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Immunotherapy-chemotherapy combination extends survival in newly diagnosed metastatic lung cancer
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CHICAGO — The addition of the anti-PD-1 therapy pembrolizumab to chemotherapy significantly improved outcomes among patients with newly diagnosed metastatic nonsquamous non-small cell lung cancer who do not harbor EGFR or ALK alterations, according to results of the randomized phase 3 KEYNOTE-189 trial presented at American Association for Cancer Research Annual Meeting.
Trial results showed improvements in PFS, OS and overall response rate among all patient groups, halving the risk for death and demonstrating “an unprecedented effect of therapy in the first-line setting” for this patient population, said researcher Leena Gandhi, MD, PhD, associate professor in the department of medicine and director of the thoracic medical oncology program at Perlmutter Cancer Center at NYU Langone Health.
The combination also exhibited a manageable safety profile.
“[This] really may represent a new standard of care for first-line treatment of this group, irrespective of PD-L1 expression,” Gandhi said during a press conference.
Long-term survival of patients with advanced NSCLC is poor. Standard treatment typically consists of chemotherapy, but the survival benefit is measured in months, according to study background.
Results from one cohort of the KEYNOTE-021 trial showed the addition of the anti-PD-1 therapy pembrolizumab (Keytruda, Merck) to chemotherapy with pemetrexed plus carboplatin significantly improved PFS and overall response rate among patients with advanced nonsquamous NSCLC.
In the double-blind KEYNOTE-189 trial, Gandhi and colleagues assessed whether an immunotherapy-chemotherapy combination would confer benefit as first-line therapy for patients with metastatic nonsquamous NSCLC.
The analysis included 616 patients with previously untreated stage IV nonsquamous NSCLC. All patients had ECOG performance status of 0 or 1, and they had no EGFR or ALK alterations.
Researchers randomly assigned 410 patients to pembrolizumab 200 mg, pemetrexed 500 mg/m2, and either carboplatin area under the curve 5 or cisplatin 75 mg/m2. The other 206 patients received placebo plus chemotherapy.
Patients received their assigned treatment every 3 weeks for four cycles, followed by maintenance therapy with pemetrexed plus either pembrolizumab or placebo.
Investigators stratified patients by PD-L1 tumor proportion score (< 1% vs. 1%), platinum agent and smoking status. The majority (63%) of enrolled patients had tumor proportion score of at least 1, carboplatin was chosen for 72.2% of patients, and 88.1% were current or former smokers.
Eligible patients assigned the placebo regimen who developed verified progressive disease could cross over to pembrolizumab monotherapy.
OS and PFS in the intention-to-treat population served as primary endpoints.
More than three-quarters (76.5%) of patients assigned pembrolizumab and two-thirds (66.8%) of those assigned placebo received at least five cycles of pemetrexed.
Median follow-up was 10.5 months (range, 0.2-20.4). At that time, 33.8% of patients assigned pembrolizumab and 17.8% of those assigned placebo remained on treatment.
Patients assigned pembrolizumab plus chemotherapy achieved significantly longer median OS (not reached vs. 11.3 months; HR = 0.49; 95% CI, 0.38-0.64). Researchers observed the OS benefit regardless of whether patients had PD-L1 tumor proportion scores less than 1% (HR = 0.59; 95% CI, 0.38-0.92), scores of 1% to 49% (HR = 0.55; 95% CI, 0.34-0.9), or scores of 50% or greater (HR = 0.42; 95% CI, 0.26-0.68).
Results also showed significantly longer median PFS (8.8 months vs. 4.9 months; HR = 0.52; 95% CI, 0.43-0.64) among pembrolizumab-treated patients.
The PFS benefit persisted regardless of whether patients had PD-L1 tumor proportion scores less than 1% (HR = 0.75; 95% CI, 0.53-1.05), scores of 1% to 49% (HR = 0.55; 95% CI, 0.37-0.81), or scores of 50% or greater (HR = 0.36; 95% CI, 0.25-0.52).
Researchers also reported a higher ORR among pembrolizumab-treated patients (47.6% vs. 18.9%; P < .00001). Again, the ORR benefit persisted regardless of whether patients had PD-L1 tumor proportion scores of less than 1% (32.3% vs. 14.3%), 1% to 49% (48.4% vs. 20.7%), or 50% or higher (61.4% vs. 22.9%).
Sixty-seven patients assigned placebo crossed over to pembrolizumab. This equated to a 41.3% crossover rate in the intention-to-treat population, or a 50% rate when excluding patients who remained on treatment at the time of analysis.
“Despite a 50% crossover rate, there was still a very clear survival benefit, suggesting that combination therapy upfront may be better than if PD-1/PD-L1 inhibitors are given later in the course of illness,” Gandhi said in a press release.
A similar percentage of patients assigned pembrolizumab and placebo experienced grade 3 or higher adverse events (67.2% vs. 65.8%). However, a higher percentage of patients assigned pembrolizumab discontinued any treatment due to adverse events (27.7% vs. 14.9%), discontinued all treatment due to adverse events (13.8% vs. 7.9%) or died due to adverse events (6.7% vs. 5.9%).
Most toxicities were expected, except for an elevated rate of acute kidney injury in the pembrolizumab group (overall incidence, 5.2% with pemetrexed vs. 0.5% with placebo; grade 3 to grade 5 incidence, 2% vs. 0%).
Nephritis incidence was 1.7% in the pembrolizumab group and 0% in the placebo group.
The study was not designed to assess whether patients with high PD-L1 expression benefitted from pembrolizumab monotherapy compared with pembrolizumab plus chemotherapy.
“[Also], the control arm did not perform as well as some historical controls, but this was a rigorous randomized study which did show a clear difference between the two arms,” Gandhi said in the release. – by Mark Leiser
Reference:
Gandhi L, et al. Abstract CT075. Presented at: American Association for Cancer Research Annual Meeting; April 14-18, 2018; Chicago.
Disclosure: Merck sponsored this study. Gandhi reports advisory board roles with and research funding from Merck, as well as study funding from Merck Sharpe & Dohme. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Edwin Yau, MD, PhD
These results are practice changing — or, at the very least, practice confirming depending whether you have already been using this approved regimen. In my clinical practice, I have been having a discussion with my patients about this regimen, and it will be nice to be able to go back to them and tell them we have survival data. Going forward, this definitely will be my choice of regimen for nonsquamous patients, regardless of PD-L1 expression.
The issue becomes, what are we going to do with PD-L1-high patients? I think it will require a discussion with individual patients. But, certainly, anyone who has low or intermediate PD-L1 expression — or, if we don’t know their PD-L1 status — this would become the standard of care.
In a real-world setting, the KEYNOTE regimen is definitely intriguing from a patient tolerability standpoint compared with ipilimumab (Yervoy, Bristol-Myers Squibb) plus nivolumab (Opdivo, Bristol-Myers Squibb). The regimen is a lot easier to tolerate. That being said, there is an area where they don’t overlap, so all of these modalities will be in play. I definitely think the KEYNOTE data are very strong. The ipilimumab-nivolumab data in the tumor mutation burden-high population also is very intriguing, and I would consider it for patients who are tumor mutation burden high and PD-L1 low, who can tolerate the immune therapy. Certainly it’s great to have both of these options clinically, but I think the tumor mutation burden biomarker is not as well developed, and it will take integration into our clinical workflow in terms of how we sequence the information we get from our biopsy samples.
Perspective
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Hossein Borghaei, DO, MS
This could be considered a practice-changing abstract. However, in the United States, the practice has already changed. This is an FDA-approved regimen based on results of the phase 2 study, and a lot of doctors are using this combination. The phase 3 trial confirms results of the phase 2 study, which is always heartwarming to see.
Still, this is a significant study because the combination is highly effective, even when you look across patient groups based on levels of PD-L1 expression. Response rates were high, PFS was good, OS was really good and durable responses were reported. This regimen also has an ease of administration, given it includes a chemotherapy backbone that a lot of people are familiar with.
There seems to be a con for every study. In this case, if there is one, the question would be: Once patients progress through a chemotherapy-immunotherapy combination, what do you do with them? Unless there are clinical trials or other studies to suggest once one immuno-oncology agent fails you can add another and recover something, these patients are probably looking at old-fashioned chemotherapy with docetaxel, gemcitabine or whatever else might be available.
As an academician, you can always come up with things you might worry about. For instance, I worry that we might get less tissue collected and less testing performed. Because this regimen appears effective for everybody with nonsquamous histology, clinicians may think, ‘I don’t have to wait for tissue or get more tissue. This regimen is good for everybody so I’m just going to give it.’ I’m not saying that is going to happen, but there are those theoretical risks.
It also is important to keep in mind that patients with EGFR or ALK translocations were not allowed to participate in this study, and this is for treatment-naive patients without molecularly driven tumors. Other than that, this is a highly positive phase 3 study that can change the treatment landscape in lung cancer for a long time.
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