Newsflash
Prodotti competitors / Area Oncology

Merck phase 3 trial evaluating MK-2870 (sacituzumab tirumotecan/SKB264; TROP2 ADC) ± pembrolizumab (Keytruda; anti-PD-1) vs treatment of physician’s choice (TPC) in HR+/HER2- metastatic Breast Cancer

  • 15 marzo 2024
Immagine News
Attenzione! Il presente contenuto è disponibile solo in lingua originale.

Merck listed a new Phase 3 MK-2870-010 (NCT06312176) trial evaluating MK-2870 (sacituzumab tirumotecan/SKB264; TROP2 ADC) ± pembrolizumab (Keytruda; anti-PD-1) vs treatment of physician’s choice (TPC)  in HR+/HER2- mBC that has progressed on ≥1L of endocrine therapy (ET) with at least 1L of ET in combination with a CDK4/6i inhibitor (chemo-naïve) (N=1,200; SSD: Mar 29, 2024; PCD: Jul 11, 2027; SCD: Apr 12, 2031). 

MK-2870 is a key in-class competitor to ADC with the MK-2870-010 trial directly competing against Trodelvy’s ongoing ASCENT-07 trial.

Highlights and implications 

  • Trial sites are yet to be listed; however, global sites are expected (ex China) given Merck’s previous public guidance at ESMO 2023 concerning plans for a global trial in the chemo-naïve HR+ mBC population
  • Patients are required to have disease progression on ≥1L of endocrine therapy (ET) for unresectable locally advanced/metastatic disease, with at least 1L of ET in combination with a CDK4/6i
    • This is a slightly different criteria than Trodelvy’s ASCENT-07which does not specifically require prior CDK4/6i and allows for either disease progression after ≥2L of ET in the metastatic setting, within 6mo of starting 1L ET or while on the first 24mo of adj ET + CDK4/6i
  • The trial’s primary outcome is PFS (MK-2870 vs TPC; MK-2870 + pembrolizumab vs TPC)
    • Secondary outcomes include OS, PFS (MK-2870 + pembrolizumab vs MK-2870), ORR, DOR and AEs
  • Given that MK-2870 will likely be a 3rd to market TROP2 ADC in the HR+ space, Merck may potentially be positioning its ADC-IO combination as an avenue for efficacy differentiation
    • Note, this is the first trial to evaluate an ADC + IO regimen in the chemo-naïve HR+ population 
    • Merck may also be building on its Phase 3 KEYNOTE-B49trial which evaluates pembrolizumab + CT in chemo-naïve, PD-L1+ HR+/HER2- mBC

Additional Background 

  • Merck is in collaboration with Kelun-Biotech to develop MK-2870 where Merck holds global right to MK-2870 outside of China, Hong Kong, Macau, and Taiwan 
  • Merck’s partner, Kelun-Biotech, is also evaluating MK-2870 in the following China-only pivotal trials:
    • Phase 3 trialin 1L TNBC
    • Phase 3 trialin 3L+ TNBC
    • Phase 3 trialin 2L+ HR+/HER2- mBC
  • Other Phase 3 trials for ADCs in chemo-naïve HR+/HER2- mBC include: 

Merck completed recruitment of its Phase 3 KEYNOTE-B49 trial evaluating pembrolizumab (Keytruda, anti-PD-1) + chemo vs placebo + chemo in chemo-naïve PD-L1+ (CPS >=1) HR+/HER2- mBC

  • The overall status was updated from “recruiting” to “active, not recruiting”
    • This may signal that the KEYNOTE-B49 trial is close to completion and topplingdata may be expected in 2024
  • Merck seeks to move pembrolizumab into both the HR+/HER2- mBC and eBC settings through the Phase 3 KEYNOTE-B49 and KEYNOTE-756 trials
    • Initial data from KEYNOTE-756 was presented at ESMO 2023 showing a significant improvement in pCR for neoadj. pembrolizumab + chemo vs neoadj. placebo + chemo in ER+/HER2- eBC; the study is currently ongoing to evaluate EFS in adjuvant portion of the trial
    • in the EU and US, pembrolizumab + chemo is currently approved for 1L PD-L1+ (CPS ≥ 10) mTNBC and as a neoadjuvant/adjuvant treatment for high-risk eTNBC.
  • If successful, Merck is positioned to have the first anit-PD-1 approved in HR+/HER2- mBC presenting an out-of-class competition 
  • The impact of pembrolizumab will be limited by its confinement to the PD-L1+ population though the eligible population may depend on if efficacy is demonstrated in the CPS ≥ 1 or the CPS ≥ 10 population

 

====================================================================================================================================

Merck initiated also a new P3 trials for MK-2870 (TROP2 ADC, also known as SKB264/sacituzumab tirumotecan):

  • MK-2870-019 (NCT06312137): Adjuvant MK-2870 + pembrolizumab (anti-PD-1) vs pembrolizumab in resectable stage II-IIIB NSCLC patients not achieving pCR after receiving neoadjuvant pembrolizumab with platinum-based doublet chemotherapy followed by surgery

The initiation of these trials brings the total number of ongoing global P3 studies for MK-2870 to six, with at least another three studies planned to initiate in 2024, continuing to increase the overall threat of MK-2870.

Implications:

  • MK-2870 is a direct threat to Trodelvy and DOM/ZIM in NSCLC and Trodelvy in HR+ BC with multiple on-going pivotal trials
    • MK-2870’s move into resectable NSCLC marks the first time that a TROP2 ADC has moved into early-stage NSCLC, moving past both Dato-DXd and Trodelvy
    • MK-2870-019 will directly compete with Gilead’s planned P3 STAR-131 trial; however, DOM/ZIM has the potential to be differentiated from MK-2870 based on a more favorable safety profile and pCR rate
    • MK-2870-010 presents a direct threat to the ongoing ASCENT-07 trial for Trodelvy in an ET resistant but chemo-naïve HR+/HER2- patient population; While MK-2870 is expected to be a 3rd to market TROP2 ADC, the IO combination may provide a point of differentiation
  • NSCLC: MK-2870-019: adjuvant MK-2870 + pembro builds on Merck’s KEYNOTE-671: perioperative pembro regimen and adds MK-2870 to pembro in the adjuvant regimen in patients that did not achieve pCR
    • A very low number of patients that receive perioperative regimens achieve pCR (18% in KEYNOTE-671), so this adjuvant trial addresses a large portion of patients
    • KEYNOTE-671: perioperative pembro + chemo was recently approved in Oct 2023 and received a positive EU CHMP Opinion in Feb 2024
    • Merck also has an ongoing adjuvant trial in resectable NSCLC: ALCHEMIST Chemo-IO (ACCIO): adjuvant pembro + chemo in resectable stage IIA-IIIB NSCLC
  • HR+/HER2- mBC: The three-armed P3 MK-2870-010 (NCT06312176) trial marks the first pivotal trial for MK-2870 in breast cancer outside of China
    • This is also the first trial to evaluate an ADC + IO regimen in the ET resistant/ chemo-naïve HR+ population though the trial is in an all-comer patient population with no stratifications based on PD-L1 status
    • The trial population for MK-2870-010 include HR+/HER2- mBC patients whose disease progresses on ≥1L of endocrine therapy (ET) with at least 1L of ET in combination with a CDK4/6i is slightly different from that of  ASCENT-07
      • ASCENT-07’s criteria does not specifically require prior CDK4/6i but requires either disease progression after ≥2L of ET in the metastatic setting, within 6mo of starting 1L ET or while on the first 24mo of adj ET + CDK4/6i
    • The primary endpoint of PFS for MK-2870 vs TPC and MK-2870 + pembrolizumab vs TPC will allow for MK-2870 to be used as both a monotherapy and as a combination; a key point of differentiation from both Trodelvy and Dato-DXd
      • Secondary outcomes include OS, PFS (MK-2870 + pembrolizumab vs MK-2870), ORR, DOR and AEs
      • Current trial information does not specify any subsets of interest such as TROP2 high or PD-L1 positive
    • Given that MK-2870 will likely be a 3rd to market TROP2 ADC in HR+ mBC, Merck is likely positioning its ADC-IO combination as an avenue for efficacy differentiation and to drive portfolio synergies
      • Merck may also be building on its Phase 3 KEYNOTE-B49trial which evaluates pembrolizumab + CT in chemo-naïve, PD-L1+ HR+/HER2- mBC

Additional Details

  • Merck exclusively licensed MK-2870 (previously known as SKB264) as well as several other early-stage ADCs in a string of deals with Kelun-Biotech in 2022
    • MK-2870’s composition includes a sacituzumab TROP2 antibody, TOPO1 payload, and modified CL2A linker, closely resembling that of Trodelvy
  • Merck has initiated several pivotal trials with MK-2870 in tumor types of interest to Gilead, and Merck remains a competitive threat across oncology due to its clinical trial and operational expertise
    • NCT06170788: MK-2870 + pembro vs pembro in 1L PD-L1 ≥50% mNSCLC
    • NCT06074588: MK-2870 mono vs pemetrexed or docetaxel in 2L+ Nsq mNSCLC with EGFRmt (and other AGAs)
    • NCT06305754: MK-2870 mono vs pemetrexed + carboplatin in post EGFR TKIs Nsq NSCLC with EGFRmt
    • NCT06132958: MK-2870 mono vs chemo in 2L endometrial cancer
      • Additional P3 trials across GYN tumors (1 in Cervical, 2 in Ovarian) are also planned for 2024
    • As well as those with an Asia focus, sponsored by Kelun
      • NCT05347134: 3L+ TNBC vs physician’s choice
      • NCT06081959: 2L+ ER+ HER2- breast cancer vs physician’s choice
      • NCT05870319: 2L+ (post EGFR TKIs) EGFRmt non-squamous NSCLC Vs pemetrexed + carboplatin
      • NCT06279364: 1L TNBC vs chemo

 

Tags:
Grazie per il tuo feedback!