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Breast Cancer competitive landscape Updates

  • 27 ottobre 2023 - Newsletter n. 42 - Ottobre 2023
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HR+/HER2-

 

Kelun-Biotech

Kelun-Biotech listed a new Phase 3 trial evaluating SKB264 (sacituzumab tirumotecan/MK-2870, TROP2-ADC) vs chemotherapy in 2L+ HR+/HER2- mBC after ≥1L chemotherapy (N=376; SSD: Nov 2023; PCD: Mar 2026; SCD: Dec 2027)

  • Primary outcome is the PFS; Secondary outcomes include OS, ORR, DCR, DoR, QoL, AEs, and SAEs
  • No trial sites currently listed; given that Merck is not listed as a collaborator of this trial, the trial is likely China-only
  • Kelun-Biotech recently announcedthat the primary endpoint of PFS has been met in its Phase 3 trial of SKB264 in 2L+ mTNBC
  • Kelun-Biotech is in collaborationwith Merck to develop SKB264 (MK-2870) and seven investigational preclinical ADCs; Merck holds global right to SKB264 outside of China, Hong Kong, Macau, and Taiwan
    • Merck has indicated it plans to initiate a global Phase 3 trial for SK264 in chemo-naïve HR+/HER2- mBC

Roche

Roche delayed PCD and SCD of its Phase 2/3 INAVO120 trial evaluating inavolisib (PI3Kα inhibitor) + palbociclib (Ibrance, CDK4/6i) + fulvestrant vs palbociclib + fulvestrant in 1L PIK3CAmut HR+/HER2- mBC after progression on ET

  • The PCD was delayed by 26 mos to Nov 2025 (previously Sept 2025) and the SCD has been delayed by 58 mos to Sept 2030 (previously Nov 2025)
  • Roche anticipatesa data readout for this trial in Q4 2023
    • Roche is also evaluating inavolisib + fulvestrant in the Phase 3 INAVO121trial in 1-3L PIKCAmut HR+/HER2- after progression on ET + CDK4/6i 
  • Currently, Novatis’s alpelisib (Piqray) is the only on-market PI3K inhibitor in BC being approved in 2L PIK3CAmut HR+/HER2- mBC

 

Novartis 

Novartis updated the Phase 3b ADJUVANT WIDER trial evaluating ribociclib (Kisqali, CDK4/6i) + ET in HR+/HER2- Stage III, IIB or IIA eBC

  • The SSD has been delayed to Jan 2024 (previously Sept 2023) and the PCD has been brought forward to Jul 2028 (previously Jun 2030) 
  • The data from this P3 ADJUVANT WIDERtrial includes a broader population than the Phase 3 NATALEE trial with the data potentially being used to pursue a broader label for ribociclib 
    • The P3 ADJUVANT WIDERtrial includes participants that have received any standard neoadjuvant and/or adjuvant ET, including tamoxifen (SERM) or toremifene (SERM); however, patients who have received prior treatment with tamoxifen (SERM), raloxifene (SERM) or AIs are excluded in the P3 NATALEE trial 
    • Novartis is expected to file for regulatory approval in EU, US, and other countries for adjuvant ribociclib + ET in eBC based on the Phase 3NATALEE trial in H2 2023

 

TNBC

 

AstraZeneca/ Daiichi Sankyo

AstraZeneca and Daiichi Sankyo listed a new Phase 3 TROPION-breast05 trial evaluating datopotamab deruxtecan (Dato-DXd; TROP2 ADC) +/- durvalumab (Imfinzi; anti-PD-L1) vs ICC + pembrolizumab (Keytruda; anti-PD-L1) in PD-L1+ (CPS≥10) locally recurrent inoperable or metastatic 1L TNBC (N=625; SSD: Nov 2023; PCD: Sep 2026; SCD: Apr 2029)

Highlights and implications

  • The primary outcome measure is PFS (by BICR); the secondary outcome measures include OS, ORR, DoR, and PFS (by investigator)
  • Participants will be randomized either 1:1 to Dato-DXd + durvalumab arm or the ICC + pembrolizumab arm
    • In select countries, randomization will be 1:1:1 to include an additional Dato-DXd monotherapy arm; a total of 75 participants will be randomized into the monotherapy arm 
  • Trial sites are listed across US, EU, and Asia
  • The companies’ decision to further investigate the combination of Dato-DXd + durvalumab was likely prompted by the positive Phase 1b/2 BEGONIAtrial data in 1L TNBC presented at ESMO 2023
    • PFS data for Dato-DXd + durvalumab in 1L TNBC (13.8 mos) showed a numerical increase against the current PD(L)1 + chemo benchmarks (mPFS: 7.5mo); furthermore, the combo demonstrated robust response rates and durability regardless of PD-L1 status
  • This trial makes it a direct competition with Gilead’s Phase 3 ASCENT-04 trial where both trials are evaluating a TROP2 ADC + IO combo in the overlapping 1L PD-L1+ TNBC population  
    • Trodelvy’s current development plan may have an advantage in the 1L PD-L1+ TNBC space given its head-start as well as being combined with SoC pembrolizumab over durvalumab, which currently holds no BC approvals 
  • During AstraZeneca’s virtual investor callon October 23rd , 2023, they announced plans to initiate this trial alongside the Phase 3 TROPION-Breast04 evaluating Dato-DXd + durvalumab in eTNBC (trial not yet listed on gov)
    • Plans for these two new trials highlight AstraZeneca’s ambitions to build their dominance across the whole breast cancer spectrum;  

Additional Background

  • Dato-DXd is also being evaluated in the following pivotal trials:

 

Kelun-Biotech

Kelun-Biotech updated the overall status of the Phase 3 trial evaluating (sacituzumab tirumotecan/MK-2870, TROP2-ADC) vs chemotherapy in 3L+ TNBC

  • The overall status has been updated to “Active, not recruiting” from “Not yet recruiting”
  • Trial site have been added, all in China
  • Recall, Kelun-Biotech previously announced that this trial met its primary endpoint for PFS

 

LegoChem Biosciences/AntibodyChem Biosciences

LegoChem Biosciences/AntibodyChem Biosciences updated the Phase 1/2 trial evaluating LCB84 (TROP2-ADC) +/- anti-PD1 mAb in advanced solid tumors including 2L+ TNBC

  • The overall status was updated from “not yet recruiting” to “recruiting”
  • SCD was updated from September 2023 to October 5, 2023
  • Given the early stage of development and later LoT as target, LCB84 will unlikely pose immediate threat to Trodelvy in the TNBC space
  • The trial does not exclude patients with prior TROP2-directed therapy, which may provide potential insights into ADC sequencing  

 

General BC

 

Daiichi Sankyo / Merck

Daiichi Sankyo and Merck announced global development and commercialization collaboration for three Daiichi Sankyo DXd ADCs

Highlights and implications

  • The three DXd ADCs include patritumab deruxtecan (HER3-DXd), ifinatamab deruxtecan (I-DXd, DS-7300a; B7-H3 ADC) and raludotatug deruxtecan (R-DXd, DS-6000; CDH6 ADC)
    • HER3-DXd wasgranted Breakthrough Therapy Designation by the FDA in Dec 2021 for EGFRmut mNSCLC with disease progression on or after third-generation TKI + Pt-based therapies
      • The BLA submission in the US is planned by the end of Mar 2024 based on the data for the P2 HERTHENA-Lung01trial presentedat the IASLC-WCLC 2023 
      • HER3-DXd is also being evaluated in various BC indications including in the Phase 2 VALENTINEtrial in operable, high-risk HR+/HER2- eBC and Phase 2 ICARUS-BREASTtrial in 3L+ HR+/HER2- mBC
      • I-DXd is being evaluated in the P2 IDeate-01trial in 2-4L ES-SCLC and in the P1/2 trial in advanced solid tumors 
      • R-DXd is being evaluated in the P1trial in advanced RCC and ovarian cancer 
    • Under the terms of the agreement, Daiichi Sankyo will receive a total potential consideration across the three programs up to $22B
      • $750M for HER3-DXd upon execution and $750M after 12 mos
      • $1.5B for I-DXd upon execution 
      • $750M for R-DXd upon execution and $750M after 24 mos
      • Daiichi Sankyo will also receive up to an additional $5.5B for each DXd ADC contingent upon the achievement of certain sales milestones
    • Both companies highlighted multi-billion dollar worldwide commercial revenue potential for each company approaching the mid-2030s
    • The collaboration agreement signals that Merck is heavily investing and prioritizing its ADC programs

Additional Background

  • Merck is also in collaboration with Kelun-Biotech to develop SKB264 (MK-2870; TROP2 ADC) and seven investigational preclinical ADCs
  • In Sept 2020, Merck entered into an agreement with Seagen for global development and commercialization of ladiratuzumab vedotin (SGN-LIV1A, LIV-1 ADC)
  • Merck also lists MK-2140 (zilovertamab vedotin, ROR1-ADC) in its portfolio that are being investigated in multiple solid tumors, including breast cancer

 

Merck / Kelun-Biotech

Kelun-Biotech announced that Meck opted out of co-developing two preclinical ADCs with Kelun-Biotech

  • The termination does not affect three clinical-stage ADCs including SKB-264/MK-2870 (TROP2 ADC), SKB-315/MK-1200 (Claudin ADC), and SKB-410 (Nectin-4 ADC) and four other preclinical assets
  • The announcement on discontinuation came after the disclosure of Merck and Daiichi collaboration deal for three of Daiichi’s DXd-based ADCs 
  • Kelun noted that it intends to seek for other collaborators to co-develop the two terminated programs

 

Daiichi Sankyo

Daiichi Sankyo announced that the Texas District Court issued amended final judgement in patent dispute filed by Seagen against Daiichi Sankyo

  • The US District Court’s amended final judgment requires Daiichi Sankyo to pay Seagen a royalty of 8% on sales of Enhertu from April 1, 2022 through November 4, 2024 in addition to the $41.8M in damages previously awarded by the Court following the jury’s verdict
    • The amendment follows the patent infringement ruling by a Texas federal jury back in April 2022
    • The dispute stems from the ongoing dispute of the ADC technology rights following the collaboration between Seagen (formerly Seattle Genetics) and Daiichi Sankyo between 2008 and 2015
  • Daiichi Sankyo intends to appeal the amended final judgement 

 

Kelun-Biotech

Kelun-Biotech updated its Phase 2 trial evaluating SKB264 (TROP2 ADC) +/- KL-A167 (anti-PD-1) in 1L TNBC

  • The study has expanded to include HR+/HER2- cohorts adding two additional arms, the SKB264 monotherapy arm and the SKB264+KL-A167 arm in 1L HR+/HER2- mBC
  • The enrollment increased from 95 to 175
  • The overall status has been updated from “Not yet recruiting” to “Recruiting”
  • The PCD and SCD have been delayed by one year to Apr 2025 and Jul 2025 respectively 

 

AbbVie

AbbVie listed a new Phase 1 basket trial evaluating ABBV-400 (cMET ADC) that includes TNBC and HR+/HER2- cohorts (N=220; SSD: Nov 2023; PCD: Jul 2026; SCD: Jul 2026)

  • Primary outcome is ORR; Secondary outcomes include DOR, Clinical Benefit Rate (CBR), PFS, and OS
  • No trial sites are currently listed

 

ADC Sequencing

 

Gilead

A new Phase 2 ISS SATEEN trial was listed evaluating Trodelvy + trastuzumab (Herceptin) in HER2+ mBC after progression on trastuzumab deruxtecan (T-DXd, Enhertu, HER2-ADC) (N=40; SSD: Apr 2024; PCD: Nov 2026; SCD: Nov 2027)

  • Participants must have received prior treatment with a taxane, trastuzumab, and T-DXd; T-DXd does not need to be the most recent prior therapy 
  • Primary outcome is the ORR; Secondary outcomes include PFS, OS, Clinical Benefit Rate (CBR), DOR, and Grade 3-5 TRAEs
  • Two US trial sites are currently listed 
  • Gilead is supporting this research by providing funding for the trial as well as providing Trodelvy
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