Bernstein: New first-line combinations for lung cancer: ADCs show efficacy, bispecific antibodies target longer-term replacement

Which data have created a new first-line option?

In OptiTROP-Lung-06, a first-line trial in PD-L1-negative non-small cell lung cancer, defined as TPS below 1%, median progression-free survival was 15 months with sac-TMT plus pembrolizumab, versus 6 months with pembrolizumab plus chemotherapy in the control group; the progression-free survival hazard ratio was 0.49.
The expert interviewed by Bernstein said that, although the trial was conducted only in China, the control group received the global first-line standard of care, giving the results international relevance. Ultimate adoption will also depend on the absolute survival benefit, tolerability, tumor histology and competition from other regimens.
Overall survival benefit is the key threshold for changing clinical practice. Subsequent treatments and longer follow-up may weaken or delay separation of the two groups’ overall survival curves, so the early progression-free survival advantage must still be assessed alongside overall survival results.

The expert envisions that a sufficiently effective combination of a Trop2 ADC and an immunotherapy drug could replace platinum plus pemetrexed doublet chemotherapy. Platinum may enhance early tumor shrinkage, but whether the additional efficacy is enough to offset toxicity remains a key trade-off.
Tolerability will also affect commercial use. The expert believes sac-TMT may be better than Datroway with respect to stomatitis, but the trials enrolled different populations and used different preventive measures, limiting cross-trial comparisons. Stomatitis can lead to treatment delays or interruptions, and adherence to preventive mouthwash also affects real-world use.
For a trial conducted only in China, the expert has greater confidence in the efficacy signal than in the reported incidence of toxicity. Differences in smoking habits, tumor types, genetic characteristics and adverse-event reporting make global trials particularly important for assessing safety and broader use.

The interviewed expert believes Datroway still has a first-line opportunity, but estimates the probability of success for the AVANZAR trial at slightly below 50%, with a more optimistic view of the QCS-positive subgroup. Concerns include changes to the trial protocol, a biomarker selected later during development, and previously poor or inconsistent results from Tropion Lung 01.
Efficacy in QCS-positive patients could support a narrower patient market, but centralized testing may limit reach: large US medical institutions can conduct testing more easily, while community oncology clinics may be constrained by testing rates and result turnaround times.
The expert also cautioned that a delayed readout from an event-driven trial may reflect slower events in both the treatment and control groups, rather than particularly strong efficacy in the treatment group alone.

The expert is optimistic about ivonescimab, a PD-1／VEGF bispecific antibody. Squamous non-small cell lung cancer is its most compelling near-term application, and the global Harmoni-3 trial is a key test. The expert considers a progression-free survival hazard ratio of around 0.65 or lower good, and below 0.60 very good.
Patients with squamous cancer generally have fewer effective treatment options after progression, so subsequent treatments may interfere less with overall survival results; non-squamous cancer includes more genetically defined subgroups that can be targeted, making subsequent treatment more complex.
The expert believes that over the next 5 to 10 years, PD-1 bispecific antibodies combined with ADCs could become a first-line regimen for some patients and spare many people platinum-based chemotherapy; the combinations’ actual tolerability must be established in trials.