Immunotherapies battle for lead in lung cancer

Much of the buzz in lung cancer is around new immunotherapy combinations – and whether recent data from Bristol Myers Squibb will allow it to regain ground from market-leader Merck, whose Keytruda (pembrolizumab) continues to lead the pack.


Bristol in September 2019 released data showing that combining two of its immuno-therapy drugs, Opdivo (nivolumab) and Yervoy (ipilimumab), improved life-expectancy, relative to chemotherapy alone, among some patients with advanced non-small cell lung cancer (NSCLC). After two years, 40% of patients on the combination were alive, versus just 33% on chemotherapy only. The data was presented at the European Society for Medical Oncology meeting.


Will it be enough to unseat Keytruda? Bristol’s challenge is that Keytruda is the immuno-therapy of choice in NSCLC (and many of the other almost two dozen cancer indications it is approved in), thanks to steadily accumulating – and compelling – efficacy data. Alongside chemotherapy as frontline treatment, Keytruda is shown to reduce the risk of death among metastatic NSCLC patients by over 50%. It also works in a widening group of advanced NSCLC patients. Initially approved only for patients showing at least 1% expression of the PD-L1 protein that the drug blocks, recent data shows that even patients with low or no PD-L1 expression can benefit. And Keytruda’s once-every-three-week administration fits conveniently alongside chemo, minimising the practical therapy burden.


Bristol claims that its checkpoint inhibitor combination provides an option for those that cannot or will not tolerate chemotherapy. The September data marked the first time a dual immunotherapy had shown superior overall survival over chemo in the first-line NSCLC setting, the company said. And, as for Keytruda, those improved survival rates held for patients with lower PD-L1 levels, too.


The lack of head-to-head studies comparing Keytruda efficacy head-on with Yervoy/Opdivo makes accurate comparisons difficult, though. And not everyone agrees on the rationale to skip chemo; indeed, Bristol is also testing the combo with chemotherapy. An interim analyses reported in October from another Phase III suggested that the three therapies could also improve overall survival versus chemotherapy alone, though full data has not been released.

Another issue for Bristol is that Opdivo has not stacked up as a monotherapy in first-line lung cancer: it was found in an earlier study to decrease overall survival versus chemotherapy. Opdivo is approved in various lung cancer settings as second-line therapy.


Yervoy, meanwhile, suffers from well-known toxicity risks. (This drug targets CTLA4, a protein expressed on T-cells.) Side-effects put an end to a 2017 trial of full-dose Yervoy with Opdivo in lung cancer. The recent combination studies used a lower dose of Yervoy, but even then, a third of patients in the trial reported in September suffered treatment-related adverse events.


“My treatment choice [in NSCLC] is Keytruda, since it fits nicely with the chemo dosing schedule,” said one US key opinion leader, speaking before the recent Bristol data was released. “The toxicity of combining two immuno-therapy agents puts me off, though some patients may benefit,” he continues.


But with “almost every patient now eligible for an immuno-therapy,” according to the physician, further combinations and options will find their place. AstraZeneca is testing a PD-L1/CTLA4 combination that looks similar to Yervoy/Opdivo, though read-out has been delayed to 2021.


Immuno-therapies can significantly improve the outlook for many lung cancer patients. As experience with these treatments grows, physicians are also getting better at managing associated toxicities.


Bristol’s combination, after twists and turns in the history of both agents, may offer some patients an important treatment option. But Keytruda’s dominance looks set to continue – including ex-US. The UK National Health Service – notoriously selective in what it funds – recently agreed to pay for Keytruda in the first-line setting for metastatic NSCLC patients, though the funding will come from the ring-fenced Cancer Drugs Fund until more mature evidence is available.


Analysts predict that the drug will take Humira’s place as the world’s top-selling drug in the next five years, with over $22 billion in forecast sales by 2025. Opdivo is not doing badly either: it sold $6.7 billion in 2018 across multiple cancers. But for now it is still playing second fiddle.