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We still have the option of using pemetrexed and carboplatin either alone or potentially combined with bevacizumab. But the prior regimens have not been excluded. It’s pretty unusual to see significant bleeding or clotting, and headaches and hypertension are not major features of this new combination.Īs a result of the positive findings of KEYNOTE-189, the pemetrexed/carboplatin/pembrolizumab regimen has now been included in the NCCN guidelines. We don’t see the toxicities that we typically associate with bevacizumab. Pemetrexed/carboplatin/pembrolizumab does result with a different constellation of immune-mediated toxicities, particularly including hypothyroidism, arthralgias, arthritis, rash, dermatitis, and sometimes pruritus in the absence of a significant rash. In those with a PD-L1 expression of 50% or higher, that response rate jumps up into the mid-60s.īased on these data, the triplet has now become my standard regimen. We observed an overall response benefit-46%, 48% compared with about 18%. And again, as we’ve seen with overall survival, the survival advantage was magnified in those with higher levels of PD-L1 expression. It was approaching 9 months in the triplet arm. In the control group, the median progression-free survival was just under 5 months. The progression-free survival advantage was observed across the board. The survival benefits were relatively more pronounced in the PD-L1 50% or higher group, but those survival advantages were also observed in the 1% to 49% group-in those patients without PD-L1 expression. Despite the crossover, we’ve observed a significant improvement in overall survival with, really, the best hazard ratio I’ve seen in my career. At the time of disease progression, patients on the control arm could cross over to single-agent pembrolizumab or to an immunotherapy agent of their choice. Likewise, the control arm featured indefinite maintenance with pemetrexed.
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The triplet was given for 4 cycles with pemetrexed, which was continued as maintenance therapy indefinitely, and pembrolizumab continued for up to 2 years. There was 2:1 randomization of that same combination versus standard pemetrexed and carboplatin.
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KEYNOTE-189 was the follow-up randomized phase III trial.
#KEYNOTE MEANING TRIAL#
This randomized phase II trial ultimately led to a conditional approval for the pemetrexed/carboplatin/pembrolizumab triplet regimen, which has now been firmly entrenched based on KEYNOTE-189. Pemetrexed and bevacizumab were continued together as maintenance treatment.Īll of that pretty much changed with the emergence, first, of the KEYNOTE-021g precursor trial. In phase III trial data, this had proved a clear survival advantage compared with chemotherapy alone.
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In patients who weren’t candidates for pemetrexed, I would give paclitaxel and carboplatin with bevacizumab. Up until that point, for this population, I generally treated individuals with pemetrexed and carboplatin, either alone or with bevacizumab, an angiogenesis inhibitor. Langer, MD, FACP: KEYNOTE-189 was a game changer in nonsquamous non-small cell lung cancer.