NEW YORK – In the days since the US Food and Drug Administration granted approval for Bristol Myers Squibb's nivolumab (Opdivo) and ipilimumab (Yervoy) as a first-line treatment for non-small cell lung cancer, the question as to where this new option fits into the lung cancer immunotherapy landscape has been top of mind for many oncologists.
The combination, approved last week specifically for patients with metastatic non-small cell lung cancer who do not harbor EGFR or ALK gene mutations and who express PD-L1 in 1 percent or more of their tumor cells, presents a chemotherapy-free, first-line option. Any additional treatment option for metastatic lung cancer patients with poor prognosis, of course, is welcome news. "Lung cancer is a complex disease, and every patient facing a diagnosis of lung cancer is unique," said Nicholas Botwood, BMS' VP and head of oncology clinical development. "What physicians and patients need are treatment options."
Nivolumab plus ipilimumab has previously seen approvals for melanoma as well as certain patients with colorectal, kidney, and liver cancers. But while nivolumab plus ipilimumab may be a new option for fist-line lung cancer, it is entering a crowded treatment landscape in this setting, and the debate is on regarding how this combination stacks up to other available options for PD-L1-positive NSCLC patients.
For some thoracic oncologists already in the practice of prescribing the approved PD-L1 inhibitor pembrolizumab (Merck's Keytruda) for patients in this setting, the nivolumab-ipilimumab approval may present more of a lateral shift from the current standard of care than it does a notable improvement.
Pembrolizumab has been approved in a number of first-line NSCLC indications. It can be given as a single-agent in patients with a PD-L1 tumor proportion score of at least 1 percent and with chemotherapy regardless of PD-L1 status. The FDA also recently approved atezolizumab as a first-line option for patients with PD-L1 expression in 50 percent or more tumor cells.
Given these other options, "I and many of my colleagues who are heavily focused on thoracic oncology are struggling to find patients in whom we think that nivolumab and ipilimumab would be a better choice than anything else that we would be considering right now," said Jack West, a medical oncologist at City of Hope Cancer Center in Los Angeles.
Rapidly changing standards
The FDA approved the nivolumab-ipilimumab combination in first-line NSCLC based on data from part 1a of the Phase III CheckMate-227 trial, which compared the immunotherapy couplet to chemotherapy alone. The outcomes were positive; three years after the trial began, among patients receiving BMS' combination, the overall survival rate was 33 percent compared to 22 percent among those receiving chemotherapy alone. Three-year progression-free survival rates were 18 percent compared to 4 percent, respectively. For BMS, these sustained survival benefits are reason enough to bring this drug combination to market.
"We're seeing deep and durable responses that really translate into long-term survival outcomes for patients," Botwood said. "It's remarkable that three years out, we're seeing over a third of patients still alive."
Even though the nivolumab-ipilimumab combo improved outcomes over chemotherapy in CheckMate-227, the trial doesn't say anything about how the regimen would compare to the other immunotherapies that doctors are actually using in this subset of patients. Oncologists like West acknowledged the combination's superiority over first-line chemo, but importantly pointed out that first-line chemotherapy by itself is no longer the standard of care in this setting.
"Nivolumab-ipilimumab is a treatment that has not been shown to be better than the treatments that we consider standard of care in 2020, specifically pembrolizumab monotherapy, potentially atezolizumab monotherapy, or most commonly, chemo and pembrolizumab in combination," West said. "So, yes, nivolumab-ipilimumab is superior to a chemotherapy alone standard of care from 2015 or 2016, but it has not demonstrated superiority in any way to what we consider our prevailing standards of care right now."
Are two drugs better than one?
In attempting to differentiate its combination from other options on the market, BMS has highlighted the durability of the response seen with the regimen and attributed it to the synergy between nivolumab's PD-1 inhibition and ipilimumab's CTLA4-blockade. "Yervoy helps activate and proliferate T cells while Opdivo actually helps existing T cells discover the tumor," said Botwood, adding that "some of the T cells that are stimulated by Yervoy can actually become memory cells, and this may allow for long-term immune response."
While the two drugs may work in a complimentary way, there are no data to show that the couplet yields consistently improved results over other single-agent checkpoint inhibitors on the market or checkpoint inhibitors combined with chemotherapy.
James Stevenson, vice chair of the hematology and medical oncology departments at the Cleveland Clinic Cancer Center, noted that in CheckMate-227, there was also an arm that consisted of patients treated with nivolumab alone, and that the addition of ipilimumab resulted in longer-term benefits over single-agent nivolumab.
"But, we don't know how that stands compared to other single-agent therapies like pembrolizumab," he said. "We can't really extrapolate to say, 'Oh, because there was a benefit of adding ipilimumab to single-agent nivolumab, that's got to be the case across the board.'"
Stevenson also acknowledged that the duration of responses with nivolumab-ipilimumab may have been longer for some patients, but the available data do not indicate exactly who those patients are. While the trial stratified patients based on PD-L1 expression status, oncologists are hoping for more information on biomarker-defined subsets. For example, many experts — including BMS' Botwood — have pointed out that additional analysis in the PD-L1-negative subgroup in the CheckMate-227 trial suggested a survival benefit. However, this evaluation was not part of the original trial design, and therefore the finding was not ultimately factored in by the FDA in approving the combination.
In the absence of a head-to-head comparison, when oncologists consider the overall survival advantage seen in CheckMate-227 against the outcomes seen in studies involving other immunotherapy drugs, such as single-agent pembrolizumab versus chemotherapy in PD-L1 positive NSCLC, the benefit appears comparable.
"If the overall survival numbers for nivolumab and ipilimumab were really eye-popping and a lot stronger than the Keynote study data, then I think people would be paying more attention and would be more interested in adopting the combination therapy in patients that are candidates," said Stevenson.  Â
Data from Keynote-042 led the FDA to expand the approval of single-agent pembrolizumab to patients with PD-L1 tumor scores of at least one percent. In both CheckMate-227 and Keynote-042, where immunotherapies were pitted against chemotherapy, the overall survival hazard ratios hovered right around 0.80, meaning the immunotherapies reduced the risk of death by around 20 percent.
'Chemotherapy-free' not 'toxicity-free'
With the combination of chemotherapy and pembrolizumab, on the other hand, long-term follow-up of Keynote-189 showed a median overall survival that was nearly double that of chemotherapy alone in all patients, regardless of PD-L1 status.
"Chemo plus pembrolizumab is a much more compellingly superior strategy," said West. Â
That said, a chemotherapy-free, first-line option may be important for some patients who either cannot receive chemotherapy due to comorbidities or for patients who categorically refuse chemotherapy based on the known side effects. But, in these cases, both West and Stevenson offered cautionary counterpoints.
"For these patients [who cannot receive chemo], you wouldn't want to go with two immunotherapies versus one, because you're looking to limit side effects and maximize benefit," said Stevenson.
While chemotherapy certainly has significant known side effects, the nivolumab-ipilimumab combination can also cause its own share of adverse effects.
"The frequency and intensity of side effects [with nivolumab-ipilimumab] are comparable to those of standard platinum doublet chemotherapy," West said. "But they're less predictable. I would really say that people who think that 'chemo-free' is the same as 'less toxic' are misled. That's not the case."
Physical side effects are not the only toxicities that increase with two immunotherapy drugs versus one. Financial toxicities — that is, the financial burden that comes with two high drug price tags — is a consideration that this new approval raises, too.
According to a spokesperson from BMS, on a per-infusion basis, the list price for an infusion of 3 mg/kg of nivolumab plus 1 mg/kg of ipilimumab is $21,583, and the infusion of nivolumab 3 mg/kg alone is $6,580. In accordance with the recent FDA approval, recommended doses for metastatic NSCLC are nivolumab 3 mg/kg every two weeks and ipilimumab 1 mg/kg every six weeks until disease progression or unacceptable toxicity. The combination can be given up to two years in patients without disease progression.
By contrast, the list price for pembrolizumab, according to Merck, is $9,724.08 per 200 mg dose. In NSCLC (both as a monotherapy and in combination with chemo), pembrolizumab is approved for 200 mg every 3 weeks or 400 mg every 6 weeks.
In both cases, the list price may not be what most patients pay, though the price tags can be useful from a cost-benefit analysis standpoint.
As a final pertinent consideration on the question of two drugs versus one, oncologists have also flagged the dosing schedule of the new approval — requiring infusions every other week — in the context of the COVID-19 pandemic.
In comparison, when the FDA approved the 400 mg/six-week dosing schedule for pembrolizumab at the end of April, Merck took the opportunity to highlight the flexibility this would afford patients during the pandemic. "The important social distancing measures for COVID-19 have created a number of challenges for people with cancer, including keeping to planned treatment schedules," said Roy Baynes, senior VP and head of global clinical development at Merck Research Laboratories. "[The] approval of an every six-week dosing schedule for Keytruda gives doctors an option to reduce how often patients are at the clinic for their treatment."
Requiring patients to visit the infusion center more often poses greater exposure risks, which, in turn, is something worth considering given that patients with lung cancer are particularly vulnerable in the face of the respiratory virus. "Especially now, we're trying to keep patients away from the hospital and the clinic as much as we can, which I think emphasizes the importance of having a drug that's given less frequently," said Stevenson.
As additional data come to light, oncologists hope for clarity on the question of which patients would truly benefit from nivolumab and ipilimumab as opposed to other available options.
"We've seen so many approvals in lung cancer that we definitely have to figure out how we're going to rank some of these treatments," said Stevenson. "Based not only on the data we have, but also on other factors, including the schedule of the drugs, the cost of the drugs … we have to put all of that together to try to do what's best for our patients."
Pivots, regulatory hurdles
While the nivolumab-ipilimumab combination was approved by the FDA in first-line, PD-L1-positive NSCLC, the combination faced more pushback from European regulators. In January of this year, Europe's Committee for Medicinal Products for Human Use (CHMP) determined that it could not assess the full application in this setting due to certain protocol changes BMS made to CheckMate-227. The company accordingly withdrew its application from the European Medicines Agency.
In an earnings call that took place at the end of 2019, BMS CEO Giovanni Caforio acknowledged that the company was "disappointed by the position taken by the CHMP," but added, "we continue to view the combination of Opdivo and Yervoy as a differentiated regimen, with the potential for long-term survival and one that should be available to patients globally."
Botwood confirmed that the company does not have plans to resubmit an application for the drug combination in Europe at this time — at least, not for the same indication for which the FDA just granted approval. The company may have better chances for European approval for the two drugs combined with chemotherapy, though.
The company has said it is particularly encouraged by the results of CheckMate-9LA, which compared nivolumab-ipilimumab plus two cycles of chemotherapy to chemotherapy alone in patients regardless of PD-L1 status. The data from CheckMate-9LA will be presented at the upcoming American Society of Clinical Oncology's virtual annual meeting.