeted Therapy Have Altered Outlook in NSCLC

Mark A. Socinski, MD

An elevated understanding of the biology of lung cancer has allowed researchers to develop highly effective immunotherapy regimens and targeted agents, said Mark A. Socinski, MD.

Based on positive data from 3 pivotal studies evaluating the use of pembrolizumab (Keytruda) in the frontline setting in patients with non—small cell lung cancer (NSCLC), 2018 was a big year for this space. The PD-1 inhibitor has been approved by the FDA for use as a single agent and in combination with traditional chemotherapy regimens across squamous and nonsquamous histologies.

Practice-changing data with immunotherapy have also made their way into stage III disease. As a result of the phase III PACIFIC trial, the FDA approved the use of durvalumab (Imfinzi) in the treatment of patients with locally advanced, unresectable stage III NSCLC who have not progressed following chemoradiotherapy in February 2018.

Results showed a significant advantage in progression-free survival (PFS) with the immunotherapy agent; the median PFS was 17.2 months in the durvalumab arm versus 5.6 months in the placebo arm. Updated data showed that the 2-year overall survival (OS) rate in those who were given durvalumab was 66.3% compared with 55.6% for patients who received placebo.

However, acquired resistance to some of these novel regimens still poise a significant challenge, Socinski explained.

OncLive: How has the outlook for patients with lung cancer changed in recent years?

In an interview with OncLive at the 16th Annual Winter Lung Cancer Conference^TM, Socinski, the executive medical director at AdventHealth Medical Group, provided an overview of the current landscape for lung cancer treatment and highlighted where much-needed work still remains.Socinski: The outlook is much better assuming you utilize what I consider to be the standard of care today. In terms of stage IV disease, you need to define the molecular nature of the disease. Many of the lung cancers that we see have molecular drivers, and we have a growing list of oral targeted therapies. The other issue is the implementation of immunotherapy in accordance with PD-L1 testing. Given the expansion of the knowledge we have regarding the basic biology of the disease, we have figured out that we should be testing for mutations like EGFR, ROS1, and BRAF at the very least, but also for RET translocations, MET alterations, and HER2 [mutations]. Comprehensive genomic testing identifies patients who have targets that we can treat with therapy that is known to work better than standard chemotherapy in many situations.

How does the advent of novel treatment approaches affect some of the more conventional modalities, such as radiation therapy?

The biggest thing that we have accomplished in the last year or so has been bringing immunotherapy—which was typically used in the second-line setting—into the frontline regimens that are standard both in squamous and nonsquamous disease. We have seen real benefit in these patients. The outlook and prognosis for patients has rapidly improved over the last few years, based on the molecular observations as well as the incorporation of immunotherapy.It is still all about the basics. There are 2 things we have to get absolutely right. First is the diagnosis, which, in 2019, includes accurately knowing the histology as well as the molecular status—particularly in stage IV disease. The second thing we have to get right is the stage. If you define stage I, then that is the surgical stage; stage II is also surgical disease. Stage III is mostly chemotherapy and radiation; that has not changed.

However, we now incorporate immunotherapy following the completion of radiation because we know it can lead to a survival advantage. Diagnosis and stage are very important because they inform the treatment approach for each patient.

Is there a role for immunotherapy in patients with driver mutations?

Most of the advancements we have made with regard to the targeted agents and immunotherapies have been in stage IV; however, immunotherapy following chemotherapy/radiation has shown promise in the PACIFIC trial. This was a huge step forward. There are also several adjuvant trials ongoing, both in [populations with driver mutations] and with immunotherapy [in patients without driver mutations]. All of us are enthusiastic about the data we are seeing with stage IV disease, and we are clearly now seeing an OS advantage in stage III disease, a setting where we had not used immunotherapy before.The data with immunotherapy in these patients have not been impressive. There is also the issue of the interplay between the use of immunotherapy and the safety of TKIs. Right now, in everyday practice, I view immunotherapy as sort of a last resort in these patients. I would consider it after exhausting TKIs and chemotherapy options, which still work. We have not dismissed chemotherapy with all this excitement about other types of treatment.

How do you choose between single-agent or combination immunotherapy for the frontline treatment of patients with squamous NSCLC?

Chemotherapy is still a vital part of our treatment; however, in these patients, immunotherapy has not quite risen to the challenge of improving outcomes. There are also safety issues, so I tend to steer away from using that approach in patients with driver mutations. I would not even use immunotherapy in combination with chemotherapy.The standard of care in lung cancer today is to measure PD-L1 expression. The KEYNOTE-024 study suggested that patients who [had PD-L1 expression] greater than 50% would derive greater benefit from pembrolizumab than standard chemotherapy. However, in that study, only 19% of patients had squamous carcinoma; it was a minority of patients, and if you look at those patients specifically, the answer to whether or not they had the same survival benefit as those with nonsquamous disease is not entirely clear. If you look at [patients with PD-L1 expression of] less than 50%, to me it is pretty clear that monotherapy is not an option and they should be treated with chemoimmunotherapy combinations.

Are there patients for whom their disease can be viewed as chronic?

Due to the small representation of squamous patients in the KEYNOTE-024 trial, many of the patients I have with squamous disease and greater than 50% PD-L1 expression would still be treated with combination therapy. We need to focus on controlling the disease, and generally, it’s better to do this with chemotherapy plus immunotherapy. I don't feel the same way about patients with nonsquamous histology.You can say this with many of the molecular subsets in which we are using oral TKIs—for instance, if a patient is diagnosed with either an EGFR or ALK alteration. [This can be said] particularly in the ALK population, where there is a growing list of active agents. When I was growing up, the median OS for patients with lung cancer was in the 8- to 10-month range. We know that with the current management in the ALK population, OS is in the 6- to 7-year range—that is 60-plus months versus what we assumed would be 8 to 10 months. Therefore, yes, there are some patients where we could say this.

What is the biggest unmet need in lung cancer?

There are also patients who have robust immunologic responses who are continuing beyond 10 years with their disease—even discontinuing therapy. Immune response has a memory component to it, so these patients are remaining in remission for quite some time. That, to me, is the definition of a chronic disease: living with the disease for many years with a normal quality of life.Today, the biggest unmet need is understanding the resistance mechanisms. We have drugs that can be highly effective for a certain period of time, so the question is, why doesn't this benefit last? What happens in the tumor that makes what was once a highly effective drug no longer effective? We had a very nice story in the EGFR-positive patients with regard to T790M. This was determined to be why the first- and second-generation TKIs were ultimately failing, so we developed osimertinib (Tagrisso). Now, we are using osimertinib in the frontline setting because it is better than the other drugs, but we don't have a clear picture as to what is driving resistance to osimertinib; it’s a pretty murky situation right now.

We also don't understand the mechanisms of resistance to immunotherapy. Why don't patients initially respond, and if they respond, why do they progress? Figuring out those answers will allow us to develop more effective strategies for [treating patients with] those resistance mechanisms.

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

<<< View More from the 2019 Winter Lung Cancer Conference