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Toxicity, costs must be considered when using chemotherapy-immunotherapy combinations for lung cancer
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Two faculty members at HemOnc Today New York debated whether immunotherapy alone or in combination with chemotherapy is the ideal treatment approach for lung cancer.
Philip D. Bonomi, MD, professor of medical oncology in the department of internal medicine at Rush University Medical Center, argued that the combination of immunotherapy and chemotherapy is an effective regimen that will be used more frequently in the future.
“Chemotherapy is a very good partner to immunotherapy and I think it is something we could see more of,” Bonomi said.
He noted the combination is particularly effective for certain patients with lung cancer, citing results from two trials published within the past several months.
The phase 3 KEYNOTE-189 trial included 616 untreated patients with metastatic nonsquamous non-small cell lung cancer regardless of PD-L1 expression. Patients had no ALK or EGFR genomic tumor aberrations and had not received prior systemic therapy for advanced disease.
Researchers randomly assigned 405 patients to pemetrexed plus the anti-PD-1 agent pembrolizumab (Keytruda, Merck) and either cisplatin or carboplatin. The other 202 patients received pemetrexed plus placebo and either cisplatin or carboplatin.
Patients assigned the pemetrexed-pembrolizumab regimen achieved significantly longer median PFS (8.8 months vs. 4.9 months; HR = 0.52; 95% CI, 0.43-0.64) and OS (not reached vs. 11.3 months; HR = 0.49; 95% CI, 0.38-0.64).
The most common any-grade adverse events in the pemetrexed-pembrolizumab group were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%) and pyrexia (20%).
The phase 3 KEYNOTE-407 trial included 559 patients with metastatic squamous NSCLC who had received no prior systemic treatment for metastatic disease. Researchers enrolled patients regardless of PD-L1 expression.
Investigators randomly assigned 278 patients to receive 200 mg pembrolizumab and carboplatin every 3 weeks for four cycles, plus paclitaxel every 3 weeks for four cycles or nab-paclitaxel on days 1, 8 and 15 of every 3-week cycle for four cycles, followed by 200 mg pembrolizumab every 3 weeks. The other 281 patients received placebo plus the same chemotherapy regimen.
Treatment continued for 24 months, or until disease progression or unacceptable toxicity. Patients assigned placebo were given the opportunity to switch to single-agent pembrolizumab at the time of disease progression.
Patients assigned the pembrolizumab regimen achieved significantly longer OS (median, 15.9 months vs. 11.3 months; HR = 0.64; 95% CI, 0.49-0.85) and PFS (median, 6.4 months vs. 4.8 months; HR = 0.56; 95% CI, 0.45-0.7). Researchers also reported a higher objective response rate in the pembrolizumab group (58% vs. 35%; P = .0008).
Safety data from the first 101 patients assigned the pembrolizumab regimen showed 15% discontinued treatment due to adverse reactions. Slightly less than half (43%) of patients required treatment interruption due to adverse events, the most common of which were thrombocytopenia (20%), neutropenia (11%), anemia (6%), asthenia (2%) and diarrhea (2%).
“Squamous cell [lung cancer] has been a really depressing area,” Bonomi said. “The patients are sicker, they are older, they have more comorbidities and ... their survival is shorter.”
However, the addition of immunotherapy to chemotherapy can increase risk for hyperprogression, Bonomi said.
“My colleagues and I have seen it in at least six patients in front-line therapy,” Bonomi said. “It may just be anecdotes, but we need to collect more real-world data to see how this plays out.”
In the second half of the debate, Melissa L. Johnson, MD, associate director for lung cancer research at Sarah Cannon Research Institute, argued in favor of immuno-oncology agents alone for lung cancer rather than in combination with chemotherapy.
“The chemotherapy-free future is very bright,” Johnson said. “[Immunotherapy alone] works and is enough for some patients. We don’t understand exactly how chemotherapy and immunotherapy work together, so managing the toxicities from combination therapies is challenging. We don’t know which drugs to stop and when to apply steroids.”
Johnson cited data from several studies to support her argument, including KEYNOTE-042 and KEYNOTE-024.
The phase 3 KEYNOTE-042 trial showed first-line pembrolizumab conferred longer median OS than chemotherapy among patients with non-small cell lung cancer and PD-L1 expression.
Researchers randomly assigned 1,274 patients with locally advanced or metastatic NSCLC without EGFR mutations or ALK translocation to receive 200 mg pembrolizumab every 3 weeks (n = 637) or investigator’s choice of maximum six cycles of paclitaxel plus carboplatin or pemetrexed plus carboplatin (n = 637) with optional pemetrexed maintenance for nonsquamous disease.
Pembrolizumab significantly improved OS among patients with PD-L1 tumor proportion score of more than 50% (median OS, 20 months vs. 12.2 months; HR = 0.69; 95% CI, 0.56-0.85), more than 20% (17.7 months vs. 12 months; HR = 0.77; 95% CI, 0.64-0.92) and more than 1% (16.7 months vs. 12.1 months; HR = 0.81; 95% CI, 0.71-0.93).
Grade 3 to grade 5 treatment-related adverse events (17.8% vs. 41%) and any-grade treatment-related adverse events (62.7% vs. 89.9%) occurred less frequently with pembrolizumab than chemotherapy.
KEYNOTE-024 evaluated the safety and efficacy of pembrolizumab vs. platinum-based chemotherapy as first-line treatment for patients with NSCLC who had PD-L1 tumor proportion scores of 50% or greater but did not have EGFR/ALK aberrations.
Researchers randomly assigned 305 patients to pembrolizumab (n = 154) 200 mg every 3 weeks for up to 2 years or chemotherapy (n = 151). The study design allowed patients in the chemotherapy group to cross over to pembrolizumab.
An independent data and safety committee recommended the trial be discontinued after an interim analysis — performed at median follow-up of 11.2 months — showed significant improvements in PFS (HR = 0.5; 95% CI, 0.37-0.68) and OS (HR = 0.6; 95% CI, 0.41-0.89) with pembrolizumab.
Treatment-related grade 3 to 5 adverse events occurred among 31.2% of patients in the pembrolizumab group and 53.3% in the chemotherapy group.
Chemotherapy-associated toxicity is one reason why immunotherapy alone may be the best approach, Johnson said.
“Adding chemotherapy to immunotherapy increases toxicity,” Johnson said. “What doesn’t come across in presentations or in bar graphs is, what do you do with diarrhea in a patient who is getting [combination therapy]? Do you stop the chemotherapy? Do you stop the immunotherapy? If you’ve inflamed the situation irrespective, can you really keep the PD-1 [inhibitor] going?”
Cost is another factor. Six months of pembrolizumab treatment costs $90,608, whereas 6 months of therapy with combination regimens can cost $130,000 to $180,000, Johnson said.
Johnson said some believe untreated cancer — not “gas on the fire” from immunotherapy — causes hyperprogression among some patients.
“I would suggest that hyperprogression really doesn’t happen,” Johnson said.
Johnson did emphasize she believes that patients with low PD-L1 expression still need chemotherapy and immunotherapy, and that is the standard approach for that subgroup in her practice. – by John DeRosier
Reference:
Bonomi P and Johnson M. Is there still a role for chemotherapy in lung cancer treatment: Chemotherapy plus IO vs. IO alone. Presented at: HemOnc Today New York; March 21-23, 2019; New York.
Gandhi L, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1801005.
Paz-Ares L, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1810865.
Reck M, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1606774.
Reck M, et al. J Clin Oncol. 2019;doi:10.1200/JCO.18.00149.
Disclosures: Bonomi reports advisory board roles with AstraZeneca, Biodesix, Boehringer Ingelheim, Genentech/Roche and Merck. Johnson reports research funding to her institution from, consultant/advisory roles with and food/beverage/travel from AbbVie, Array BioPharma, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, EMD Serono, Genentech/Roche, Guardant Health, Incyte, Janssen, Loxo Oncology, Merck, Novartis, Pfizer, Sanofi and several other pharmaceutical companies. She also reports her spouse has consultant/advisory roles with Astellas and Otsuka Pharmaceuticals.