The confirmatory Code Break 200 study for sotorasib demonstrated a statistically significant improvement in progression-free survival (PFS) over docetaxel. However, it failed to show a similar benefit in overall survival (OS), a critical distinction for oncologists weighing long-term patient outcomes.

In the SPOTLIGHT trial, adding zolbituximab to FOLFOX for Claudin-18.2 positive patients improved progression-free and overall survival. However, it did not significantly increase the objective response rate, demonstrating that survival benefit can be decoupled from tumor shrinkage metrics.

In trials like ASCENT-4, where over 80% of the control arm received sacituzumab govitecan upon progression, the true overall survival (OS) benefit is obscured. This makes progression-free survival (PFS) a more reliable endpoint for evaluating the drug's first-line efficacy.

The AscentO3 trial lacked an overall survival benefit for its primary endpoint because its design ethically allowed patients on the chemotherapy arm to receive sacituzumab govitecan upon progression. This 'crossover' improves care for the control group but makes it statistically difficult to demonstrate a first-line survival advantage.

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.

An overall survival (OS) benefit in an adjuvant trial may not be meaningful for patients in systems (e.g., the U.S.) with guaranteed access to the same effective immunotherapy upon recurrence. The crucial, unanswered question is whether treating micrometastatic disease is inherently superior to treating macroscopic disease later, a distinction current trial data doesn't clarify.

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.

As survival times for metastatic gastric cancer patients extend, managing long-term toxicity is paramount. Clinicians typically administer only 6-8 cycles of oxaliplatin to prevent severe, cumulative peripheral neuropathy, allowing for longer, better-tolerated maintenance therapy with biologics.

A sobering finding from the LAURA trial was its control arm. EGFR-mutant patients receiving standard "curative-intent" chemoradiation alone had extremely high and rapid relapse rates (PFS ~6 months), highlighting the inadequacy of this standard and underscoring the necessity of adding consolidation osimertinib.