Breast cancer HR+/HER2 competitive landscape

The latest developments in breast cancer, as of June 2023:

Highlights: 

• HER2-expressing
  • Phase 3 DESTINY-Breast06 trial of T-DXd completed recruiting with 866 participants total (T-DXd in 2L+ HR+/HER2-low/-ultralow post ET mBC)
  • Phase 1 TROPION-PanTumor01 trial evaluating Dato-DXd (TROP2 ADC) in advanced solid tumors (including 2L+ HR+/HER2- mBC and mTNBC cohorts) updated to include HR+/HER2-low mBC patients previously treated with T-DXd
  • A new investigator-initiated Phase 3 trial has been listed in China evaluating disitamab vedotin (RC48, HER2-ADC) in HR+/HER2-low mBC post-ET 
• HR+/HER2-
  • AstraZeneca announced that the FDA has accepted a NDA and granted Priority Review for capivasertib (AKTi) + fulvestrant (SERD) in HR+/HER2- mBC following recurrence or progression on or after an endocrine-based regimen based on the Phase 3 CAPItello-291 trial; PDUFA date in Q4 2023
  • Pfizer/Arvinas listed a new Phase 3 VERITAC-3 trial evaluating ARV-471 (PF-07850327, oral PROTAC) + palbociclib (Ibrance, CDK4/6i) vs letrozole (aromatase inhibitor) + palbociclib in 1L ER+/HER2- mBC

Details: 

HER2-expressing 

AstraZeneca/Daiichi Sankyo

AstraZeneca and Daiichi Sankyo have updated their Phase 3 DESTINY-Breast06 trial of T-DXd (Enhertu, HER2-ADC) in 2L+ HR+/HER2-low/-ultralow mBC post-ET

• The trial status was updated to “Active, not recruiting” indicating recruitment has completed; this is in-line with CI expectations
  • Actual recruitment = 866 participants
  • The PCD was delayed by a month to Aug 29, 2023, and the SCD was delayed by a day to Jul 20, 2026
• These updates are in-line with previous guidance from AstraZeneca stating the trial will readout in H2 2023 with regulatory submission following in 2024 
• DESTINY-Breast06 could enable T-DXd use directly after endocrine therapy, and could expand opportunity into the “HER2-ultra-low” population (ultra-low = HER2 IHC >0 and <1)
  • Note, that patients in the DESTINY-Breast06 study must have no prior chemotherapy in the metastatic setting which would position T-DXd ~2 lines ahead of Trodelvy’s current HR+ label

AstraZeneca and Daiichi Sankyo updated the Phase 1 TROPION-PanTumor01 trial evaluating Dato-DXd (TROP2 ADC) in advanced solid tumors (including 2L+ HR+/HER2- mBC and mTNBC cohorts) updated to include HR+/HER2-low mBC patients previously treated with T-DXd

• HR+/HER2-low patients must have received prior treatment of T-DXd 
• Enrollment has subsequently increased from 770 to 890 (anticipated)
• Data from this new TROPION-PanTumor01 arm will provide information on AstraZeneca’s and Daiichi’s plans for positioning of their DXd-ADCs in their overlapping patient populations
  • Sequential use of ADCs will become more common; yet, there is a lack of data on ADC resistance and the effectiveness of sequencing ADCs with common payloads
  • As a reminder, sequential use of Dato-DXd after T-DXd is currently being evaluated in the TRADE-DXd trial

AstraZeneca and Daiichi Sankyo updated the status of their Phase 1 trial evaluating DS-1103a (anti-SIRPα antibody) + T-DXd (Enhertu, HER2-ADC) for advanced HER2-expressing or HER2mut solid tumors, including HER2-low mBC previously treated with 1-2 prior lines of chemotherapy

• The trial status was updated from “Not yet Recruiting” to “Recruiting”
• Note, Daiichi has previously messaged on acceleration combination development of Enhertu with its internal assets in order to expand T-DXd’s presence within the BC space

AstraZeneca listed a new observational retrospective study of therapeutic approaches and clinical outcomes in HER2-low mBC patients in Russia (N=3,150; SSD: Jun 30, 2023; PCD/SCD: Jun 30,2024)

• The study plans on enrolling approximately 3,150 patients with HER2-negative mBC (IHC 0, + or IHC2+/ISH-) to obtain approximately 2,000 patients with confirmed HER2 low status (IHC1+ or IHC2+/ISH )
• Primary outcome measures are the overall prevalence of HER2-low among patients with HER2-negative mBC as well as clinical-pathological, histopathological, and demographic profiles of HER2-low patients identified as HER2-negative

HighField Biopharmaceuticals

HighField Bio received US FDA IND Clearance for HF158K1 (HER2-targeting doxorubicin immunoliposome drug composite) in HER2-positive and HER2-low advanced solid tumors in a Phase 1 trial

• The Phase 1 trial is expected to start this summer and will be conducted in the U.S., China, and other countries
  • A Phase 1a dose escalation portion of the study will enroll 24 patients, followed by a Phase 1b dose expansion trial with up to 60 patients
• In the PR, HighField Bio’s messaging focused on comparing its drug encapsulated immunoliposome platform to ADCs, stating that immunoliposomes may deliver larger doses of active drug and target tumor cells using multiple antibodies, making them less toxic and more efficacious than ADCs

Jiangsu HengRui Medicine 

A new investigator-initiated Phase 2 trial evaluating SHR-A1811 (HER2-ADC) for neoadjuvant HR+/HER2-low eBC patients with Ki-67 > 14% was listed (N=66; SSD: Jun 30, 2023; PCD: May 31, 2024; SCD: May 31, 2029)

• The primary outcome of the trial is ORR; secondary outcomes include AEs, RCB, pCR, EFS, and DFS
• While there is no current trial site listed, the trial is likely China-only, given it  is sponsored by Henan Cancer Hospital
• Other HER2-ADC assets being investigated in the HER2-low early-stage BC setting include T-DXd (Enhertu, Phase 2 TALENTtrial) and disitamab vedotin (Phase 2 trial in combination with penpulimab (PD-1))
• Note, Jiangsu HengRui is also currently investigating SHR-A1811 in a Phase 3 trialin HER2-low mBC

Seagen / Remegen

A new investigator-initiated Phase 3 trial has been listed in China evaluating disitamab vedotin (RC48, HER2-ADC) in HR+/HER2-low mBC post-ET (N=288)

• The primary outcome measure of the trial is PFS; secondary outcome measures are OS, ORR, DCR, CBR, QoL, AES, as well as biomarkers and treatment sensitivity analysis
• During their Seagen acquisition call, Pfizer notedplans to further pursue investigation of this asset in HER2+/HER2-low mBC
• Disitamab vedotin is also being investigated in a RemeGen-sponsored China-based Phase 3 trialin HER2-low mBC
  • Seagen and RemeGen enteredinto an exclusive worldwide licensing agreement for disitamab vedotin in Aug 2021

HR+/HER2-

AstraZeneca

AstraZeneca announced that the FDA has accepted a NDA and granted Priority Review for capivasertib (AKTi) + fulvestrant (SERD) in HR+/HER2- mBC following recurrence or progression on or after an endocrine-based regimen based on the Phase 3 CAPItello-291 trial. The company has noted the PDUFA date is in Q4 2023.

Highlights and implications

• Capivasertib was also noted to be reviewed under Project Orbis, and FDA initiative allowing for concurrent submissions and review of oncology medicines among participating international partners
• If successful, capivasertib may become a first-in-class treatment option for 2L+ HR+/HER2- all-comer patients with endocrine resistance, with AZ messaging that it will extend benefit of ET for ER-driven disease by overcoming key mechanisms of ET and CDK4/6i resistance
  • Capivasertib has the potential to delay treatment with Trodelvy in HR+/HER2- mBC given that capivaserib + fulvestrant may be used after chemotherapy and multiple rounds of endocrine therapy; however, this combination will likely replace CDK4/6i + endocrine therapy but not Trodelvy 

Background Information:

• This regulatory submission is based on results from the Phase 3 CAPItello-291trial which were presented at the SABCS 2022 and published in the New England Journal of Medicine 
  • In the trial, capivasertib + fulvestrant demonstrated a 40% reduction in the risk of disease progression or death vs placebo + fulvestrant in 2L HR+/HER2- mBC patients after ET
  • Median PFS was 7.2mo for the treatment arm, vs 3.6mo for placebo
  • Despite encouraging early OS data, it was deemed immature at the time of the analysis and the trial continues to assess OS as a key secondary endpoint
  • The safety profile was similar to that observed in previous trials evaluating this combination

Roche

Roche moved forward the PCD for its Phase 2/3 INAVO120 trial evaluating Inavolisib (PI3K inhibitor) + palbociclib (Ibrance, CDK4/6i) + fulvestrant in 1L PIK3CAmut HR+/HER2- mBC after progression on ET

• The PCD was moved up to Sept 2023 (previously Sept 2025); the SCD was also delayed to Nov 2025 (previously Sept 2025)
• Currently, Novatis’s alpelisib (Piqray) is the only on-market PI3K inhibitor in BC being approved in 2L PIK3CAmut HR+/HER2- mBC
• Note, Roche anticipatesregulatory submission of invavolisib in 2024 

Pfizer/Arvinas

Pfizer/Arvinas listed a new Phase 3 VERITAC-3 trial evaluating ARV-471 (PF-07850327, oral PROTAC) + palbociclib (Ibrance, CDK4/6i) vs letrozole(aromatase inhibitor) + palbociclib in 1L ER+/HER2- mBC (N=1,180; Start: Jun 28, 2023; PCD: Aug 28, 2028; SCD: Jul 26, 2030)

• The study will have an open-label SLI (study lead-in) before initiation of a Phase 3 trial 
  • During SLI, two dose levels of palbociclib in combination with ARV-471 will be explored in parallel
• Primary outcome measures include: PFS (Phase 3), incidence of Grade 4 neutropenia (SLI), incidence of dose reduction (SLI), and incidence of drug discontinuation (SLI)  
• Secondary outcome measures include: ORR (SLI and Phase 3), DoR (SLI and Phase 3), CBR (SLI and Phase 3), OS (Phase 3), TEAEs (SLI and Phase 3) and SAEs (SLI and Phase 3), and PK/PD measurements (SLI and Phase 3)
• The listing of the new study follows guidancefrom Arvinas in Jan 2023 stating the trial would be delayed due to a high number of AEs previously reported in patients receiving ARV-471 + palbo in a Phase 1b trial
  • At that time, Arvinas announced it sought a meeting with the FDA to discuss proposed modifications to the VERITAC-3 trial in order to initiate the trial in H2 2023
• Note, ARV-471 is also being evaluated in a Phase 3 trialas a monotherapy in 2L+ ER+/HER2- mBC previously treated with CDK4/6i + ET

General

Pfizer

Pfizer listed a new Phase 1 trial evaluating PF-07224826 (CDK2/4/6i) +/- ET in mTNBC and HR+/HER2- mBC (N=110; Start: Jul 17, 2023; PCD: Oct 14, 2025; SCD: Oct 14, 2027)

• The study is divided into dose escalation (Part 1) and dose expansion (Part 2) studies
  • Part 1 will evaluate both TNBC patients and HR+/HER2- mBC patients while Part 2 evaluates only HR+/HER2- mBC patients; in both parts, HR+ patients receive PF-07224826 + ET 
  • Part 2 is divided into two arms: Arm A evaluates HR+/HER2- mBC patients with prior CDK4/6i treatment, Arm B evaluates HR+/HER2- mBC patients whose disease has progressed on prior endocrine therapy and is naïve to CDK4/6 inhibitors
• Primary outcomes measures are DLTs (Part 1), AEs (Part 1 & 2), clinical laboratory abnormalities (Part 1 & 2), clinically significant abnormal vital signs (Part 1 & 2), ORR (Part 2) and clinically significant abnormal ECGs (Part 1 &2)
  • Secondary outcome measures include PK endpoints (Part 1 & 2), DoR (Part 1 &2), PFS (Part 1 & 2), TTR (Part 1 &2), OS (Part 2) and CBR (Part 2)

Roche

Roche provided updates on the Phase 1/2 Morpheus-panBC trial evaluating multiple treatment combinations in 1L PD-L1+(cohort 1) and 2L IO-naïve (cohort 2) TNBC, 1L+ PIK3CAmut HR+/HER2- mBC (cohort 3), and 2L+ PIK3CAmut HER2+/HER2-low mBC (cohort 4)

• Four new arms were added, including:
  • Inavolisib (PI3K inhibitor) + abemaciclib (Verzenio, CDK4/6i) + fulvestrant (SERD) (Cohort 3)
  • Inavolisib + ribociclib (Kisqali, CDK4/6i) + fulvestrant (Cohort 3)
  • Inavolisib (at 6mg) + trastuzumab deruxtecan (Enhertu, T-DXd, HER2-targeting ADC) (Cohort 4)
  • Inavolisib (at 9mg) + T-DXd for HER2+/HER2-low patients (Cohort 4)
• PCD and SCD were both moved from May 3, 2024 to May 3, 2026, likely to accommodate newly added arms
• Enrollment was increased from 133 to 242 (actual)
• Enrollment was closed for four other arms, making enrollment of all the pre-existing arms complete