First-Line Pembrolizumab Boosts Survival in PD-L1-Positive Advanced Lung Cancer

Audio Journal of Oncology, January 2, 2017

COPENHAGEN—Patients with metastatic non-small cell lung cancers (NSCLC) expressing the programmed cell-death ligand 1 (PD-L1) protein responded better to initial treatment with the anti-PD-L1 immunotherapy pembrolizumab—and lived longer with fewer toxicities—than to standard chemotherapy in the international KEYNOTE-024 (NCT02142738) study reported to the European Society for Medical Oncology 2016 congress. (Abstract LBA8_PR.)

http://annonc.oxfordjournals.org/content/27/suppl_6/LBA8_PR.full?sid=57db4b00-dd13-4ca0-ac50-086c77db63c0

Lead author Martin Reck MD PhD, a thoracic oncologist from the Grosshansdorf Lung Clinic near Hamburg in Germany, said the open-label, phase 3 study compared pembrolizumab checkpoint inhibition with platinum-doublet chemotherapy as first-line therapy for patients whose lung cancers had PD-L1 tumor proportion scores (TPS) of 50 percent or greater and did not have treatable epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) translocations.

“These data are changing our management of patients with lung cancer,” he said adding that the results implied PD-L1 had emerged as an important predictive biomarker for treating patients with metastatic non-small cell lung cancer and that for patients whose tumors have it expressed pembrolizumab was an attractive new option in first-line treatment.

“The efficacy has been clearly better for pembrolizumab compared to chemotherapy, and the tolerability has been clearly better. So this tells us that we have to change our diagnostics for lung cancer. So besides the diagnostics for EGF receptor or ALK translocation we have to implement PD-L1 testing in our up-front diagnosis for lung cancer because we have got a completely new treatment option for this group of patients,” Reck told the Audio Journal of Oncology.

In the KEYNOTE-024 study patients with nonsquamous NSCLC were randomized either to 35 cycles of pembrolizumab, or between four and six cycles of investigators’ choice of platinum doublet chemotherapy (carboplatin or cisplatin plus pemetrexed, carboplatin or cisplatin with gemcitabine, or carboplatin plus paclitaxel) with optional pemetrexed maintenance.

The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), overall response rate (ORR), and safety.

After a median follow-up of 11.2 months, nearly half of the 305 patients randomized to pembrolizumab chose to continue with their allocated initial therapy while only ten percent of those in the chemotherapy arm opted to continue with their initial treatment. Crossover was allowed, and when the disease progressed 44 percent of patients initially assigned to chemotherapy crossed over to pembrolizumab.

Disease Progression

Patients initially assigned to treatment with pembrolizumab lived a median of more than ten months before their disease progressed compared with only six months for those receiving chemotherapy. The immunotherapy was also associated with higher ORR (45percent compared with 28 percent) and longer duration of response —the median was not reached in the pembrolizumab arm and was 6.3 months with chemotherapy.

Overall Survival

Six months after starting treatment 80 per cent of patients who started on pembrolizumab were alive compared with only 72 per cent for those initially allocated to chemotherapy. This was equivalent to a 40 per cent reduction of mortality risk for patients on pembrolizumab monotherapy—despite the high crossover rate.

Toxicities

Toxicities of any-grade were less common with immunotherapy (73 percent of patients had toxicities versus 90 percent with chemotherapy), and grade three-to-five treatment-related adverse events (AEs) were half as common with permbrolizumab. (27 percent versus 53 percent).

Stefan Zimmermann, MD, from Hôpital Fribourgeois, HFR Hôpital Cantonal, in Fribourg, Switzerland, who chaired a news briefing on the KEYNOTE-024 study at ESMO noted this was the first time that an immune-oncology strategy had been demonstrated in the first-line setting. “Until now we’ve seen a lot in second and third line or further lines of therapy,” said.

ESMO officer Solange Peters, MD PhD, Médecin Cheffe of Thoracic Malignancies, at the Centre Hospitalier Universitaire Vaudois (CHUV) at Lausanne University in Switzerland told OT the KEYNOTE-024 study had demonstrated that even though chemotherapy was already quite good this form of immunotherapy had made a further improvement.

“It’s an amazing set of data because for the first time our classical standard of care—platinum-based chemotherapy—is questioned. It was very improbable until now that new combinations or new agents would dramatically change the course of the disease by replacing platinum-based chemotherapy,” she said.

The KEYNOTE-024 study authors concluded that pembrolizumab had superior PFS and OS over platinum-based chemotherapy in patients with advanced NSCLC and PD-L1 expression (TPS) of at least 50 per cent, and that these findings—together with the lower rate of treatment-related AEs—implied that the drug may be the new standard of care for first-line therapy for this group of patients.

Reck said there was a clear message for clinicians. “Management of first-line therapy of patients with advanced non-small cell lung cancer has changed. We have to add the assessment of PD-L1 in our first-line diagnosis. We have a new group of patients identified that has a substantial benefit by a mono-therapy by an anti-immune treatment—the patients with high PD-L1 expression. We have to identify the patients up-front because we have to treat them up-front.”