Immunotherapy and Targeted Therapy May Represent the Future of Later-line Lung Cancer Treatment

Konstantinos Leventakos, MD, PhD

Through focused research and clinical trials, future immunotherapy advances in later lines of lung cancer may mirror those seen in earlier lines, as potential combinations of immunotherapy and other agents could demonstrate benefits even after first-line progression, according to Konstantinos Leventakos, MD, PhD.

“Immunotherapy and targeted therapies have totally changed our practice in the past few years,” Leventakos said in an interview with OncLive^® following an Institutional Perspectives in Cancer (IPC) webinar on lung cancer, which he chaired.

In the interview, Leventakos, a medical oncologist in the Department of Medical Oncology at Mayo Clinic in Rochester, Minnesota, shared key insights from the meeting, including the emergence of immunotherapy and lurbinectedin (Zepzelca) as beneficial treatments in small cell lung cancer (SCLC), where osimertinib (Tagrisso) fits into the non–small cell lung cancer (NSCLC) treatment paradigm, and progress on the horizon regarding cellular therapy and shared decision making in lung cancer treatment.

OncLive^®: What represents the biggest developments in SCLC treatment in the past few years?

Leventakos: We have 2 advances in SCLC. Firstly, we all agree that immunotherapy is part of the standard of care [SOC] in first-line treatment. That has been supported by 2 well-designed studies. All of us are now using immunotherapy when we start first-line treatment for extensive-stage SCLC. [Secondly,] In the recurrent stage, the big advancement is that lurbinectedin is now available as an additional agent that we can use.

Manish Patel, DO, of the University of Minnesota in Minneapolis, spoke about managing NSCLC with immunotherapy. As immunotherapy has become a frontline standard, how has its use affected how you monitor for progression and think about subsequent therapy for these patients?

Immunotherapy is the SOC for patients with newly diagnosed metastatic NSCLC that does not have targetable mutations. [We recommend that] all patients get immunotherapy, and then biomarkers like PD-L1 will help us decide how to use immunotherapy alone or in combination with chemotherapy or additional immunotherapy.

Regarding monitoring, sometimes there are complicated cases that we need to investigate, such as immunotherapy-related adverse effects or progression. Here, most of the interest is in [deciding what we’ll do next for] the patients who progress on immunotherapy. [At the IPC meeting,] we had the chance to discuss some of the strategies that we can [use when patients progress] on immunotherapy.

It is important to focus on clinical trials that investigate progression on immunotherapy [and study] some of the resistance mechanisms so that we can still have the benefit of immunotherapy in later lines. [We should] enroll patients to clinical trials that are looking to combine immunotherapy with newer agents in the second line.

Aaron S. Mansfield, MD, of Mayo Clinic, discussed the role of EGFR from the adjuvant to advanced settings. How has the adoption of osimertinib in the adjuvant setting affected its use in the advanced setting? Are there situations in which you would not recommend adjuvant osimertinib?

It is our practice to suggest adjuvant osimertinib in patients with resected, EGFR-positive lung cancer. We always have a discussion and perform shared decision making with patients. At Mayo Clinic, we’re developing a tool that will help patients make these decisions.

I would not suggest adjuvant osimertinib if [a patient has] mutations that are not within the FDA approval, meaning rare EGFR mutations, because we don’t have data [to support the agent’s use with those]. Additional discussion can happen in early stages, when we talk about the balance between benefits and risks from [osimertinib]. However, in general, we do suggest adjuvant osimertinib.

Regarding how [this agent] has changed treatment in the advanced setting, it’s too early to have much experience with the treatment in these patients if they progress. However, I can imagine that [I would start this treatment again] in a patient who has progressed a good amount of time after adjuvant osimertinib.

Could you elaborate on the tool that Mayo Clinic is developing to help predict patient benefits from adjuvant therapies?

We are honored to work with a team here at Mayo Clinic who have been working in shared decision making for many years. We’re developing a tool that will be a digital interface that patients and oncologists can use after surgery to see the recent benefits of adjuvant treatment. I briefly mentioned osimertinib, but given all the advances, we [are developing] this tool to also include decisions about chemotherapy and immunotherapy, depending on the genetic and PD-L1 results of the tumor. Right now, we’re developing a prototype, and we’re planning to use that in a clinical trial about shared decision making.

Tim Larson, MD, of Minnesota Oncology in Minneapolis, highlighted actionable targets in NSCLC. What are some key data sets regarding these targets?

The list of data sets is long right now, and we’re fortunate to have so many FDA approved agents. [Most importantly, we should] perform good comprehensive genomic testing, so that if [a patient has] 1 of these genomic alterations, we can use the appropriate targeted therapy.

We have much experience with many of the classic targets like ALK, ROS1, and BRAF, but we’re eagerly getting more accustomed with the advances in the KRAS G12C area, the EGFR exon 20 mutations, and more mutations that may be a little rarer. [Treating NSCLC] with the appropriate agent makes a difference for patients.

When performing genetic testing, does it matter whether a tissue or liquid biopsy is used?

The gold standard is tissue-based biopsy because it can give us more accurate information. However, there are cases where we might use liquid biopsy. I also know practices that use tissue-based and blood-based biopsies.

Julian R. Molina, MD, PhD, of Mayo Clinic, spoke about cellular therapies for lung cancer. Although traditionally, cellular therapies have been associated with hematologic cancers, what data have been seen so far with these therapies in lung cancer?

There are promising preliminary data regarding developing cellular therapies for lung cancer. The area of SCLC may be a little more ahead, but we are actively [conducting many] clinical trials that involve different types of cellular therapies for lung cancer, and we’re looking into activating these trials and [preparing] to enroll patients.

What ongoing lung cancer research is Mayo Clinic conducting?

We’re fortunate at Mayo Clinic to have quite an extensive portfolio of clinical trials. We have tried to have a balanced portfolio so that we have trials both for new therapies, targeted therapies, and SCLC. I am invested in a SCLC study that is looking at patients who are progressing on chemotherapy and immunotherapy. [We are investigating] second-line treatment [in these patients]. In this study, we are combining durvalumab [Imfinzi] with lurbinectedin. This study includes biopsy because we want to answer many questions about the genetics and the immune environment of SCLC when it progresses.

Another interesting study that we are involved in is [looking at] the progression of lung cancer after treatment with osimertinib. We have a clinical trial called [the phase 2] SAVANNAH trial [NCT03778229] that is looking into adding a MET inhibitor for patients who have MET overexpression.

What main message would you like to impart to colleagues from the IPC program overall?

It is always nice to get colleagues who work with lung cancer together. There are so many advances. Thoracic oncology has changed. The advances are so many that getting together and giving practical advice to all our colleagues is important. For this reason, I’m grateful to OncLive^® for [organizing] this meeting.