Merck & Co’s enthusiasm for the anti-TROP2 ADC sacituzumab tirumotecan, for which it’s now sponsoring 17 of its own pivotal trials, got an endorsement with Thursday’s unveiling of data from a Kelun-sponsored phase 3 trial testing the drug in first-line lung cancer.
The revelation came among the regular ASCO abstracts, for which all the texts are now available to view. The sac-tmt trial in question, Optitrop-Lung05, is a Chinese study that was last November toplined positive for progression-free survival; not only does the abstract bear this out, it also suggests that a significant OS benefit is in the making.
The presenters claim that Optitrop-Lung05 is the first phase 3 trial in front-line, PD-L1-positive NSCLC adding an ADC to Keytruda to show a statistically significant PFS benefit versus Keytruda alone. Specifically, it enrolled 413 patients with PD-L1 expression of 1% or higher, stratified by 1-49% and ≥50% levels, as well as by squamous versus non-squamous histologies.
On the primary endpoint of PFS, sac-tmt plus Keytruda cut risk of progression or death by a remarkable 65% (p<0.0001), with the median for the Keytruda comparator coming in at 5.7 months; this is in line with the 5.4 months of median PFS that Keytruda scored in its registrational Keynote-042 study in this setting, suggesting that the control hasn’t underperformed.
Even better, the ASCO abstract reveals that OS data, while still immature, have yielded a 0.55 hazard ratio. No medians or landmark analyses are stated, and there’s no p value for this result, but the confidence interval’s upper bound is well under 1.00, suggesting that the results are already in the realms of statistical significance, and could improve with further follow-up.
And VEGF bispecifics?
And the final cherry on the cake could come from a cross-trial comparison against Akeso/Summit’s high-profile anti-PD-1 x VEGF bispecific ivonescimab, which is also notable for beating Keytruda in a first-line, PD-L1-positive NSCLC study conducted in China.
That trial was Harmoni-2, which at the 2024 World Lung congress yielded a 0.51 hazard ratio for PFS versus Keytruda. Notably, this is worse than than 0.35 hazard ratio just revealed in Optitrop-Lung05. Of course in Harmoni-2 ivonescimab wasn’t added on top of Keytruda, but since the molecule itself blocks PD-1 it’s logical to compare the results against each other.
Cross-trial comparisons in first-line NSCLC
| Study | Sac-tmt + Keytruda | Ivonescimab | Keytruda | Stats |
|---|
| | Median PFS in PD-L1≥1% expressers | |
| Optitrop-Lung05 | NR | – | 5.7mth | HR=0.35 (p<0.0001) |
| Harmoni-2 | – | 11.1mth | 5.8mth | HR=0.51 (p<0.0001) |
| Keynote-042 | – | – | 5.4mth | HR=1.07 vs chemo |
Still to be fully revealed is sac-tmt’s safety profile in Optitrop-Lung05, but the abstract discloses no treatment-related deaths, and doesn’t mention interstitial lung disease or pneumonitis. Treatment-emergent adverse events caused more discontinuations in the control than in the active cohort.
With the Optitrop-Lung05 authors concluding that the data support sac-tmt as a new treatment option in this setting, it’s only a matter of time before Kelun files the results for approval in China. There sac-tmt is already greenlit for breast cancer and relapsed NSCLC.
Interestingly, in the US Merck is pursuing a slightly different tack with sac-tmt in first-line NSCLC: the pivotal TroFuse-007 trial does test the ADC on top of Keytruda, versus Keytruda, but enrols high (≥50%) PD-L1 expressers, and tests OS as its sole primary endpoint.
