Lung Cancer—First-Line Checkpoint Inhibitor Combination Benefit

COPENAGEN—Adding the PD-1 (programmed cell death protein 1) antibody pembrolizumab to standard first-line chemotherapy with carboplatin and pemetrexed for previously-untreated patients with advanced non-squamous non-small-cell lung cancer (NSCLC) and good performance status significantly improved objective response rate (ORR) and progression-free survival (PFS) in the phase II KEYNOTE-021 study reported at the 2016 European Society for Medical Oncology (ESMO) Congress in Copenhagen. (Abstract LBA46_PR)

“Pembrolizumab enables T cells to reactivate and accomplish what they are designed to do—facilitate tumor cell killing,” said principal investigator Corey Langer MD FACP, Professor of Medicine and Director of Thoracic Oncology at the Abramson Cancer Center, University of Pennsylvania in Philadelphia PA, commenting on the findings with this “checkpoint inhibitor” immunotherapy.

Langer told the Audio Journal of Oncology the study showed a “statistically significant and clinically meaningful improvement for both response and progression-free survival for the combination.”

The KEYNOTE-021 study randomized 123 patients with stage IIIB or stage IV, NSCLC to receive four cycles of carboplatin and pemetrexed (500 mg/m2 every three weeks), with or without 24 months treatment with pembrolizumab (200mg every three weeks).

After a median follow-up of 10.6 months, there was a significantly greater objective response rate (55 percent) in the patients who received pembrolizumab in addition to chemotherapy, compared to those treated with chemotherapy alone (29 percent).

PD-L1 (programmed cell death-ligand 1) expression was not used to select patients for treatment with the immune checkpoint inhibitor, but the investigators found a higher response rate (around 80 percent) for the combination in tumors with PD-L1 over-expression, consistent with the known and licensed activity of the agent in patients with metastatic NSCLC tumors testing positive for this biomarker.

Progression free survival was longer for patients treated with the pembrolizumab combination (median 13.0 months) as compared with those receiving chemotherapy (8.9 months). More than 90 per cent of patients lived longer than six months but there was no difference in overall survival between the two arms.

There were more grade 3 or 4 adverse events with the pembrolizumab combination (39 percent) than with chemotherapy (26 percent), but Langer said toxicity was readily manageable and did not affect rates of treatment discontinuation or treatment-related deaths.

“So even though toxicity may be a little bit worse it’s not a show-stopper,” he said, adding that he was encouraged by the findings. “With the judicious use of immunotherapy I believe we are moving the bar forward for this population,” he said.

ESMO congress officer Solange Peters MD PhD, Head of Medical Oncology and Médecin Cheffe of Thoracic Malignancies at the Centre Hospitalier Universitaire Vaudois (CHUV) in Lausanne, Switzerland said the KEYNOTE-021 finding reinforced the idea that every single patient should be exposed to immunotherapy at some time.

“On present [evidence] this should be sequential,” she said. “But I would advise doctors to keep an eye on these data about combination chemo and immuno-[therapies]—not only in lung, but in other diseases too, because it might be of great interest in the future.”

Peters said it was worth continuing to investigate combinations of chemotherapy plus immunotherapy as first line therapy for NSCLC since any worries that chemotherapy might damage T-cells had been lessened with the arrival of the KEYNOTE data.

“This combination was almost doubling the response rate as compared to chemotherapy alone—and the PFS [was] influenced positively by the combination. So it means that this is not a regimen that will damage the T-cell,” she said.

But she emphasized that we do not presently know if the benefits giving the two treatments concurrently were likely to be superior—in the long run—to using the same agents sequentially. Data on overall survival and long-term follow up of the PFS were needed, she said. “So I think it’s a bit early to say [this is] going to be a standard because we need to see that long-term benefit.”

Commenting on the study, Raffaele Califano MD, Consultant in Medical Oncology at The Christie Hospital and University Hospital of South Manchester in Manchester, UK said: “Data for the combination of chemotherapy plus pembrolizumab in this population is certainly encouraging, and it is reassuring to see that the addition of pembrolizumab to first-line chemotherapy has a manageable toxicity profile and doesn’t increase the incidence of treatment-related adverse events or deaths.”

“Notably, the progression-free survival reported in the standard arm was much longer than expected and nearly doubled when compared to historical data,” Califano said. But he added that this could be due to patient selection or other clinical or molecular characteristics of the patients enrolled in this study.

“In order to establish if this strategy should be adopted in clinical practice, these results should be investigated further in a phase III randomized study with a similar design, adequately powered for progression-free survival and with robust assessment of patient’s reported outcomes,” he said.