Keytruda immunotherapy may become new standard of care – NEJM

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lungcancerfocuswebClinical data shows Merck’s Keytruda immunotherapy offered big benefits in previously untreated lung cancer patients, either when given on its own or with chemotherapy, reports Reuters Health. ‘It’s a new day for lung cancer treatment,’ Stefan Zimmermann of Lausanne’s University Hospital is quoted as saying at the European Society for Medical Oncology congress.

As a monotherapy, Keytruda halved the risk of disease progression and cut overall deaths by 40% compared to chemotherapy alone in pre-selected patients whose tumors had been tested using a biomarker. And when given with two older chemotherapy drugs in non-selected patients, it was almost twice as likely to shrink tumors as chemotherapy alone.

Another similar drug from Roche also demonstrated broad efficacy as a so-called second-line option in patients who had received prior treatment.

“Remember this day. It’s a new day for lung cancer treatment,” Stefan Zimmermann of Lausanne’s University Hospital is quoted as saying at the European Society for Medical Oncology (ESMO) congress as the results were presented.

An editorial in the New England Journal of Medicine said Keytruda could become “a new standard of care”.

The various findings suggest that treating lung cancer – the biggest cancer killer globally – with powerful new immune system-boosting medicines is going to involve more permutations than some experts originally expected.

The report said rival drugmaker Bristol-Myers Squibb had tried a catch-all approach with its Opdivo drug but it failed to help previously untreated patients when given on its own in a trial that included people with low levels of a protein called PD-L1. Keytruda, as a sole agent, was targeted only at patients with high PD-L1, making them more receptive to immunotherapy.

Lead researcher Martin Reck of Germany’s Lung Clinic Grosshansdorf predicted that testing for the PD-L1 biomarker would now become standard “from today”.

The report says US regulators are expected to decide whether to approve Keytruda for first-line non-small cell lung cancer, the most common type, by 24 December 2016.

Merck had already said in June that Keytruda worked in the trial but the scale of the benefit was only disclosed at ESMO.

The report says the second trial, mixing Keytruda with chemotherapy, was much smaller but was notable because it was the first time that a combination of immunotherapy and chemotherapy has been shown to work in a randomised Phase II study.

Many experts have been sceptical about this approach and investors’ expectations, up until now, have been quite low. In the event, researchers reported that Merck’s combination cut the risk of disease progression or death by 47% compared to chemotherapy alone after 10.6 months, while 55% of patients saw their tumours shrink versus 29%.

Patients in this trial were not selected by PD-L1 expression but the study did find that those with higher PD-L1 had a higher response.

Roger Perlmutter, Merck’s head of research, said both trials suggested Keytruda could offer a broad array of patients meaningful improvement over standard platinum-based chemotherapy, which is now more than two decades old.

The report says drugs like Keytruda and Opdivo work by taking the brakes off the immune system and allowing the body’s natural killer cells to home in on tumours. They are expected to sell tens of billions of dollars in the years ahead, with lung cancer the largest market.

Results of Bristol’s failed Opdivo trial, which included patients with tumours testing only 5% or higher for PD-L1 against the 50% cut-off used by Merck, were also presented at ESMO. These showed progression-free survival was 4.2 months with Opdivo and 5.9 months with chemotherapy, although the difference was not statistically significant. Overall survival was 14.4 months with Opdivo versus 13.2 months.

The failure of Opdivo to work for “all comers” in lung cancer was first announced in August, without any details. It was a major setback for Bristol, wiping out around a quarter of the company’s market value, and it has caused investors to rethink prospects for immunotherapy treatments.

Many now believe that combination therapy is the way ahead, with Bristol and AstraZeneca working primarily on using two immunotherapies together, while Roche and Merck look at adding chemotherapy, the report said.

 

KEYNOTE-024 investigated the efficacy of pembrolizumab compared to standard of care with platinum-based chemotherapy in untreated patients with advanced NSCLC and high PD-L1 expression (defined as expression in at least 50% of tumour cells). Patients with EGFR activating mutations and ALK translocations were excluded from recruitment. “There is a substantial need to find better options than chemotherapy for these patients,” said Reck.

The trial included 305 patients from 16 countries who were randomised 1:1 to pembrolizumab or chemotherapy. Patients in the chemotherapy arm who progressed were eligible to crossover to pembrolizumab as second line treatment – this occurred in 44% of these patients.

The investigators found that pembrolizumab significantly improved the primary endpoint of progression-free survival by approximately four months compared to chemotherapy (10.3 months versus 6.0 months, hazard ratio [HR] 0.50). The secondary endpoint of overall survival was also significantly prolonged, and 80% of patients on pembrolizumab were alive at six months compared to 72% on chemotherapy (HR=0.60).

“The significant improvement in overall survival with pembrolizumab was remarkable given that more than 40% of patients crossed over from the control arm to pembrolizumab after progression of the disease,” said Reck.

Pembrolizumab was associated with a higher overall response rate compared to chemotherapy (45% versus 28%), a longer duration of response, and lower incidences of all and serious (3/4) adverse events.

“This data will completely change the management of patients with advanced NSCLC,” said Reck. “All endpoints of efficacy and tolerability favoured 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. This is primarily an opportunity for patients without oncogenic alterations. More information is needed for those with alterations.”

He concluded: “This is a landmark trial for the 30% of patients with advanced NSCLC who are high expressers of PD-L1. The new treatment algorithm should include upfront testing for PD-L1 expression to identify patients who will benefit from first line treatment with pembrolizumab.”

Commenting on the results, Professor Johan Vansteenkiste, professor of medicine, Catholic University Leuven, and chief oncology physician, unit of respiratory oncology, University Hospital  KU Leuven, Belgium, said: “This study may change current practice for the treatment of patients with advanced NSCLC. It is the first time a therapy has improved progression-free survival over the current standard first line treatment with platinum-based doublet chemotherapy.”

“The reason KEYNOTE-024 met its primary endpoint, in contrast with other studies, is probably because the trial only included patients who had PD-L1 expression of at least 50% and were therefore optimal candidates for treatment with pembrolizumab,” he added.

“A study is needed to confirm these findings in patients with high PD-L1 expression,” continued Vansteenkiste. “Additional research should be done to find out whether patients with lower levels of PD-L1 expression also benefit more from pembrolizumab than chemotherapy.”

 

Abstract
Pembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non–small-cell lung cancer (NSCLC), with increased activity in tumors that express programmed death ligand 1 (PD-L1).
Methods: this open-label, phase 3 trial, we randomly assigned 305 patients who had previously untreated advanced NSCLC with PD-L1 expression on at least 50% of tumor cells and no sensitizing mutation of the epidermal growth factor receptor gene or translocation of the anaplastic lymphoma kinase gene to receive either pembrolizumab (at a fixed dose of 200 mg every 3 weeks) or the investigator’s choice of platinum-based chemotherapy. Crossover from the chemotherapy group to the pembrolizumab group was permitted in the event of disease progression. The primary end point, progression-free survival, was assessed by means of blinded, independent, central radiologic review. Secondary end points were overall survival, objective response rate, and safety.
Results: Median progression-free survival was 10.3 months (95% confidence interval [CI], 6.7 to not reached) in the pembrolizumab group versus 6.0 months (95% CI, 4.2 to 6.2) in the chemotherapy group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.37 to 0.68; P<0.001). The estimated rate of overall survival at 6 months was 80.2% in the pembrolizumab group versus 72.4% in the chemotherapy group (hazard ratio for death, 0.60; 95% CI, 0.41 to 0.89; P=0.005). The response rate was higher in the pembrolizumab group than in the chemotherapy group (44.8% vs. 27.8%), the median duration of response was longer (not reached [range, 1.9+ to 14.5+ months] vs. 6.3 months [range, 2.1+ to 12.6+]), and treatment-related adverse events of any grade were less frequent (occurring in 73.4% vs. 90.0% of patients), as were grade 3, 4, or 5 treatment-related adverse events (26.6% vs. 53.3%).
Conclusion: In patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells, pembrolizumab was associated with significantly longer progression-free and overall survival and with fewer adverse events than was platinum-based chemotherapy.

Authors
Martin Reck, Delvys Rodríguez-Abreu, Andrew G Robinson, Rina Hui, Tibor Csőszi, Andrea Fülöp, Maya Gottfried, Nir Peled, Ali Tafreshi, Sinead Cuffe, Mary O’Brien, Suman Rao, Katsuyuki Hotta, Melanie A Leiby, Gregory M Lubiniecki, Yue Shentu, Reshma Rangwala, Julie Brahmer

Reuters Health report
ESMO 2016 material
New England Journal of Medicine abstract
New England Journal of Medicine editorial


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