Most patients with advanced non-small cell lung cancer (NSCLC) can now avoid having chemotherapy as a first-line treatment, after a large, randomized trial showed that immunotherapy with the programmed cell death ligand 1 (PD-L1) blocker pembrolizumab (Keytruda, Merck) is effective even in patients with minimal PD-L1 expression.
The findings could double the population of patients with advanced NSCLC eligible to receive first-line immunotherapy alone and were hailed as a "true milestone" by experts here at the American Society of Clinical Oncology (ASCO) 2018.
In patients with only 1% or greater PD-L1 expression, pembrolizumab was associated with around 20% better overall survival than chemotherapy, reported Gilberto Lopes, MD, MBA, a medical oncologist at the Sylvester Comprehensive Cancer Center, University of Miami Health System, Florida, and colleagues.
For patients with greater PD-L1 expression, the benefit from immunotherapy vs chemotherapy was even greater, with 23% better overall survival seen in patients with 20% or greater expression, and 31% better survival in those with 50% or greater expression.
Moreover, the Keynote-042 trial, which involved more than 1250 patients with advanced NSCLC, showed that the immunotherapy more than doubled the duration of overall treatment response, regardless of the level of PD-L1 expression.
Patients given first-line pembrolizumab also experienced far fewer toxicities than those treated with chemotherapy, with less than half the rate of grade 3 or greater adverse events.
Commenting on the findings, ASCO expert John Heymach, MD, PhD, said at a press briefing, "I really see this as a double-win for patients."
"Often, advances in survival for lung cancer patients come at a cost of significant toxicities," he added.
"Here, by contrast, not only are patients living longer…they're also receiving a treatment that has substantially less toxicity across virtually all measures."
That, Heymach emphasized, has a major impact on patients' day-to-day lives, as the toxicities associated with pembrolizumab are "typically easily managed" compared with those seen with chemotherapy and are "reversible on stopping the drug."
Heymach, who is from the University of Texas MD Anderson Cancer Center in Houston, said that the current and recent studies show that "we're now leaving an era where the only choice for NSCLC patients is to start with chemotherapy, because now we can say that the vast majority of patients can potentially receive benefit from immunotherapy instead of chemotherapy."
More Patients Now Eligible
Pembrolizumab is currently approved by the US Food and Drug Administration for the initial treatment of NSCLC in patients with PD-L1 expression of at least 50%, which is based on results from the earlier KEYNOTE-024 study and covers around one third of patients.
However, other, primarily second-line, trials have suggested that anti–PD-L1 immunotherapies can also be effective in patients with little or no expression of the protein.
The researchers therefore conducted the KEYNOTE-042 study, which involved 1274 patients with NSCLC and PD-L1 expression of 1% or greater who did not have epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) translocation.
They were randomly assigned in a 1:1 fashion to pembrolizumab 200 mg or the investigator's choice of six or fewer cycles of paclitaxel plus carboplatin or pemetrexed plus carboplatin with optional paclitaxel plus carboplatin maintenance.
PD-L1 expression was 50% or greater in 599 patients and 20% or greater in 818 patients. After a median follow-up of 12.8 months, 13.7% patients were still receiving pembrolizumab and 4.9% were receiving maintenance chemotherapy.
The results showed that overall survival was significantly greater with pembrolizumab than with chemotherapy at all levels of PD-L1 expression.
For patients with 50% or greater PD-L1 expression, the hazard ratio for overall survival for pembrolizumab vs chemotherapy was 0.69 (P = .0003), at a median survival of 20.0 months vs 12.2 months.
In those with 20% or greater expression, the hazard ratio was 0.77 (P = .0020), at a median survival of 17.7 months for pembrolizumab vs 13.0 months for chemotherapy, while in those with greater than 1% expression, the hazard ratio was 0.81 (P = .018), at a median survival of 16.7 months and 12.1 months, respectively.
The duration of treatment response was also longer with pembrolizumab than chemotherapy at all levels of PD-L1 expression, at 20.2 months vs 10.8 months for PD-L1 expression of 50% or greater, 20.2 months vs 8.3 months for 20% or greater expression, and 20.2 months vs 8.3 months for 1% or greater expression.
The toxicity profile seen with pembrolizumab was also substantially more favorable than that with chemotherapy, with rates of 62.7% vs 89.9% for treatment-related adverse events, and 17.8% vs 41.0% for grade 3 to 5 treatment-related adverse events.
As expected, the rates of immune-mediated adverse events were higher with pembrolizumab at 27.8% vs 7.2% for chemotherapy. There also was only one immune-related death in the pembrolizumab group, but the investigators are unsure whether the death was directly related to treatment as the patient had also progressed.
Lopes said, "We can come to the conclusion that pembrolizumab becomes an option for patients who have advanced NSCLC and who do not have EGFR mutations and ALK translocation and who express PD-L1 at the at least 1% level."
However, he emphasized that "we do need to do a lot more work."
"Even though patients do better today, they still did not do well enough," he said.
"The vast majority of patients with advanced lung cancer will have disease progression and will succumb to lung cancer, so we do need to continue doing a lot more work."
"We are seeing new studies at this ASCO with combinations of chemotherapy and immunotherapies. We are looking at combinations of immunotherapies and we hope that at the next few meetings, we can see results that are even better than the ones I have shown here today."
While describing the study as "a true milestone for the field," Heymach agreed that there is more work to be done to further refine who will benefit the most from which drugs or combinations of drugs.
He said, "There are still important unanswered questions, of course, but there's a host of studies addressing these."
"For example, are there some patients for whom immunotherapy with chemotherapy is superior to immunotherapy alone? Are combinations of immunotherapy going to be superior to a single agent? How do we integrate targeted agents? And how do we deal with tumors once they've progressed after PD-1 monotherapy?
"But those will be addressed in time."
Heymach concluded: "For right now, I think this represents an important milestone because an era in which chemotherapy was the only option for NSCLC is drawing to a close.
"Now, virtually all NSCLC patients can receive a nonchemotherapy, either with immunotherapy or, if they have a driver mutation, with an appropriate targeted agent.
"So immunotherapy is here to stay for the vast majority of NSCLC patients as first-line treatment, and this represents a real importance advance for patients," Heymach concluded.
Discussing the findings following their presentation, Leena Gandhi, MD, PhD, director of thoracic oncology at the NYU Perlmutter Cancer Center, New York City, said that the question is whether patients should be "lumped back together" and treated as large groups or whether treatment should continue to be targeted.
She noted that while PD-L1 inhibition has "changed the landscape" for advanced NSCLC treatment, questions remain over which patients should receive which drugs.
Gandhi said that within this context, a key feature of the current study was that no patients in the treatment groups were allowed to cross over to the other therapy; this contrasts with studies conducted by using nivolumab (Opdivo, Bristol-Myers Squibb).
The results of KEYNOTE-042, she pointed out, showed that most of the benefit of pembrolizumab was "being driven" by the group with 50% or greater PD-L1 inhibition, with any improvement in overall survival taking much longer to appear in groups with lower levels of expression.
Given that, she asked: Is the benefit seen with pembrolizumab in advanced NSCLC worth it, and for whom? Or, to put it another way, do the findings meet the ASCO definition of a clinically meaningful benefit?
She pointed to the KEYNOTE-189 study (published online May 31 in the New England Journal of Medicine ), which showed that the combination of pembrolizumab and chemotherapy led to greater benefits in overall survival, as well as in progression-free survival and overall response rates, than those seen in the current study.
Another issue affecting patient choice for therapy is that of biomarkers for therapeutic outcome, with PD-L1 expression, for example, not well correlated with response and hampered by differences in results between assays.
Although tumor mutation burden has not yet been validated as a biomarker for response and changes over time, Gandhi said that it appears to have additive value when combined with PD-L1 levels.
Moreover, molecular profiling can be performed in ever-shorter timeframes and can therefore offer useful information for decision making.
Gandhi believes that with further biomarker refinement and better profiling of patient responses, it will eventually be possible to define specific patient groups who will benefit from immunotherapy alone, combination immunotherapy, or combination chemotherapy and immunotherapy.
Consequently, she said that there are "multiple caveats" for saying that pembrolizumab alone is the new standard of care in advanced NSCLC and that lung cancer is "no longer a one-size-fits-all" disease.
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