An ADC may show better response rates than chemotherapy, but its true benefit is compromised if toxicities lead to treatment discontinuation. As seen with failed PARP/IO combinations, if patients cannot tolerate a drug long enough, the regimen's overall effectiveness can become inferior to standard therapy.

When debating immunotherapy risks, clinicians separate manageable side effects from truly life-altering events. Hypothyroidism requiring a daily pill is deemed acceptable, whereas toxicities like diabetes or myocarditis (each ~1% risk) are viewed as major concerns that heavily weigh on the risk-benefit scale for early-stage disease.

Immunotherapy antibodies bind to immune cells for weeks or months, a pharmacodynamic (PD) effect far longer than their pharmacokinetic (PK) half-life. This long-lasting binding suggests that minor variations in infusion timing for subsequent doses are unlikely to impact overall outcomes, casting doubt on the study's core hypothesis.

While the feared side effect of severe lung inflammation (pneumonitis) did not increase, other immune-mediated adverse events did. This led to higher rates of treatment discontinuation in the experimental arm, potentially negating any benefits of the concurrent approach and contributing to the trial's failure.

Developers often test novel agents in late-line settings because the control arm is weaker, increasing the statistical chance of success. However, this strategy may doom effective immunotherapies by testing them in biologically hostile, resistant tumors, masking their true potential.

A significant criticism of the pivotal KEYNOTE-564 trial is that only half the patients in the control arm received standard-of-care immunotherapy upon relapse. This lack of subsequent optimal treatment complicates the interpretation of the overall survival benefit, raising questions about its true magnitude.

While KEYNOTE-905 showed dramatic survival benefits with neoadjuvant plus adjuvant EV-pembrolizumab, its design makes it impossible to isolate the benefit of each phase. The high (57%) pathologic complete response after neoadjuvant therapy alone suggests many patients may be overtreated with adjuvant cycles, risking unnecessary long-term toxicity like neuropathy.

The study presented three different datasets over a short period. While efficacy endpoints like PFS and OS changed, the toxicity data remained identical. This is highly unusual, as resolving censored patient data for efficacy should also lead to updated toxicity information, suggesting a rushed or incomplete analysis process.

Immunotherapies can be effective even without causing significant tumor shrinkage. Immunocore's drug KimTrack had a low 5-7% objective response rate (ORR) but demonstrated a massive overall survival (OS) benefit, challenging the reliance on traditional chemotherapy metrics for evaluating modern cancer treatments.