Lung Cancer Field Targets Immunotherapy, Acquired Resistance, and Genomic Testing

Suresh S. Ramalingam, MD, FACP, FASCO

To build on the advances that have been made in lung cancer over the past several years, researchers have their sights set on improving the efficacy of immunotherapy with novel approaches, the ability to overcome acquired resistance to targeted therapies, and the accessibility to molecular testing and approved targeted therapies, said Suresh S. Ramalingam, MD, FACP, FASCO.

“We have seen substantial improvement in overall outcomes for patients with lung cancer in the past decade. There is an annual 2% to 4% decline in deaths related to lung cancer in the United States. Advances in treatments have been one of the major contributors to that. We’re making progress, and progress is coming by delivering personalized treatment approaches to patients based on biomarkers,” Ramalingam said in an interview with OncLive® following a State of the Science Summit™ on lung cancer.

In the interview, Ramalingam, executive director, Winship Cancer Institute of Emory University, professor and Roberto C. Goizueta Distinguished Chair for Cancer Research, Department of Hematology and Medical Oncology, Emory University School of Medicine, discussed current applications for frontline immunotherapy and targeted therapy for non–small cell lung cancer (NSCLC) and the current management of small cell lung cancer (SCLC).

OncLive^®: How can patients with NSCLC derive the most benefit from therapy in the current era?

Ramalingam: Targeted therapies are making a difference in improving the lives of patients with oncogenic driver mutations in advanced NSCLC. Now, we’re beginning to use EGFR-targeted therapy in patients with early-stage, EGFR-mutant NSCLC. For patients to derive these benefits, it’s important that molecular testing be incorporated into the diagnostic algorithm for NSCLC, specifically for nonsquamous histology. It is our recommendation that patients have NGS [next-generation sequencing] at the time of diagnosis to make sure they can benefit from appropriate targeted therapies if they have a driver mutation. There are at least 9 targets in lung adenocarcinoma that have FDA-approved, targeted therapy approaches.

Often, tissue availability can be a rate-limiting step, and if that is the case, using plasma-based circulating tumor DNA testing can be helpful in achieving a molecular diagnosis. Sometimes a repeat biopsy may be necessary, but regardless, whatever it takes, getting a complete molecular diagnosis is the most important step in the diagnostic workup [of patients with lung cancer].

In which situations would you opt for a repeat biopsy?

When patients undergo diagnostic testing, sometimes the initial specimen acquired may be insufficient to conduct molecular testing or to complete all the testing that we would require for patients to go through. In those situations, the first next step could be to do a liquid biopsy to see whether you can find a driver mutation. If you find an actionable driver mutation on liquid biopsy, that is sufficient grounds to start targeted therapy.

On the other hand, if the liquid biopsy does not yield a diagnosis, one should not assume that there is no molecular target for that patient. That is a situation where, if possible, we would recommend a second biopsy to obtain enough tissue to do molecular testing.

Your presentation focused on EGFR-directed therapy. What have been some of the most notable advances in this setting?

My presentation focused on EGFR-targeted therapies in advanced and early-stage NSCLC. The third-generation EGFR inhibitor osimertinib [Tagrisso] is used for frontline therapy and adjuvant therapy in patients with exon 19 [deletions] and [exon] 21 [insertions]. We’re learning more about how to manage acquired resistance. There are some promising new approaches that are being developed that are currently in clinical trials. For now, chemotherapy remains the go-to approach in patients who have disease progression on osimertinib. 

For patients with EGFR exon 20 insertion mutations, there are now 2 drugs approved: amivantamab-vmjw [Rybrevant] and mobocertinib [Ekivity]. These agents provide modest benefits to patients and have now become new treatment options for this subgroup of patients. We’re making progress, and the next step is managing and overcoming acquired resistance to EGFR inhibition.

For patients who develop resistance to EGFR TKIs, what avenues are open to investigators?

There’s a lot of interest in tailoring therapy for acquired resistance to EGFR inhibition, based on the underlying molecular mechanisms that lead to the resistance. Testing for acquired resistance mechanisms at the time of progression is increasingly being adopted in the clinic. We also have to keep in mind that some patients with oligoprogression can continue with targeted therapy with appropriate management of local sites of progression.

Patritumab deruxtecan is an antibody-drug conjugate that targets HER3. HER3 is activated as one of the acquired resistance mechanisms [to EGFR TKIs]. There have been clinical investigations to evaluate patritumab deruxtecan in patients with acquired resistance to EGFR TKIs. The single-agent response rate with patritumab deruxtecan in the acquired resistance setting appears to be between 35% and 40%, with a median progression-free survival [PFS] of about 8 months. These are promising results and need validation and verification in larger cohorts of patients, which is currently being undertaken.

There are also other events that happen such as fusion abnormalities that are mechanisms of acquired resistance. Case reports of combining specific inhibitors, such as RET inhibitors in patients who develop RETfusions as the acquired resistance mechanism, have shown clinical benefit. We’re going to start seeing even acquired resistance sub-segmented into groups based on the mechanisms [at play] and develop appropriate therapies [for those patients]. As the numbers of patients become smaller and smaller, conducting large scale phase 2 and phase 3 trials will not be easy.

Is there rationale to study combination approaches with osimertinib in the frontline setting as well?

There is a lot of interest in studying combinations with osimertinib in the frontline setting to improve the effectiveness of osimertinib and delay the emergence of acquired resistance. One study that we’re keeping our eyes out for is the FLAURA2 study [NCT04035486] that’s combining chemotherapy with osimertinib. There’s also a study looking at amivantamab and lazertinib as first-line therapy in EGFR-mutated patients. There is clinical rationale to combine patritumab deruxtecan with osimertinib in the frontline setting, and those efforts are under way. The space is rich, and we’re eagerly awaiting results to see what sort of combination approaches may help extend the benefit of osimertinib.

Conor E. Steuer, MD, of Winship Cancer Institute of Emory University, discussed the use of immunotherapy in advanced NSCLC. How is PD-L1 being used to guide treatment recommendations in this setting?

Immunotherapy is associated with long-term survival in a subset of patients with NSCLC. The use of immunotherapy is primarily driven by PD-L1 expression levels as a biomarker. Patients with a driver mutation should get targeted therapy. Patients without a driver mutation who have high PD-L1 expression greater than 50% are treated with pembrolizumab [Keytruda] or atezolizumab [Tecentriq], or even cemiplimab-rwlc [Libtayo] as monotherapy.

If patients have less than 50% PD-L1 expression, one could use chemotherapy plus immunotherapy, or one could use the combination of ipilimumab [Yervoy] and nivolumab [Opdivo]. Recently, 2 cycles of chemotherapy with ipilimumab and nivolumab become an approved regimen. For patients with low or negative PD-L1 expression, the immunotherapy combination approaches seem to be of interest.

Treatment decisions have to be individualized to patients. We use biomarkers to the best extent possible, but all we have is PD-L1 expression level as a biomarker. Beyond that, using patient-specific factors such as the disease burden, symptomatology, comorbid conditions, and patient preferences all should drive our decision making. At the end of the day, sitting in front of the patient and discussing all options and coming up with the best option that would help that patient is the best approach.

Although treatment is individualized, are there certain regimens that you gravitate towards in practice?

For a patient with PD-L1 expression greater than 50%, checkpoint inhibition as monotherapy appears to be appropriate and sufficient for most patients. Occasionally, if the disease burden is high and the symptom burden is high, one could consider using chemotherapy in combination with immunotherapy. For patients with PD-L1 expression between 1% and 49%, using chemotherapy plus PD-1 inhibition or 2 cycles of chemotherapy plus ipilimumab/nivolumab seems appropriate. For patients with PD-L1 negativity, which is approximately one-third of patients, I prefer to use the combination of the CTLA-4 and PD-1 inhibitors based on promising and robust data in the CheckMate-227 [NCT02477826] trial for this patient population.

Jennifer W. Carlisle, MD, of Winship Cancer Institute of Emory University, discussed targeted therapy is NSCLC. What target has seen the most progress in recent years?

We have approved options for patients with ROS1, RET, NTRK, and more recently KRAS G12C mutations. KRAS G12C is a subtype of the KRAS mutation. The KRAS G12C mutation is seen in approximately 12% to 13% of lung adenocarcinomas. We have an approval in the form of sotorasib [Lumakras], which is an orally administered therapy given to patients with KRAS G12C mutations after they have progressed on a prior platinum-based regimen. It has a response rate of approximately 40% and a median PFS of approximately 7 months. This is a good next step as targeted therapy and a breakthrough in a group of patients for who we have not had targeted therapies for a very long time.

Adagrasib is another KRAS G12C inhibitor that is in clinical trials and is likely to enter the clinic in the upcoming months or year. We’re making progress in that area. There is a lot of interest in non KRAS G12C–mutated patients, and we’re beginning to see some new agents and new trials enter the clinical space for this group as well.

For example, KRAS G12V, which is another common mutation, has been difficult to treat. There is at least one trial that involves a combination strategy of FAK inhibition plus combined BRAF/MEK inhibition that we’re pursuing at Winship in partnership with other institutions. It’s early days, but that combination seems to have activity in KRAS G12V–mutated patients. There is also development in the KRAS G12D–mutated patients where specific agents are beginning to enter the clinic in the form of phase 1 studies. We’re seeing a lot of exciting activity in this group of patients. Investment in clinical investigations is critical, because these promising discoveries cannot get into the clinic without testing them in clinical trials.

Ticiana Leal, MD, of Winship Cancer Institute of Emory University, discussed management of SCLC. What research are you tracking in this space?

SCLC has seen some improvements in therapeutic approaches in the past few years. We now use checkpoint inhibition in combination with chemotherapy in the frontline setting. Lurbinectedin [Zepzelca] has been approved in the refractory or relapsed setting. The big question is: What is the next step? Combination approaches that combine inhibition of TIGIT with PD-L1 inhibition and chemotherapy are in phase 3 clinical trials and we hope to see results of this study soon. There’s also a lot of interest in another approach with a drug called tarlatamab, a bispecific antibody that targets CD3 and DLL3, which is a relevant target in SCLC. This agent has shown some promising activity in early phase 1 studies and is now being conducted for expanded groups of patients with relapsed/refractory SCLC.

Finally, we’re beginning to look at SCLC as subsets based on the transcriptional profile of the tumor. Although it’s early days for incorporation into routine clinical setting, this approach has the potential to identify specific targets and approaches for each of these major transcriptional subtypes of SCLC.