No Survival Bump in Metastatic NSCLC With Addition of ADC to Immunotherapy

Survival in metastatic non-small cell lung cancer (NSCLC) did not improve with the addition of the antibody-drug conjugate (ADC) sacituzumab govitecan (Trodelvy) to immunotherapy, a large randomized trial showed.

Median progression-free survival (PFS) in the EVOKE-03 trial did improve from 7.7 months with pembrolizumab (Keytruda) alone to 11.8 months with sacituzumab, but the difference did not meet prespecified criteria for statistical significance. An interim analysis of overall survival (OS), a second primary endpoint, showed a slight advantage for the control arm (22.8 vs 21.5 months) in a study population selected for PD-L1 positivity. Prespecified analyses of patients from East Asia and China suggested an OS benefit for the sacituzumab arm, but neither difference achieved statistical significance.

Treatment-emergent adverse events (AEs), including serious, treatment-discontinuation, and fatal AEs, all occurred more often in the sacituzumab group, reported Giannis Mountzios, MD, PhD, of Henry Dunant Hospital Center in Athens, Greece, at the World Conference on Lung Cancer (WCLC) in Seoul, South Korea.

“At this primary analysis for PFS, the study did not meet its primary endpoint because the difference was not statistically significant,” said Mountzios. “Confirmed objective response rates and disease control rates were numerically higher with the combination than with pembrolizumab monotherapy, and median duration of response [DOR] was similar between the treatment groups. At the interim analysis for overall survival, a statistically significant difference for this dual primary endpoint was not met, and it is highly unlikely that it will occur in the future.”

He noted that “the safety profile of sacituzumab govitecan plus pembrolizumab was consistent with the know profiles of each agent, and no new or additional toxicities were observed with the combination.”

The results showed a familiar pattern of attrition from phase II to phase III trials, said WCLC discussant Ji-Youn Han, MD, PhD, of the National Cancer Center in Goyang, South Korea. Pembrolizumab had already set a high bar in the KEYNOTE-024 trial with an objective response rate (ORR) of 44.8%. In the phase II EVOKE-02 trial evaluating sacituzumab add on, the 95% confidence intervals included 44.8%, which she described as a “recipe for overestimation.”

Although EVOKE-02 showed an ORR of 66.7%, the results came from a 30-patient study, Han continued. In EVOKE-03, ORR decreased to 55.6%, a 12% absolute difference versus pembrolizumab alone, the same as chemotherapy previously has been shown to add. The median DOR did not differ between treatment groups, suggesting that the sacituzumab payload “acts like chemotherapy on top of immuno-oncology, turning non-responders into short-term responders.”

“Pembrolizumab monotherapy remains a standard for PD-L1-high groups,” said Han. “Sacituzumab govitecan plus pembrolizumab should not be pursued in this setting outside of clinical trials. An ADC plus anti-PD-1 antibody gives an early chemotherapy-like effect without a survival tail. Future trials need overall survival as the primary endpoint, with deliverable biomarker selection and prespecified histology/geography stratification.”

EVOKE-03 evolved from the recognition that more than half of patients with metastatic NSCLC do not respond to initial treatment with pembrolizumab monotherapy, said Mountzios. Sacituzumab is a TROP-2-directed ADC that showed preliminary encouraging activity in EVOKE-02 across tumor histologies and in patients with PD-L1 total positive score (TPS) ≥50%.

Patients eligible for EVOKE-03 had untreated stage NSCLC, PD-L1 TPS ≥50%, no untreated/unstable brain metastases, and no EGFR/ALK/ROS1 mutations. Investigators in the international trial randomized 620 patients to pembrolizumab alone or in combination with sacituzumab. PFS and OS were dual primary endpoints, and secondary endpoints included ORR, DOR, patient-reported outcomes, and safety.

The primary analysis occurred after a median follow-up of 14.7 months. The 4.1-month improvement in PFS translated into a hazard ratio of 0.81 in favor of the combination, associated with a P-value of 0.0250. However, the protocol specified a P-value of 0.007 for statistical significance, resulting in a negative trial.

A subgroup analysis suggested statistical superiority of the combination in patients younger than 65 (HR 0.65, 95% CI 0.47-0.91), non-white race/ethnicity (HR 0.69, 95% CI 0.51-0.98), patients from East Asia (HR 0.68, 95% CI 0.48-0.97), non-squamous histology (HR 0.70, 95% 0.54-0.90), no brain metastases (HR 0.77, 95% CI 0.62-0.95), and absence of liver metastases (HR 0.76, 95% CI 0.61-0.96).

The OS analysis showed no statistically significant advantages for the addition of sacituzumab. ORR favored the combination (55.6% vs 43.7%), as did disease control rate (83.3% vs 73.1%). DOR was 21.3-21.4 months in both groups.