Emerging Treatments | Lung Cancer

Session Focus

Gerberry framed the R&D landscape at large cap pharma as a search for novel combinations capable of unseating the KEYNOTE-189 and KEYNOTE-407 regimens as standards of care. Two components dominate: PD-1 VEGF inhibitors and antibody-drug conjugates.

The session moved from those combinations through the question of whether Chinese trial data generalizes, and on to personalized approaches.

PD-1 VEGF: From PFS to Overall Survival

Justin Gainor MD described the debate shifting from progression-free survival to overall survival. PFS benefits have appeared consistently with PD-1 VEGF combinations, and those benefits are now beginning to translate into OS benefits.

He cited two recent readouts. At ASCO, Harmoni-6 examined the squamous population, showing that adding a PD-1 VEGF bispecific to platinum doublet chemotherapy improved both progression-free survival and overall survival against historical standards. A week and a half before the Forum, at World Lung, Harmoni-2 reported in squamous patients on a cleaner randomization of pembrolizumab monotherapy versus the comparator, also showing an overall survival improvement.

He acknowledged the difficulty of keeping trial names and naming conventions straight given the pace of reporting.

Three themes emerged in his reading.

Safety in squamous histology. The old teaching was never to give VEGF in squamous cell lung cancer because of fatal hemoptysis risk. These agents appear safer, possibly due to a shorter half-life or the bispecific nature.

Activity appears somewhat better in squamous than non-squamous.

Geographic consistency. In the Harmoni EGFR data, hazard ratios for patients enrolled in China and in Western populations looked fairly comparable, which he called reassuring even where the OS benefit was nominal rather than statistically significant.

Whether Chinese Data Generalizes

Rebecca Heist MD raised the key qualifier. An EGFR-mutated tumor population is relatively homogeneous across ethnic groups, which makes comparability less surprising there than it would be in squamous or non-genomically driven populations.

Zofia Piotrowska MD made the same point with specifics. Characteristics of an EGFR population in a Chinese study versus a global study, including smoking status, are likely to be similar. Non-genomically defined studies carry far more heterogeneity in demographics and tobacco use history, factors that matter particularly for immunotherapy-based regimens.

Her conclusion: the jury remains out on applying Chinese studies to global populations, and confidence will build as follow-on global studies recapitulate the findings.

She added a point about endpoint selection. Overall survival is a harder endpoint and more broadly applicable, while PFS endpoints are somewhat more subjective.

Asked to name the biggest uncertainties, Gainor identified adverse event reporting, distinguishing subjectively reported toxicities from more objective ones, and response assessment methodology.

His observation on the latter was blunt and drew agreement: local investigator assessment is always going to be better than blinded independent review, no matter where the trial runs. Gerberry clarified that by better he meant more optimistic. Gainor confirmed it, noting that you always love your own children better.

What Made Harmoni-6 Notable

Asked whether the Harmoni-6 results are clinically meaningful in isolation and whether a global study might dilute them, Heist allowed that dilution is possible and unknown pending Harmoni-3.

What excited people about Harmoni-6, in her account, was progress in a squamous population specifically. Despite exclusion criteria, the trial included patients with hemoptysis, cavitation and large central tumors. Delivering a drug of this class safely in that population, with potential to improve overall survival, is what made the result significant.

Key Takeaways

1. PD-1 VEGF combinations are converting consistent PFS benefits into overall survival benefits, seen in two squamous readouts.

2. VEGF in squamous lung cancer was long avoided over fatal hemoptysis risk, and these agents appear safer.

3. EGFR populations are genomically homogeneous, which makes cross-geography comparability less informative than it appears.

4. Non-genomically defined populations carry demographic heterogeneity that matters most for immunotherapy regimens.

5. Local investigator assessment consistently reads more optimistic than blinded independent review.

6. Harmoni-6 mattered because it delivered in squamous patients with hemoptysis, cavitation and large central tumors.