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Purpose: In this single-institution phase II investigator-initiated study, we assessed the ability of MAPK and VEGF pathway blockade to overcome resistance to immunotherapy in microsatellite-stable metastatic colorectal cancer (MSS mCRC)., Patients and Methods: Patients with MSS, BRAF wild-type mCRC who progressed on ≥2 prior lines of therapy received pembrolizumab, binimetinib, and bevacizumab until disease progression or unacceptable toxicity. After a safety run-in, patients were randomized to a 7-day run-in of binimetinib or simultaneous initiation of all study drugs, to explore whether MEK inhibition may increase tumor immunogenicity. The primary endpoint was objective response rate (ORR) in all patients combined (by Response Evaluation Criteria in Solid Tumors v1.1)., Results: Fifty patients received study drug treatment; 54% were male with a median age of 55 years (range, 31-79). The primary endpoint, ORR, was 12.0% [95% confidence interval (CI) 4.5%-24.3%], which was not statistically different than the historical control data of 5% (P = 0.038, exceeding prespecified threshold of 0.025). The disease control rate was 70.0% (95% CI, 55.4%-82.1%), the median progression-free survival 5.9 months (95% CI, 4.2-8.7 months), and the median overall survival 9.3 months (95% CI, 6.7-12.2 months). No difference in efficacy was observed between the randomized cohorts. Grade 3 and 4 adverse events were observed in 56% and 8% of patients, respectively; the most common were rash (12%) and increased aspartate aminotransferase (12%)., Conclusions: Pembrolizumab, binimetinib, and bevacizumab failed to meet its primary endpoint of higher ORR compared with historical control data, demonstrated a high disease control rate, and demonstrated acceptable tolerability in refractory MSS mCRC., (©2024 The Authors; Published by the American Association for Cancer Research.)

Nestling birds may honestly signal their need for food to provisioning adults, or begging might be a manipulative attempt to coerce additional food from providers, but in either case, providers respond to an increase in begging with an increase in feeding. We used playback of begging calls recorded from nestlings to determine whether male and female red-winged blackbirds increase their feeding rates in response to an apparent increase in begging. Both females and males fed broods at significantly higher rates after 5-min begging call playbacks than before, although only eight of 30 males were observed to feed nestlings in this study. In contrast, using the same playback design, neither females nor males altered their feeding rates significantly in response to broadcasts of noise. These results and others suggest that begging vocalizations are a basis for short-term adjustments in the rate at which nestling birds are provisioned. These results are also compared with those of a similar study of the same species, in which playback had no significant effect on rates of provisioning. Copyright 1998 The Association for the Study of Animal Behaviour.