Trodelvy plus Keytruda, when given within the frontline, prolonged survival with out development versus chemo plus Keytruda in PD-L1+ metastatic TNBC: © inventory.adobe.com.
Trodelvy (sacituzumab govitecan-hziy) and Keytruda (pembrolizumab), when given as a first-line therapy, considerably improved survival with out development versus chemo plus Keytruda amongst sufferers with PD-L1–constructive, superior or metastatic triple-negative breast most cancers (TNBC).
These main findings had been generated from the section 3 ASCENT-04/KEYNOTE-D19, which had been shared in the course of the 2025 ASCO Annual Assembly.
At an information cutoff date of March 3, 2025, out of the 221 sufferers handled with Trodelvy plus Keytruda, there was a median progression-free survival of 11.2 months by blinded impartial central assessment (BICR) versus 7.8 months within the 222 sufferers handled with chemotherapy plus Keytruda, translating to a 35% discount within the threat of illness development or loss of life. The six- and 12-month progression-free survival charges within the Trodelvy arm had been 72% and 48%, respectively; within the chemotherapy arm, these respective charges had been 63% and 33%.
“Outcomes from ASCENT-04/KEYNOTE-D19 assist the usage of Trodelvy plus Keytruda as a possible new customary of look after sufferers with beforehand untreated, PD-L1–constructive, domestically superior unresectable or metastatic TNBC,” Dr. Sara M. Tolaney, chief of the division of Breast Oncology at Dana-Farber Most cancers Institute, in Boston, Massachusetts, mentioned within the briefing. She can also be an affiliate professor of medication at Harvard Medical Faculty.
Unmet Wants Paving the Path to ASCENT-04
Information from earlier research confirmed that median progression-free survival achieved with chemotherapy with immune checkpoint inhibition ranges from 7.5 months to 9.7 months in sufferers with PD-L1–constructive metastatic TNBC; nevertheless, most sufferers will expertise progressive illness and roughly half of these therapy for metastatic TNBC within the first line don’t go on to obtain second-line therapy.
Trial Design: Eligibility, Remedy, Goals
The worldwide, randomized, section 3 research enrolled sufferers with treatment-naive, domestically superior unresectable or metastatic TNBC who had PD-L1 positivity outlined as a mixed constructive rating of no less than ten per the 22C3 assay. At the least six months will need to have handed since therapy within the healing setting, the place prior anti–PD-(L)1 inhibition was permitted.
A complete of 443 individuals had been randomly assigned to obtain both 10 milligrams per kilogram (mg/kg) of intravenous Trodelvy on days one and eight, plus 200 mg of Keytruda on day considered one of 21-day therapy cycles versus Keytruda on the similar dose and schedule mixed with chemotherapy. Remedy continued till progressive illness and insupportable toxicity. All sufferers who skilled illness development by BICR had been permitted to cross over to obtain single-agent Trodelvy within the second line.
Stratification components comprised area (US/Canada/Western Europe vs the remainder of the world), earlier publicity to PD-(L)1 inhibition (sure versus no), and healing treatment-free interval (de novo TNBC versus recurrence inside six to 12 months from therapy completion within the healing setting versus recurrence longer than 12 months from completion of therapy within the healing setting).
The first finish level of the research was progression-free survival by BICR, and secondary finish factors included general survival, goal response price and length of response by BICR, security and high quality of life.
All sufferers had been feminine and had a PD-L1 mixed constructive rating of 10 or increased. Most sufferers had been White (Trodelvy arm, 63%; chemotherapy arm, 63%), from the remainder of the world (62%; 62%) and had an ECOG efficiency standing of 0 (71%; 69%). Relating to healing treatment-free interval, most sufferers had been recurrent in over 12 months (48%; 48%), adopted by de novo (34%; 34%) and recurrent inside 6 to 12 months (18%; 18%). Metastatic websites included lymph nodes (72%; 69%), lung (50%; 43%), different (37%; 32%), bone (28%; 20%), liver (25%; 26%) and mind (4%; 3%).
The chemotherapy chosen earlier than randomization within the Trodelvy arm was taxane for 52% of sufferers and gemcitabine/carboplatin for 48% of sufferers; within the chemotherapy arm, these respective charges had been 51% and 49%. 4 % of sufferers within the antibody-drug conjugate arm vs 5% of these within the chemotherapy arm had prior publicity to PD-(L)1 inhibition.
Extra Efficacy Revelations
Though general survival information had been immature on the time of the report, with a maturity price of solely 26%, a constructive enchancment was noticed for the Trodelvy plus Keytruda arm vs chemotherapy plus Keytruda arm — regardless of a excessive crossover price. Particularly, 43% of these on the chemotherapy arm crossed over to obtain the antibody-drug conjugate as a single agent within the second line, which accounted for 81% of those that had been subsequently given therapy after chemotherapy/Keytruda was discontinued.
The median general survival was not reached within the Trodelvy arm, and it was additionally not reached within the chemotherapy arm; 53 and 61 occasions had been reported within the arms, respectively. The hazard ratio for general survival was 0.89.
Trodelvy plus Keytruda induced an goal response price of 60% vs 53% with chemotherapy plus Keytruda. Within the antibody-drug conjugate arm, 13% of sufferers achieved a whole response and 47% had a partial response; 32% had steady illness, 4% progressed and 5% weren’t response evaluable. Within the chemotherapy arm, the whole response and partial response charges had been 8% and 45%, respectively; 32% of sufferers had steady illness, 12% skilled illness development and 4% weren’t evaluable.
The median time to response within the Trodelvy arm was 1.9 months (vary, 1.0-9.3); it was additionally 1.9 months (vary, 1.1-11.4) within the chemotherapy arm. Notably, the median length of response was 16.5 months within the antibody-drug conjugate arm and 9.2 months within the chemotherapy arm.
Security Highlight
Any-grade treatment-emergent uncomfortable side effects occurred in over 99% of these within the Trodelvy and chemotherapy arms; these results had been grade 3 or increased for 71% and 70% of sufferers, respectively. Remedy-emergent critical uncomfortable side effects had been skilled by 38% of those that obtained the antibody-drug conjugate vs 31% of these given chemotherapy; 28% and 19% of instances, respectively, had been therapy associated.
Within the Trodelvy plus Keytruda arm, treatment-emergent uncomfortable side effects led to dose reductions or interruptions in 35% and 77% of sufferers, respectively; treatment-emergent uncomfortable side effects led to therapy discontinuation for 12% of sufferers and proved deadly for 3% of sufferers. Three of the 7 treatment-emergent uncomfortable side effects that led to loss of life had been decided to be associated to therapy. Within the chemotherapy plus Keytruda arm, treatment-emergent uncomfortable side effects led to dose reductions and interruptions for 44% and 74% of sufferers, respectively; treatment-emergent uncomfortable side effects led to discontinuation for 31% of sufferers. treatment-emergent uncomfortable side effects led to loss of life for 3% of these on this arm; 1 of those instances was associated to therapy.
“General, the protection profile of Trodelvy plus Keytruda was in step with the recognized security profiles of every drug,” Tolaney mentioned. “The speed of great uncomfortable side effects was increased within the Trodelvy plus Keytruda group in contrast with the chemotherapy plus Keytruda group; nevertheless, the speed of treatment-emergent uncomfortable side effects resulting in dose discount or therapy discontinuation was decrease.”
Topline Takeaway
Dr. Jane L. Meisel, professor within the Departments of Hematology and Medical Oncology and Gynecology & Obstetrics, and codirector of Breast Medical Oncology at Emory College Faculty of Drugs in Georgia, commented on the importance of the findings.
“I do suppose that is actually such doubtlessly practice-changing information. We have seen in earlier research how Trodelvy works so effectively for sufferers with metastatic TNBC in a while of their therapy. And now, to see this mixed with Keytruda and in contrast with chemotherapy plus Keytruda with such each statistically and clinically significant advantages for sufferers, I believe it actually does change the sport for this subgroup,” she mentioned. “That is very thrilling, and I stay up for seeing this doubtlessly make its manner into medical follow. I believe the great factor too, is that as clinicians, many people have used each of those brokers — Trodelvy and Keytruda — fairly a bit, and so the very fact that there have been no extra toxicities seen [beyond what we have] seen earlier than, will assist folks get used to utilizing this and really feel comfy with it as soon as it makes its manner into the clinic.”
Reference
Tolaney SM, de Azambuja E, Kalinsky Ok, et al. Sacituzumab govitecan (SG) + pembrolizumab (pembro) vs chemotherapy (chemo) + pembro in beforehand untreated PD-L1–constructive superior triple-negative breast most cancers (TNBC): Major outcomes from the randomized section 3 ASCENT-04/KEYNOTE-D19 research. J Clin Oncol. 2025;43(suppl 17):LBA109. doi:10.1200/JCO.2025.43.17_suppl.LBA109
For extra information on most cancers updates, analysis and schooling, don’t overlook to subscribe to CURE®’s newsletters right here.
