Combining immunotherapy with other drugs may become a more common choice as an initial treatment for lung cancer, bolstered by positive results from two major clinical studies testing checkpoint inhibitors made by Merck & Co. and Bristol-Myers Squibb Co.
Data from these trials, presented Monday at the annual meeting of the American Association for Cancer Research, could represent the next step forward in a years-long quest to further unlock the potential of the immune-boosting drugs. Metastatic lung cancer, a deadly and tough-to-treat disease, has seen clinical advances but remains a leading cause of death in the U.S.
"There is no question this is a watershed period in the treatment of lung cancer," said John Heymach, chair of thoracic/head and neck medical oncology at The University of Texas MD Anderson Cancer Center, in an interview ahead of the conference.
Long a staple of chemotherapy, combination treatment approaches remain in early stages for immuno-oncology. Drugmaker interest is high, however, in discovering partner therapies that can raise the effectiveness of immunotherapy without compromising safety. Across the industry, roughly 1,100 combination studies testing other drugs together with checkpoint inhibitors in dozens of cancer types are underway, according to a recent analysis from the Cancer Research Institute.
In the near term for first-line lung cancer, Merck's triplet of Keytruda (pembrolizumab) and two older chemotherapy drugs appears to be a clear winner. Yet the success of a pairing of Bristol-Myers' immunotherapies Opdivo (nivolumab) and Yervoy (ipilimumab), as well as a four-drug combination from Roche, indicate Merck's edge in the lung cancer market is far from guaranteed.
"There is no question this is a watershed period in the treatment of lung cancer."
John Heymach
Oncology, MD Anderson Cancer Center
Practice changing?
In Merck's KEYNOTE-189 study, treatment with Keytruda plus chemo cut the risk of death by 51% compared to chemo alone in patients with metastatic non-squamous non-small cell lung cancer (NSCLC). Across patients who expressed higher levels of PD-L1, a biomarker correlated with responsiveness to immunotherapy, an even greater risk reduction of 58% was reported.
After one year, nearly 70% of patients on treatment were alive compared to about 50% of those receiving chemo.
Those overall survival results are likely to be practice changing, according to Alice Shaw, an oncologist at the Massachusetts General Hospital Cancer Center and co-chair of the clinical trials committee for AACR's annual meeting.
While Keytruda plus chemo won an OK for NSCLC last spring, physicians have been relatively slow to prescribe the combo due to the small size of the study supporting the Food and Drug Administration's initial approval.
KEYNOTE-189, then, was designed as a larger Phase 3 study to confirm that early efficacy signal.
Roy Herbst, chief of medical oncology at the Yale Cancer Center, believes the new data will prompt more physicians to use Keytruda plus chemo as a frontline option. He was not involved in the current trial but has worked on studies of Keytruda in the past.
A poll conducted ahead of the conference by the investment firm Cowen showed oncologists expected the Keytruda combo would likely deliver a risk reduction of around 30% — suggesting the more significant number reported by Merck may surpass the oncology community's expectations.
The chemotherapy arm of KEYNOTE-189, however, did not perform as well as might be expected from historical results, potentially flattering the statistical comparison between arms to some degree.
Grade 3 or higher adverse events occurred at similar rates in both treatment and control arms, although a greater share of patients discontinued Keytruda than did the corresponding placebo.
Patients on Keytruda did experience a higher rate of renal toxicity, which occurred in 5.2% of patients in the treatment arm versus 0.5% in the control cohort.
Betting on tumor mutation burden
While Merck has pushed more heavily into combinations pairing checkpoint inhibition with chemo, rival Bristol-Myers' principal bet is on adding its anti-CTLA4 drug Yervoy to Opdivo, a PD-1 blocker.
Results from its CheckMate-227 study in first-line NSCLC show that inhibiting both checkpoint molecules can help delay disease worsening or death over chemo. A progression-free survival benefit was most pronounced, however, in a subset of patients who had high tumor mutational burden (TMB), another biomarker designed to identify those most likely to benefit.
Patients with greater than 10 mutations per megabase — a cutoff which includes about 45% of NSCLC patients without EGFR or ALK mutations — were 42% less likely to see their cancer progress than those who received platinum-doublet chemotherapy.
Across all randomized patients on the study, the relative risk reduction from treatment checked in at a more modest 17% due to worse performance by those patients below the TMB cutoff. For TMB-low patients, treatment with chemo actually resulted in better results.
Overall survival data remained immature at the time of analysis, while median progression free survival among TMB high patients was 7.2 months on treatment versus 5.5 months on chemo.
Bristol-Myers expects data on overall survival by PD-L1 expression to come in late 2018 or early 2019, after which a submission to regulators could follow if the data remains positive.
Importantly, Bristol-Myers' combination could allow patients to skip chemotherapy in first-line treatment, saving those cytotoxic regimens as an effective second-line backup.
"It is attractive to avoid chemotherapy completely. If [Bristol-Myers' combo] is no more toxic, or less toxic and it works well, I think that would be many of our preference," said Yale's Herbst.
If the combo wins approval, patient interest in a non-chemo option could also drive interest. In the meantime, however, Merck will likely be in a strong position to solidify its advantage. And recent results from another study, KEYNOTE-042, showed Keytruda monotherapy also led to a survival benefit in patients with PD-L1 expression greater than 1%. Monotherapy, of course, would also be chemo-free.
"I think there is a belief and acceptance throughout the field that combination immunotherapy is probably what the future holds."
Jill O'Donnell-Tormey
CEO, Cancer Research Institute
Complex choices
For all the clinical progress in combination treatment, physicians will still face complex choices to decide which treatment to prescribe.
"There has never been a time in lung cancer therapy when we have seen such rapid advances for lung cancer patients," said Heymach of MD Anderson. "But it does present more challenges than ever to practicing physicians about what they will choose and how they will sequence [the therapies]."
Mass General's Shaw notes that Merck's study leaves one major question unanswered: which regimen to prescribe for those patients who express high-levels of PD-L1. Both Keytruda monotherapy and Keytruda plus chemo deliver a survival benefit, but the two regimens have not been compared directly to test comparative efficacy.
Bristol-Myers' use of TMB, meanwhile, adds another biomarker by which to stratify patients, introducing further complexity and requiring new tests.
Roche, meanwhile, is advancing Tecentriq (atezolizumab) in NSCLC, revealing last month a four-drug combination involving the checkpoint inhibitor extended survival versus a three-drug chemo regimen. Detailed results are expected this summer, and could add another twist to the back-and-forth competition between Merck and Bristol-Myers.
"I think there is a belief and acceptance throughout the field that combination immunotherapy is probably what the future holds," said Jill O'Donnell-Tormey, CEO of the Cancer Research Institute. "What that combination looks like I think is very much an open question."
Taken together, though, Monday's study results more firmly place combination immunotherapy alongside chemotherapy and radiation treatment as therapeutic tools in the treatment arsenal for lung cancer.
