Pemetrexed appears safe for maintenance therapy with pembrolizumab in metastatic nonsquamous NSCLC
The addition of pemetrexed plus platinum chemotherapy to the immune checkpoint inhibitor pembrolizumab showed manageable toxicity among patients with metastatic nonsquamous non-small cell lung cancer, according to results of a post-hoc analysis of the KEYNOTE-189 trial presented at the virtual American Association for Cancer Research Annual Meeting.
Researchers found most treatment-related adverse events occurred early in the study and resolved quickly from onset, demonstrating that a maintenance regimen of pembrolizumab (Keytruda, Merck) plus pemetrexed could be safely tolerated with long-term use.
“Results from a recent study showed that about half of practitioners continued pembrolizumab alone during maintenance therapy rather than a combination of pembrolizumab and pemetrexed,” Edward B. Garon, MD, associate professor of medicine in the division of hematology/oncology and director of thoracic oncology at David Geffen School of Medicine at University of California, Los Angeles, said during a presentation.
Data alone cannot explain why practitioners make a particular decision, Garon added, but the perception of toxicity that accompanies pemetrexed could be the reason why the drug is used infrequently during maintenance therapy.
“There are few data available relative to toxicities during the maintenance therapy period; therefore, we sought to further elucidate the time to onset and resolution of grade 3 or greater toxicity among patients in the KEYNOTE-189 study ... to see if this could contextualize why some practitioners use pembrolizumab alone during the maintenance period,” Garon said.
This is especially important, he noted, because phase 3 results from KEYNOTE-189 showed improved survival when pemetrexed plus platinum-based chemotherapy is given in tandem with an immune checkpoint inhibitor.
The post-hoc analysis included the all-subjects-as-treated population from the KEYNOTE-189 trial, with a data cut-off date of Nov. 8, 2017.
Researchers assessed the safety of pembrolizumab plus pemetrexed maintenance based on time to symptom onset, time to grade 3 to grade 5 adverse event resolution and time to discontinuation due to adverse events after receipt of pemetrexed and platinum chemotherapy with pembrolizumab vs. with placebo.
The analysis included 607 patients (median age, 64 years) — 405 in the pembrolizumab group and 202 in the placebo group. Seventy-two percent of patients received carboplatin and 18% had a history of brain metastases at baseline.
Median treatment duration was 7.4 months in the pembrolizumab group and 5.4 months in the placebo group.
Researchers observed similar rates of grade 3 to grade 5 adverse events in the pembrolizumab and placebo groups (67.2% vs. 65.8%). They reported onset and resolution times for adverse events with a greater than 2% incidence.
The shortest time to onset of symptoms was 6 days for nausea, whereas the longest was 125 days for pneumonitis. Median time from onset to resolution of symptoms ranged from 4 days for vomiting to 25 days for pneumonitis and anemia.
Most grade 3 or greater adverse events occurred within the first four cycles of treatment, except for pneumonitis. Similarly, most grade 3 or greater adverse events resolved within 2 weeks of onset, except for pneumonitis and acute kidney injury. Pneumonitis (2.7%) and acute kidney injury (2%) were the most common treatment-related adverse events in the pembrolizumab group.
Nearly twice as many patients in the pembrolizumab group discontinued the study drug compared with the placebo group (20% vs. 10.9%). Pemetrexed was discontinued due to adverse events at a similar rate when combined with pembrolizumab vs. placebo (2% vs.1.4% on average per cycle, respectively).
“The superior efficacy of pembrolizumab plus pemetrexed plus platinum-based chemotherapy was achieved with manageable toxicity, including limited treatment discontinuation for adverse events, especially during the pembrolizumab-plus-pemetrexed maintenance phase,” Garon said. “This is important due to the frequently prolonged duration of maintenance therapy based on the efficacy seen in the KEYNOTE-189 regimen.” – by Drew Amorosi
Reference:
Garon EB, et al. Abstract CT082. Presented at: AACR Annual Meeting; April 27-28, 2020 (virtual meeting).
Perspective
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In this post-hoc safety analysis of KEYNOTE-189, the superior efficacy of pembrolizumab, pemetrexed and platinum was achieved with manageable toxicity, including limited treatment discontinuation for adverse events, particularly during the pembrolizumab-plus-pemetrexed maintenance phase. Most grade 3 or higher adverse events, except pneumonitis, first occurred during cycles 1 through 4 and were resolved within 2 weeks from onset (except pneumonitis and acute kidney injury). Pneumonitis was the only toxicity that developed during the maintenance period in the pembrolizumab-plus-pemetrexed arm vs. the pembrolizumab-plus-placebo arm. Only two adverse events leading to discontinuation in more than 1% of the population were observed in the maintenance phase: pneumonitis in both arms and acute kidney injury in the pembrolizumab-plus-pemetrexed arm.
The novelty of the current analysis is to assess toxicities that are specific to the maintenance period and to show feasibility of maintenance combination treatment with pembrolizumab and pemetrexed. It is of particular importance, especially in patients with NSCLC whose tumors show low PD-L1 expression or low tumor mutation burden, to continue combination pembrolizumab-pemetrexed in the maintenance phase.
Patients and providers are particularly interested in understanding the benefit to continue the pembrolizumab-pemetrexed combination. Therefore, future research should investigate the toxicity profile and patients’ reported outcomes of pembrolizumab plus pemetrexed vs. pembrolizumab alone in the maintenance phase of advanced, incurable NSCLC, considering the significant length of time patients spend on maintenance therapy.
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These are important but mostly practice-reinforcing data. After the onslaught of new immunotherapy trials and rapid approvals, it is nice to look back at some of the data and learn more about the possible toxicities of these combination therapies. Looking at the all-subjects-as-treated population gives us more insight about when to look for certain toxicities and how long to expect them to last. This allows us to better inform our patients and make the best treatment and supportive care decisions with them. As we continue to produce an unprecedented amount of novel therapies and combinations, it will be important to continue to highlight the safety of these interventions.
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KEYNOTE-189 was the pivotal trial that established chemoimmunotherapy with pemetrexed and carboplatin plus pembrolizumab as the standard of care for first-line treatment of metastatic nonsquamous NSCLC. The purpose of this post-hoc analysis was to assess toxicities specific to the maintenance period.
This type of analysis is important to determine patterns and reasons for discontinuation of treatment, and it does so with a straightforward approach for two arms of KEYNOTE-189.
The rate of adverse events was comparable between the two groups; however, the rate of adverse events leading to discontinuation of treatment was approximately twice as high in the pembrolizumab arm when compared with the placebo arm. Approximately one-third of discontinuations occurred within the induction phase, or the first four cycles of therapy.
In the absence of randomized controlled trials assessing the relative efficacy of pemetrexed plus pembrolizumab compared with pembrolizumab alone as maintenance therapy, these data support efforts to continue pemetrexed during the maintenance phase in the absence of unacceptable toxicity.
Knowledge of patterns of late toxicity during the maintenance phase of therapy may inform clinical decisions to discontinue or restart one or both drugs.
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Garon EB, et al. Abstract CT082. Presented at: AACR Annual Meeting; April 27-28, 2020 (virtual meeting).