Targeted Therapies Bring “Proven Benefits” for Patients With EGFR Exon 20 Insertion+ NSCLC, Ramalingam Says

Suresh Ramalingam, MD, FACP, FASCO, a professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine, is the executive director of the Winship Cancer Institute and associate vice president for cancer, Woodruff Health Sciences Center, Atlanta, Georgia.

Board-certified in medical oncology, Ramalingam is nationally recognized as a physician-scientist and investigator and in the area of small cell (SCLC) and non-small cell lung cancer (NSCLC) and has conducted in clinical trials to study agents in both diseases. His current research areas involve the development of immune checkpoint inhibitors and improving outcomes for patients with EGFR mutation. Ramalingham spoke with The American Journal of Managed Care® (AJMC®) about the current treatment and research landscape involving EGFR Exon 20 insertion+ NSCLC.

This interview has been edited lightly for clarity.

AJMC®: What are some complications seen in individuals with EGFR Exon 20 insertion+ NSCLC?

Ramalingam: Let's first talk about the prevalence of EGFR insertion 20 insertion. As you know, EGFR mutations are seen in approximately 15% of lung cancer patients, specifically lung adenocarcinoma patients. Of those, nearly 85% of the mutations are exon 19 or exon 21, and the other 10% to 15% tend to be the uncommon mutations or atypical mutations. Among those, the insertion 20 mutations are seen in about 10% of the patients, so overall, insertion 20 seems to be approximately 3% of patients with lung adenocarcinoma, which is a substantial subset of patients when you look at the absolute numbers. These patients have disease that has specific characteristics that we see with some of the other oncogene addicted lung cancers. For instance, brain metastases seem to occur in a higher proportion of patients compared with patients without a driver mutation, and these patients—like most other lung cancer patients—unfortunately present with more advanced stages of the disease.

AJMC®:Please discuss the current treatment landscape for EGFR exon 20 insertion+ non-small cell lung cancer, and perhaps include some of the most common side effects that are seen with today’s novel tyrosine kinase inhibitors.

Ramalingam: I'll focus on advanced stage disease, since that's the setting where agents targeting insertion 20 have been approved. The FDA last year approved 2 targeted therapy approaches for this subset of patients. One is amivantamab, which is an antibody that targets EGFR and MET. The second is mobocertinib, which is a tyrosine kinase inhibitor. Both agents are approved for patients who have progressed on prior platinum-based therapy. So, for insertion 20 mutated patients, the standard first-line therapy still remains platinum-based chemotherapy with or without the addition of immune checkpoint inhibition; when the patients undergo disease progression on platinum-based therapy, either one of these targeted treatments is appropriate for insertion 20. For amivantamab, the more common side effects tend to be skin rash and related issues and infusion reactions, which typically happen in the first or second infusion cycles. For mobocertinib, diarrhea is the more common toxicity seen, with skin toxicity being less of an issue. With it being an orally administered agent we do not have to worry about infusion related issues.

AJMC®:How do you balance efficacy and toxicity with immunotherapy options for this disease? Is dose reduction appropriate in some instances? Do you ever look at that?

Ramalingam: Unlike some of the newer generation of targeted agents that we use for EGFR or ALK, we're still in early days of targeting insertion 20 mutations. Given the receptor structure it is not an easy target to induce pharmacological inhibition, so the drugs used currently are associated with a higher level of toxicity. Their efficacy is also relatively modest, I would say, compared with some of the more recent therapies in other oncogene addicted tumors. That being said, I think we've made the first important steps in targeting this patient population. The toxicity management is based on which agent you choose. If it's amivantamab, a proactive approach to manage the skin and manage infusion reactions are critical. If it's mobocertinib, prophylactic anti-diarrheal therapy and more aggressive antimotility treatments are going to be critical. Dose reduction is certainly an option in situations where one encounters toxicity. Sometimes treatment holidays may be necessary to allow patients to continue with their daily activities.

AJMC®:And what's the biggest area of unmet need with respect to EGFR exon 20 insertion positive non-small cell lung cancer?

Ramalingam: This is a group of patients for whom the currently available therapies produce modest outcomes, so we definitely need better options that can improve the efficacy and reduce the side effect profile of agents that are used. We also know that when patients develop disease progression on these targeted agents, they don't have any good options, so that is another area of need. Finally, I'll talk about brain metastases, which are common in this group of patients; the existing agents don't provide a great level of coverage against them. As we think about drug development in this space, [central nervous system] activity is going to be an important prerequisite for successful agents.

AJMC®:You presented data that led to the accelerated approval of mobocertinib at ASCO 2021. Can you describe the results of these data, which included a cohort from the EXCLAIM study,1 and what benefits mobocertinib offers over other therapies?

Ramalingam: Absolutely. Mobocertinib is a tyrosine kinase inhibitor that's administered orally. It's specific to insertion 20 mutations of the EGFR. The data we presented at [the American Society of Clinical Oncology] last year—and there have been subsequent updates providing additional information—the EXCLAIM study evaluated the use of mobocertinib in a cohort of patients that had received prior platinum-based chemotherapy for insertion 20 mutations. Approximately 100 patients were included in this study. We showed that the response rate by independent assessment was approximately 25% and by investigator assessment was approximately 35%. The median duration of response was very robust at 17 months and the median [progression-free survival] was approximately 7 months. We saw that mobocertinib was effective regardless of the specific insertion 20 mutation that the patient had. Among the toxicities we discussed earlier, the study noted that diarrhea was by far the most common adverse event. Grade 3 diarrhea was seen in about 20% of the patients, and this calls for prophylactic use of antimotility drugs and more aggressive management of these patients. Overall, it has shown modest clinical activity in patients with insertion 20 mutations and is now an FDA approved option.

AJMC®: Can you discuss any preliminary data or results from the clinical trials with novel agents for EGFR exon 20 insertion positive NSCLC?

Ramalingam: Having talked about how insertion 20 mutated patients need better treatment options, I would say that this is a specific area where there are a number of trials being done with new agents. I will talk about one new agent for which we heard data from at ASCO 2022, and that's CLN081. That's another small molecule broad spectrum EGFR tyrosine kinase inhibitor. It has activity in insertion 20 mutated patients, and Dr Helena Yu from Memorial Sloan Kettering presented preliminary results with this drug. She demonstrated response rate of approximately 40% and a median PFS of approximately 10 months with this drug. It also appeared to have a tolerable safety profile with a lower incidence of diarrhea compared to some of the other TKIs in this space. So further investigations of CLN081 are currently ongoing.

AJMC®: Are there any closing thoughts on disease management considerations for NSCLC exon 20 insertions that you would like to share with colleagues?

Ramalingam: The first point I would make is that molecular testing is a critical part of managing patients with advanced stage non-small cell lung cancer. While we have a number of mutations that are of low frequency, if you combine them all together, nearly 35% to 40% of patients will have an effective targeted therapy option for advanced stage disease. So, performing next-generation sequencing to look for whatever molecular aberration the patient's tumor may have is a critical first step in the diagnostic algorithm. Specifically with regards to insertion 20 mutations, the approval of targeted therapies means that there are proven interventions that can extend the patient clinical benefit beyond platinum-based chemotherapy, and there are a number of clinical trials that are ongoing that will hopefully provide even more effective agents in this space. Identifying these patients, and making sure that physicians understand that insertion 20 mutation is not similar to the other common exon 19 or exon 21 mutations so they treat these very differently, is another important piece of information I would like to share.

Reference

Zhou C, Ramalingham SS, Kim TM, et al. Treatment outcomes and safety of mobocertinib in platinum-pretreated patients with EGFR Exon 20 insertion-positive metastatic non-small cell lung cancer: a phase 1/2 open-label nonrandomized clinical trial. JAMA Oncol. 2021;7(12):e214761. doi: 10.1001/jamaoncol.2021.4761.