Maya Khalil, MD, assistant professor of medicine, Division of Hematology and Oncology, the University of Alabama at Birmingham (UAB), oncologist, O’Neal Comprehensive Cancer Center, UAB Medicine, discusses the future investigations of immunotherapy in non–small cell lung cancer (NSCLC).

Currently, when determining treatment for patients with metastatic NSCLC who do not harbor a targetable driver mutation, data from previously conducted trials could help inform that decision, Khalil says. For example, in the phase 3 CheckMate 9LA trial (NCT03215706) that evaluated nivolumab (Opdivo) and ipilimumab (Yervoy) plus chemotherapy vs chemotherapy alone in the frontline setting for patients with metastatic NSCLC, patients who had pretreated, stable, or asymptomatic brain metastases experienced progression-free survival and overall survival benefits with the combination vs chemotherapy alone. However, combination treatment with checkpoint inhibitors may not benefit patients with liver metastases, Khalil explains.

Evaluating data from different trials could help inform treatment decisions for individual patients, she says, adding that there is no longer a one-size-fits-all approach for treating patients with NSCLC. Factors that could help tailor treatment include burden of disease and sites of disease. For example, a patient with liver metastases and a large burden of disease may not be ideal candidates for immunotherapy alone, Khalil expands.

In the future, stratifying patients by PD-L1 expression and other molecular markers should be integrated into clinical trial designs, Khalil says. Investigating novel immunotherapy combinations, such as with anti–CTLA-4, anti–LAG-3, or other immune checkpoint inhibitors under development, could lead to a shift in the immunotherapy landscape in NSCLC, Khalil continues.

Immunotherapy has been proven to be an effective treatment option for many patients with NSCLC, displaying long-term disease control and durable responses, Khalil says. However, current immunotherapy options will not be effective for every patient, making it vital to find ways to identify those patients more or less likely to benefit from these therapies, Khalil concludes.

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Maya Khalil, MD, discusses the future investigations of immunotherapy in non–small cell lung cancer.


Dr Khalil on the Future Investigations of Immunotherapy in NSCLC

Maya Khalil, MD, assistant professor of medicine, Division of Hematology and Oncology, the University of Alabama at Birmingham (UAB), oncologist, O’Neal Comprehensive Cancer Center, UAB Medicine, discusses the use of first-line durvalumab (Imfinzi) plus tremelimumab (Imjudo) in patients with non–small cell lung cancer (NSCLC) enrolled in the phase 3 POSEIDON trial (NCT03164616), and sheds light on histologies and mutations that are associated with increased benefit with this regimen.

The addition of tremelimumab to durvalumab and platinum-based chemotherapy has improved patient outcomes in the treatment of NSCLC. 

The regimen received FDA approval in November 2022

, providing another option to patients with metastatic disease who do not have sensitizing 

 aberrations. Notably, the approval was supported by data from the POSEIDON study.

Unlike the phase 3 CheckMate-9LA trial (NCT03215706), which examined nivolumab (Opdivo) and ipilimumab (Yervoy) plus 2 cycles of platinum-based chemotherapy vs chemotherapy alone in the frontline treatment of patients with NSCLC, those on the POSEIDON trial were randomized to receive 1 of 3 regimens: 4 cycles of the triplet followed by 4 weeks of durvalumab and maintenance chemotherapy, and another dose of tremelimumab at week 16; durvalumab plus 4 cycles of chemotherapy followed by durvalumab and maintenance chemotherapy; or 6 cycles of chemotherapy followed by maintenance chemotherapy, Khalil says.

Results from the trial showed that the triplet regimen provided a durable overall survival (OS) benefit vs chemotherapy alone, Khalil reports. Three-year OS rates were 25% and 13.6% in favor of the doublet regimen. Patients in the experimental arm experienced a median OS of 14.0 months (95% CI, 11.7-16.1) compared with 11.7 months (95% CI, 10.5-13.1) in the control arm (HR, 0.75; 95% CI, 0.63-0.88). Additionally, in the durvalumab and chemotherapy treatment arm, the median OS was 13.3 months and the OS rate at 36 months was 20.7%.

A subgroup analysis of OS according to patient histology showed that those with nonsquamous NSCLC experienced improved OS with the triplet vs those with squamous histology, Khalil adds. The 3-year OS rates were 31.4% vs 17.3%, respectively. Notably, the analysis also revealed a signal that those with co-alterations, including 

, derived benefit from the triplet regimen in this setting, Khalil states. However, these patients were more likely to develop primary resistance to immune checkpoint inhibitor monotherapy, she explains.

Based on these data, a dual checkpoint inhibitor and chemotherapy combination should be considered for patients with metastatic NSCLC who present with a 

mutation, provided that the patient can tolerate the therapy and they do not have any treatment contraindications, Khalil concludes.

Disclosures: Dr. Khalil reports serving as a principal investigator on trials in collaboration with/sponsored by: National Cancer Institute, Bristol Myers Squibb, Amgen, Top Alliance, Janssen, Cantargia, Guardant Health, Numab, Nitto BioPharma, Spectrum Pharmaceuticals, Eastern Cooperative Oncology Group (ECOG), Southwest Oncology Group (SWOG), Alliance cooperative group.

Maya Khalil, MD, discusses the use of first-line durvalumab plus tremelimumab  in patients with non–small cell lung cancer enrolled in the phase 3 POSEIDON trial, and sheds light on histologies and mutations that are associated with increased benefit with this regimen.

Dr Khalil on Benefits Derived From the POSEIDON Regimen in Metastatic NSCLC  

Maya Khalil, MD, assistant professor of medicine, Division of Hematology and Oncology, the University of Alabama at Birmingham (UAB), oncologist, O’Neal Comprehensive Cancer Center, UAB Medicine, discusses key clinical trial updates on the use of nivolumab (Opdivo) and ipilimumab (Yervoy) with or without chemotherapy in non–small cell lung cancer (NSCLC).

Updated analyses from the phase 3 CheckMate 227 (NCT02477826) and CheckMate 9LA(NCT03215706) trials have aided in clarifying and identifying patient subgroups that have the potential to benefit from the use of nivolumab (Opdivo) and ipilimumab (Yervoy) either with or without chemotherapy.

The phase 3 CheckMate 227 trial evaluated the use of nivolumab and ipilimumab vs platinum-based chemotherapy in patients with stage IV or recurrent NSCLC without prior exposure to systemic therapy, Khalil begins. Patients with PD-L1 positivity were randomly assigned to recieve nivolumab and ipilimumab vs chemotherapy, while those in the PD-L1-negative group received nivolumab and ipilimumab vs nivolumab alone or chemotherapy. 

The experimental regimen provided a clear overall survival benefit to patients in both groups compared with chemotherapy, Khalil states. Similarly, progression-free survival (PFS) and duration of response (DOR) were both improved in the PD-L1–positive group with nivolumab and ipilimumab, she says. Additionally, the 5-year median OS in the PD-L1–negative group was 17.4 months. The subgroup analysis of the trial demonstrated that the experimental regimen was not favored in patients with liver metastasis and no smoking history, Khalil adds.

The combination of nivolumab and ipilimumab was also evaluated in combination with 2 cycles of platinum chemotherapy in the phase 3 CheckMate 9LA trial, Khalil continues. Patients in this same population were randomized to the experimental regimen vs 4 cycles of chemotherapy alone, and were treated until disease progression, unacceptable toxicity, or the completion of 2 years of immunotherapy. In this trial, the experimental regimen improved 3-year overall survival rate vs chemotherapy alone regardless of PD-L1 status, Khalil reports.

Additional mutation analysis revealed that patients with 

 mutations experienced the most benefit from nivolumab and ipilimumab plus chemotherapy, Khalil notes. As patients with these mutations often develop resistance to immunotherapy, the use of CTLA-4 and PD-L1 inhibitor combinations with or without chemotherapy should be considered.

Editor's Note: Dr. Khalil reports serving as a principal investigator on trials in collaboration with/sponsored by: National Cancer Institute, Bristol Myers Squibb, Amgen, Top Alliance, Janssen, Cantargia, Guardant Health, Numab, Nitto BioPharma, Spectrum Pharmaceuticals, Eastern Cooperative Oncology Group (ECOG), Southwest Oncology Group (SWOG), Alliance cooperative group.

Maya Khalil, MD, discusses key clinical trial updates on the use of nivolumab and ipilimumab with or without chemotherapy in non–small cell lung cancer. 

Maya Khalil, MD

Articles

Dr Khalil on the Future Investigations of Immunotherapy in NSCLC

Dr Khalil on Benefits Derived From the POSEIDON Regimen in Metastatic NSCLC

Dr Khalil on the Use of Nivolumab/Ipilimumab Combination in NSCLC