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Immunotherapy Continues to Transform the Treatment Landscape for Advanced Non–Small-Cell Lung Cancer

JHOP - June 2021 Vol 11, No 3 - HOPA Highlights
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Lung cancer remains the leading cause of cancer death worldwide, but the treatment landscape is rapidly evolving. In the past 10 years alone, the number of drugs approved by the US Food and Drug Administration (FDA) for non–small-cell lung cancer (NSCLC) has exceeded the previous 10 decades combined.

At the 2021 Hematology/Oncology Pharmacy Association annual conference, Michelle A. Worst, PharmD, BCOP, MBA, Associate Director of Clinical Strategy at Medscape Oncology, discussed recent advances in immunotherapy, the introduction of the programmed cell death (PD)-1 and PD ligand 1 (PD-L1) inhibitors, and the management of patients with NSCLC.

“NSCLC treatment has undergone drastic changes over the last year alone, with plenty more changes on the horizon,” Dr Worst said. “The use of immunotherapy has revolutionized the treatment of NSCLC and proved to have consistent improvement for patients, regardless of PD-L1 expression.”

According to Dr Worst, the 5-year survival rate for metastatic NSCLC between 2009 and 2015 was only 25%. Thanks to recent progress in screening, diagnosis, and treatment, the 5-year survival rates have improved to up to 50% in patients who are eligible for novel agents.

In the first-line setting of advanced NSCLC, immunotherapy has proved to be a safe and effective treatment option for a variety of tumor types, said Dr Worst. She noted that all newly diagnosed patients are now eligible for immunotherapy-containing regimens, unless the patient has contraindications to PD-1 or PD-L1 inhibitors.

The phase 3 CheckMate-227 clinical trial randomized patients with stage IV or recurrent NSCLC and a PD-L1 expression of ≥1% to receive nivolumab, a PD-1 inhibitor, plus ipilimumab, nivolumab alone, or chemotherapy. The results showed that first-line treatment with the combination of nivolumab plus ipilimumab led to a longer overall survival than chemotherapy alone (17.9 months vs 14.9 months, respectively).

On May 15, 2020, the FDA approved the combination of nivolumab and ipilimumab for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 ≥1%, as detected by the companion diagnostic test approved on the same day.

Dr Worst noted, however, that the arm with the 2 immunotherapies had much higher rates of any-grade and grade 3 to grade 4 adverse events.

“Patients can stay on these therapies longer, but they’re not benign agents, particularly when combined with one another,” Dr Worst said.

In the phase 3 CheckMate-9LA clinical trial, investigators explored whether the addition of a limited course (ie, 2 cycles) of chemotherapy to the combination of nivolumab plus ipilimumab would further enhance the clinical benefits in patients with stage IV or recurrent NSCLC who had not received any previous systemic therapy.

The results showed a significant improvement in the median duration of overall survival with the dual immunotherapy plus chemotherapy arm (14.1 months) versus chemotherapy alone (10.7 months). The objective response rate was greater and the time to response was shorter with the triplet regimen compared with chemotherapy alone.

On May 26, 2020, the FDA approved the combination of nivolumab plus ipilimumab and 2 cycles of platinum doublet chemotherapy as first-line treatment for patients with metastatic or recurrent NSCLC.

In the phase 3 IMpower110 clinical trial, investigators compared the use of the PD-L1 inhibitor atezolizumab versus chemotherapy alone in patients with stage IV NSCLC and a PD-L1 expression of ≥1%.

The results showed a significant improvement in overall survival, at 20.2 months, in the atezolizumab arm versus 13.1 months in the chemotherapy-alone arm. For patients with PD-L1 expression ≥50%, the duration of progression-free survival was approximately 3 months longer in the immunotherapy arm than in the chemotherapy arm, and the objective response rate was improved as well with the PD-L1 inhibitor.

Based on these data, on May 18, 2020, the FDA approved atezolizumab for the first-line treatment of adults with metastatic NSCLC whose tumors have PD-L1 expression ≥50%, based on an FDA-approved test, and no EGFR or ALK genetic alterations.

The phase 2, single-arm KEYNOTE-158 clinical trial enrolled patients with select solid tumors or advanced solid tumors with high tumor mutational burden (TMB), defined as ≥10 mutations per megabase (mut/Mb), who had failed at least 1 line of therapy. All the patients received the PD-1 inhibitor pembrolizumab, 200 mg every 3 weeks, for 35 cycles, or until documented disease progression, unacceptable toxicity, or patient or investigator decision.

“This trial did not specifically include NSCLC patients in the analysis, but it is worth mentioning a potential treatment paradigm,” said Dr Worst.

Dr Worst noted that patients with high TMB status had improved objective response rate and tumor reduction. “With this information and our knowledge of TMB in the NSCLC population, we can extrapolate these data and keep this as an option for patients in the approved indication,” she suggested.

On June 16, 2020, the FDA granted accelerated approval to pembrolizumab for adult and pediatric patients with unresectable or metastatic solid tumors and high TMB (≥10 mut/Mb), as determined by an FDA-approved test, that have progressed after previous therapy.

“The use of immunotherapy has consistently improved outcomes in a variety of patients with NSCLC, and is still evolving,” said Dr Worst. “All patients should be closely monitored for both immune-related adverse events and treatment-related adverse events throughout their treatment courses, and therapy selection should always be based on the individual patient,” she concluded.

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