Early Phase 3 trials like JAVELIN adding immunotherapy to chemoradiation failed to improve outcomes. However, subgroup analyses consistently showed a potential benefit in PD-L1 high-expressing patients, a crucial lesson that informed the design of subsequent, more successful studies.

In the Keynote 522 trial for early-stage TNBC, adding pembrolizumab to chemotherapy resulted in only a modest improvement in pathological complete response (pCR). Surprisingly, this small initial gain translated into much more robust and significant long-term improvements in event-free and overall survival.

The TOURMALINE study confirmed that pairing the checkpoint inhibitor Durvalumab with various gemcitabine-based chemo combinations (not just cisplatin) is safe and effective in biliary tract cancer. This provides crucial real-world evidence supporting clinical flexibility beyond the rigid protocols of pivotal trials.

The positive outcome of the KEYNOTE-B96 trial in platinum-resistant ovarian cancer, in contrast to prior failed immunotherapy trials, is likely attributable to the weekly paclitaxel backbone. This metronomic dosing promotes an immune-active tumor microenvironment, enhancing the efficacy of pembrolizumab.

The Matterhorn study found that adding the immunotherapy drug Durvalumab to FLOT chemotherapy significantly improved survival in localized gastric cancer. Surprisingly, this benefit extended to patients with low or negative PD-L1 expression, challenging the biomarker's predictive value for immunotherapy efficacy in this perioperative setting.

The discontinuation rate for pembrolizumab due to side effects was lower in the LITESPARK 022 trial compared to the earlier Keynote 564 trial (20%). This trend suggests that as clinicians gain more experience with immune checkpoint inhibitors, they are becoming more adept at managing immune-related adverse events, allowing more patients to complete their therapy.

In the Matterhorn trial, while completing the full perioperative FLOT plus durvalumab regimen yields the best outcomes, the immunotherapy's benefit persists even with partial adherence. Patients receiving some or even no adjuvant durvalumab still showed superior event-free survival compared to chemotherapy alone, a key finding for real-world practice.

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.

Despite being the backbone for new combination therapies in trials like Matterhorn, the FLOT chemotherapy regimen has significant toxicity. Approximately 30% of patients discontinue treatment due to adverse events, and only half manage to complete the post-surgery adjuvant portion, posing a major clinical challenge in real-world settings.