Pembrolizumab's Big Win in Immunotherapy Battle for Frontline in Lung Cancer

Edward B. Garon, MD

It has been about 18 months since the first immunotherapy checkpoint agent was approved for patients with non—small cell lung cancer (NSCLC). Now there are 3 monoclonal antibodies that target the PD-1/PD-L1 pathway on the market for the tumor type and the focus has shifted rapidly to establishng immunotherapy as a new frontline standard.

Pembrolizumab (Keytruda) scored a big victory in that battle on October 24 when the FDA approved the PD-1 inhibitor for the frontline treatment of patients with metastatic NSCLC whose tumors show ≥50% PD-L1 expression based on an FDA-approved test and who do not harbor EGFR or ALK aberrations.

The decision opens the door to immunotherapy as initial treatment for approximately one-quarter of patients diagnosed with advanced lung cancer, according to Edward B. Garon, MD, whose research has been critical to the development of pembrolizumab.

“It is exciting to have an expanded group of patients who are now eligible for this drug,” Garon, who is director of Thoracic Oncology at the Jonsson Comprehensive Cancer Center at UCLA, said in a statement.

The FDA’s ruling came just weeks after research presented at the 2016 ESMO Congress demonstrated that single-agent pembrolizumab reduced the risk of death by 40% compared with doublet chemotherapy for previously untreated patients with NSCLC with PD-L1 expression on ≥50% of cells, called a tumor proportion score (TPS).^1,2

Pembrolizumab, which the FDA initially approved in a second-line setting in October 2015 on an accelerated basis, also gained full approval status for patients with NSCLC and a TPS of ≥1% who have progressed on platinum-based chemotherapy and targeted therapy, if appropriate, according to Merck, which is developing the drug.

The new indications for pembrolizumab come amid continuing research into the 2 rival agents as potential frontline therapies, as evidenced by findings presented during the 2016 ESMO Congress and ongoing clinical trials.

Nivolumab (Opdivo) initially was approved in March 2015 for patients with metastatic squamous NSCLC following progression on or after platinum-based chemotherapy. That indication was expanded to include nonsquamous tumors in October 2015.

However, nivolumab missed the primary endpoint of improving progression-free survival (PFS) compared with standard chemotherapy in patients with PD-L1 positive NSCLC in the front line.³ The PD-1 inhibitor, which was approved without any requirement for PD-L1 expression, remains under investigation in a phase III frontline trial that randomizes patients by PD-L1 level.

Atezolizumab (Tecentriq) entered the frontline race on October 18, when it became the first PD-L1 inhibitor approved in NSCLC. The FDA granted an indication for patients with metastatic disease with progression during or following platinum-containing chemotherapy or targeted therapy if appropriate, regardless of PD-L1 expression levels.

The approval came on the heels of a strong showing at the 2016 ESMO Congress, where atezolizumab was reported to have reduced the risk of death by 26% compared with docetaxel in previously treated patients.⁴ The agent is being evaluated for chemotherapy-naïve patients in several phase II and phase III trials.

Pembrolizumab

The following is a summary of key findings for each of the agents:Pembrolizumab findings in the KEYNOTE-024 trial have been hailed as practice changing.¹ The study screened 1934 patients with NSCLC for eligibility, of which 1653 yielded appropriate tissue for testing. Overall, 30.2% of samples expressed PD-L1 on ≥50% of cells by immunohistochemistry. Patients with EGFR- or ALK-positive tumors were excluded.

Of those who met the PD-L1 expression requirements, 305 were randomized to receive pembrolizumab (n = 154) or chemotherapy (n = 151), which most commonly included carboplatin plus pemetrexed (n = 67). In the chemotherapy arm, 46 patients went on to receive maintenance therapy with pemetrexed and an additional 66 patients (43.7%) crossed over to the pembrolizumab arm following progression.

The estimated 6-month overall survival (OS) rate was 80.2% with pembrolizumab versus 72.4% with chemotherapy (HR, 0.60; 95% CI, 0.41-0.89; P = .005). The median PFS was 10.3 months with pembrolizumab versus 6.0 months with chemotherapy (HR, 0.50; 95% CI, 0.37-0.68; P <.001). Fewer treatment-related adverse events were seen with the PD-1 inhibitor versus chemotherapy (73.4% vs 90%).

“This data will completely change the management of patients with advanced NSCLC,” lead author Martin Reck, MD, PhD, chief oncology physician, Department of Thoracic Oncology, Lung Clinic Grosshansdorf, Germany, said in a statement. “All endpoints of efficacy and tolerability favored treatment with pembrolizumab, suggesting it should become one standard of care for first-line treatment of patients with advanced NSCLC and high PD-L1 expression.”

Reck also noted the importance of the molecular screening that was conducted during the trial. “The new treatment algorithm should include upfront testing for PD-L1 expression to identify patients who will benefit from first-line treatment with pembrolizumab,” said Reck. “This is a landmark trial for the 30% of patients with advanced NSCLC who are high expressors of PD-L1.”

Similarly, the addition of pembrolizumab to frontline platinum-based chemotherapy almost doubled the objective response rate to 55% versus 29% with chemotherapy alone for patients with stage III/IV, nonsquamous NSCLC in the phase I/II KEYNOTE-021 study.⁵ The response rate reached nearly 80% for patients whose tumors expressed PD-L1 ≥50%.

Nivolumab

“This is the first randomized phase II trial in advanced, treatment-naïve nonsquamous non—small cell lung cancer to assess the benefit of adding a monoclonal antibody targeting PD1 to standard chemotherapy,” said principal investigator Corey J. Langer, MD, director of the Thoracic Oncology Program at the Abramson Cancer Center at the University of Pennsylvania, in a statement. “If these benefits are confirmed in an ongoing phase III trial, the results may radically alter the treatment paradigm in advanced non–small cell lung cancer.”Results for nivolumab in the phase III CheckMate-026 study proved disappointing, as the drug failed to improve PFS compared with standard chemotherapy in patients with advanced NSCLC.³ The primary endpoint was based on PFS among patients with ≥5% PD-L1 expression on the tumor cells, although the trial was open to individuals with ≥1% PD-L1.

Investigators randomized 541 patients to receive nivolumab 3 mg/kg every 2 weeks or a platinum-based chemotherapy doublet determined by the treating physician’s preference. Treatment continued until disease progression, when patients could cross over to nivolumab.

In the 423 patients with ≥5% PD-L1 expression, nivolumab-treated patients demonstrated a median PFS of 4.2 months compared with 5.9 months for patients treated with a chemotherapy. The median OS and response rate also did not differ significantly between treatment groups.

Additionally, a benefit was not observed for nivolumab versus chemotherapy in those with PD-L1 expression on ≥50% of cells; the HR was 1.07 for PFS and 0.90 for OS.

More than 60.4% of patients in the chemotherapy arm crossed over to nivolumab at progression, as compared with 43.6% of patients in the nivolumab arm who crossed over to chemotherapy.

“There are a number of possible reasons for the disappointing progression-free survival results,” lead investigator Mark Socinski, MD, executive medical director of the Florida Hospital Cancer Institute in Orlando, said in a statement.

“Regarding overall survival, there was a high rate of crossover to immunotherapy on the chemotherapy arm,” Socinski said. “Overall survival in the chemotherapy arm was better than historical standards, which could be due to the fact that it had a greater proportion of women and Asian patients. We are conducting further analyses to evaluate these results.”

Fouad Namouni, MD, head of oncology development at Bristol-Myers Squibb, said the results demonstrated that patients with advanced NSCLC may need combination therapy in order to surpass the benefits offered by standard chemotherapy. He pointed to the company’s ongoing CheckMate-227 trial that is investigating the combination of nivolumab and ipilimumab (Yervoy) in a frontline setting.

Atezolizumab

In commenting on the results, Johan Vansteenkiste, MD, PhD, of Catholic University Leuven in Belgium, said he believes nivolumab did not improve PFS because the trial included a broad range of patients with a low PD-L1 expression. “Standard first line treatment with platinum-doublet chemotherapy gives a progression-free survival of 6 months, and to beat that may require being more selective on who receives the drug,” he said.The FDA’s approval of atezolizumab in the second-line setting is based on multiple clinical trials, the largest being the phase III OAK trial, which was presented at the 2016 ESMO Congress.⁴

The international trial included 1225 patients with locally advanced or metastatic NSCLC—regardless of histology or PD-L1 status—who progressed during or after platinum-containing chemotherapy. Patients were randomized in a 1:1 ratio to 75 mg/m2 of intravenous docetaxel or 1200 mg of intravenous atezolizumab every 3 weeks.

In the intent-to-treat population (N = 850), the median OS was 13.8 months in the atezolizumab arm (n = 425) versus 9.6 months in the docetaxel arm (n = 425; HR, 0.74; 95% CI, 0.63-0.87; P = .0004). The PFS was 2.8 months versus 4 months (HR, 0.95), respectively.

Regarding PD-L1 status, PD-L1—positive patients had expression on at least 1% of their tumor cells (TC) or tumor-infiltrating immune cells (IC). PD-L1–negative patients had >1% expression on their TC and IC.

Among the PD-L1—positive group, the median OS was 15.7 months in the atezolizumab arm (n = 241) compared with 10.3 months in the control arm (n = 222; HR, 0.74; 95% CI, 0.58-0.93; P = .0102). Among PD-L1—negative patients, the median OS was 12.6 months in the atezolizumab cohort (n = 180) versus 8.9 months in the docetaxel group (n = 199; HR, 0.75; 95% CI , 0.59-0.96; P = .0205).

“Atezolizumab offers a new second-line therapeutic strategy for patients with non—small cell lung cancer, regardless of the PD-L1 status of the tumor,” lead study investigator Fabrice Barlesi, MD, PhD, head of the Multidisciplinary Oncology and Therapeutic Innovations Department at Aix-Marseille University and the Assistance Publique HoÌ‚pitaux de Marseille, France, said in a statement.

Meanwhile, Genentech, which is a member of the Roche Group, has a broad development program underway for atezolizumab in a variety of settings in NSCLC as monotherapy and in combination regimens in phase II and phase III trials that are expected to take several years to complete.

One of the trials on a faster track is the IMpower 150 study (NCT02366143) for chemotherapy-naïve patients with stage IV nonsquamous NSCLC with no requirement for PD-L1 positivity. The 3-arm trial randomizes patients to atezolizumab plus paclitaxel and carboplatin with or without bevacizumab (Avastin), or to bevacizumab plus the chemotherapy doublet.

The study, which is seeking to enroll 1200 patients, has a primary endpoint of PFS at up to 2 years and an estimated primary completion date for data collection of January 2017, according to ClinicalTrials.gov.

References

1. Reck M, Rodgriguez-Abreu D, Robinson AG, et al. KEYNOTE-024: Pembrolizumab (pembro) vs platinum-based chemotherapy (chemo) as first-line therapy for advanced NSCLC with a PD-L1 tumor proportion score (TPS) ≥50%. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA8.
2. Reck M, Rodgriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1—Positive Non–Small-Cell Lung Cancer [published online October 9, 2016]. N Engl J Med. DOI: 10.1056/NEJMoa1606774.
3. Brahmer J, Reckamp KL, Baas P, et al. CheckMate 026: a phase 3 trial of nivolumab vs investigator's choice (IC) of platinum-based doublet chemotherapy (PT-DC) as first-line therapy for stage IV/recurrent programmed death ligand 1 (PD-L1)−positive NSCLC. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA7.
4. Barlesi F, Park K, Ciardiello F, et al. Primary analysis from OAK, a randomized phase III study comparing atezolizumab with docetaxel in 2L/3L NSCLC. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract for LBA44.
5. Langer CJ, Gadgeel SM, Borghaei H, et al. Randomized phase 2 study of carboplatin and pemetrexed + pembrolizumab as first-line therapy for advanced NSCLC: KEYNOTE-021 cohort G. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. LBA46.