As the 2024 American Society of Clinical Oncology (ASCO) annual meeting approaches, excitement builds over the latest in cancer treatment advancements. From May 31 to June 4, industry leaders will unveil new data on different therapies. Leading pharmaceutical companies, including AstraZeneca, Daiichi Sankyo, Merck, Gilead Sciences, Blueprint Medicines, Eisai, Pfizer, and others are prepared to unveil the eagerly anticipated results as ASCO 2024 draws to a close, and are looking at this opportunity to present their innovations in breast cancer. 

Breast cancer, HR+/HER2-negative, and triple-negative breast cancer (TNBC), in a trio of oral LBAs, the company will look for proof-of-concept (PoC) signals on whether the Trop2-ADC class’s promising single-agent activity in advanced breast cancer will translate to the early-stage setting and/or in combination with anti-PD-(L) 1. For Trodelvy, initial randomized data from the Phase II investigator-sponsored SACI-IO HR+ trial will be the ADC’s first test with anti-PD-1 (pembrolizumab) in the 2L+ HR+/HER2- mBC setting. Additional Trop2 ADC monotherapy datasets in the metastatic setting will also be presented at ASCO. This includes pivotal Sacituzumab tirumotecan data from the China-focused Phase III OptiTROP-Breast01 study in 2L+ advanced TNBC, as well as updated TROPION-Breast01 data for Dato-DXd in the 3L+ HR+/HER2- setting with a focus on patient-reported outcomes.

Breast Cancer Highlights

1. Abstract Number – 1056

Title: Blueprint Medicines is showcasing its groundbreaking research on BLU-222, an investigational oral medication with potent and highly selective properties as a CDK2 inhibitor (CDK2i).

Commentary - At ASCO, Blueprint Medicines will unveil highly promising clinical data on BLU-222 for HR+ breast cancer. This marks a significant milestone, offering early evidence of clinical efficacy and potential as a pivotal treatment in breast cancer management, including in the front-line metastatic setting.

Executive Summary – BLU-222 is undergoing investigation in the VELA trial, targeting CCNE1-amplified cancers and HR+/HER2- breast cancer post-CDK4/6 inhibitor treatment. Blueprint Medicines plans to partner with this program, though facing competition in the crowded CDK2 inhibitor space. With various CDK2 inhibitor programs in Phase I, including Pfizer's PF-07104091 and Cyclacel Pharmaceutical's Fadraciclib, BLU-222's efficacy data from VELA could draw interest from potential collaborators.

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Blueprint Medicines' BLU-222 is generating significant interest in the oncology community as a promising CDK2 inhibitor, particularly in the context of HR+/HER2- breast cancer and other malignancies where CDK2 dysregulation plays a critical role. The lifting of the partial clinical hold by the US FDA marks a significant milestone, indicating that the safety concerns surrounding BLU-222 have been adequately addressed. The decision to pursue a partnership for BLU-222 in HR+/HER2- breast cancer reflects Blueprint Medicines' strategic approach to leverage external expertise and resources to maximize the potential of their therapeutic candidates. However, the competitive landscape in the CDK2 inhibitor space presents a challenge, as several other companies are also advancing their candidates targeting this pathway.

The Phase I data from other CDK2 inhibitor programs, such as Pfizer's PF-07104091, Cyclacel Pharmaceutical's Fadraciclib, Incytes’ INCB123667, and AstraZeneca's AZD8421, provide valuable insights into the efficacy and safety profiles of these compounds. Blueprint Medicines will need to carefully position BLU-222 against these competitors, emphasizing its unique attributes, such as its high selectivity and potency, to attract potential partners. Furthermore, the ongoing VELA trial evaluating the combination of BLU-222 with ribociclib and fulvestrant will provide important clinical data on the potential synergistic effects of combining CDK2 inhibition with established therapies in HR+/HER2- breast cancer. Positive results from this trial could further enhance the attractiveness of BLU-222 as a partner candidate.

Blueprint Medicines' innovative approach and the promising clinical profile of BLU-222 position the company well to secure a partnership that can accelerate its development and ultimately benefit patients with CDK2-vulnerable cancers.

Conclusion: BLU-222, a promising CDK2 inhibitor, shows potential in HR+/HER2- breast cancer and other malignancies. Positive clinical data from the VELA trial could attract potential collaborators, offering hope for improved treatment outcomes in CDK2-vulnerable cancers.

2. Abstract Number - 104

Title: Merck and Kelun’s TROP-2 ADC using a different payload when compared to Trodelvy, is all set to present its data from Phase III OptiTROP-Breast01 study 

Commentary - Kelun-Biotech is about to reveal the anticipated findings from the OptiTROP-Breast01 study during a clinical symposium at the upcoming ASCO meeting. This session will provide valuable insights into the effectiveness of Sacituzumab tirumotecan (SKB264/MK-2870) in treating patients with TNBC.

Executive Summary –The pivotal insights from the Phase III trial of this new TROP-2 ADC, emphasizing its effectiveness in TNBC patients are set to be revealed. These findings are expected to highlight the substantial efficacy of SKB264, particularly as the drug has already met its primary endpoint in the interim analysis.

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Triple-negative breast cancer, which lacks estrogen, progesterone, and HER2 receptors, is resistant to hormonal and targeted therapies, leaving chemotherapy as the main treatment. However, chemotherapy's effectiveness is limited, with progression-free survival under three months and overall survival between five and eight months for second-line TNBC patients, underscoring the urgent need for improved treatments.

SKB264, developed by Kelun-Biotech and Merck, is an innovative TROP2-targeting antibody-drug conjugate (ADC) combining a high-affinity monoclonal antibody with the T030 toxin via a stable CL2A linker. Licensed to Merck for development outside Greater China, SKB264 has received multiple Breakthrough Therapy Designations (BTDs) from China’s NMPA for various advanced cancers, including TNBC. In March 2024, it received another BTD for first-line treatment of unresectable, locally advanced, recurrent, or metastatic PD-L1 negative TNBC. 

Kelun-Biotech will present the Phase III OptiTROP-Breast01 study results on sacituzumab tirumotecan (formerly SKB264/MK-2870) for previously treated locally recurrent or metastatic TNBC at the upcoming ASCO conference. The Phase III trial of SKB264 monotherapy for advanced or metastatic TNBC patients who have failed at least second-line treatments is progressing well in China, with promising prospects of becoming the first locally produced TROP2-ADC on the market.

Conclusion: Data from the Phase III OptiTROP-Breast01 trial on sacituzumab tirumotecan will feature a post hoc analysis, focusing on progression-free survival (PFS), objective response rate, and overall survival in TNBC patients who have undergone at least second-line treatments. 

3. Abstract Number – 1110

Title: BB-1701's Journey in HER2-Low Expressing Breast Cancer.

Commentary - Eisai’s forthcoming poster presentation at ASCO and ongoing research underscore the potential of BB-1701 as an antibody-drug conjugate (ADC) targeting locally advanced/metastatic HER2-low expressing breast cancer.

Executive Summary –Eisai will unveil the latest insights on BB-1701's safety and antitumor activity from study 101 at ASCO. This presentation will specifically focus on the multiple-dose level cohort of patients grappling with locally advanced/metastatic HER2-low-expressing breast cancer.

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In the realm of HER2 antibody-drug conjugates (ADCs), Eisai is advancing with BB-1701, a compound that merges their proprietary anticancer agent eribulin with an anti-HER2 antibody through a linker. This innovative approach holds promise for treating a spectrum of solid tumors, notably HER2-expressing breast and lung cancers. 

Following the lead of AstraZeneca and Daiichi Sankyo in showcasing the efficacy of HER2-directed ADCs, Eisai clinched a significant deal with Bliss Biopharmaceutical in May 2023. This strategic collaboration positions Eisai as a frontrunner in the race to develop effective HER2-targeted therapies. With an upfront fee and the option for co-development of BB-1701, Eisai is strategically positioning itself to leverage the surging interest in HER2 ADCs. It is paving the way for Phase II trials in the US. Positive outcomes from these trials could position BB-1701 as a contender in the competitive landscape of HER2-positive or HER2-low unresectable or metastatic breast cancer treatments.

ENHERTU, developed by AstraZeneca and Daiichi Sankyo, has already shown remarkable improvements in progression-free survival, particularly in patients with HER2-ultralow expression. Eisai's upcoming presentation at ASCO 2024 will spotlight the Phase II study of BB-1701 in previously treated patients with HER2-positive or HER2-low unresectable or metastatic breast cancer (NCT06188559). This presentation represents a crucial opportunity to showcase BB-1701's potential and solidify Eisai's standing as a pivotal player in the evolving realm of HER2-targeted therapies.

Conclusion: Eisai is advancing in the development of BB-1701, a promising HER2 antibody-drug conjugate (ADC) that combines their anticancer agent eribulin with an anti-HER2 antibody. As ENHERTU has already shown significant improvements in patient outcomes, Eisai's upcoming presentation at ASCO 2024 will spotlight BB-1701's Phase II study, offering a crucial opportunity to showcase its potential and solidify Eisai's role as a pivotal player in advancing HER2-targeted therapies.

4. Abstract Number – 3108

Title: New CDK4 inhibitor PF-07220060 is poised to unveil promising updated results in the treatment of HR+/HER2− mBC

Commentary -The groundbreaking results from the Phase I/IIa study of PF-07220060, a first-in-class, next-generation CDK4-selective inhibitor, in combination with endocrine therapy (ET) for patients with HR+/HER2− mBC, will take center stage at ASCO 2024. 

Executive Summary – PF-07220060, a novel oral CDK4 inhibitor with high selectivity for CDK4 over CDK6, demonstrates promising safety and tolerability, as highlighted in updated findings presented at the 2024 ESMO Breast Cancer Congress. These results position it as a potential therapeutic option for HR+/HER2− metastatic breast cancer. Further insights into its safety profile will be unveiled at ASCO, underscoring its potential as a targeted therapy in oncology.

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The treatment landscape for HR+/HER2− breast cancer has seen significant advancements with recent promising developments. Over the past decade, endocrine therapy has been the primary approach for managing HR+/HER2− mBC, even in cases with visceral involvement. The combination of CDK4/6 inhibitors with endocrine therapy has now become the preferred first-line palliative treatment for HR+/HER2− advanced breast cancer (ABC).

The novel CDK4 inhibitor PF-07220060, when combined with endocrine therapy, has demonstrated a favorable safety profile and strong response rates in heavily pretreated patients with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer who had progressed on prior CDK4/6 inhibitors, regardless of mutation status. These findings from a Phase I/IIa trial (NCT04557449) were already presented at the 2024 ESMO Breast Cancer Congress.

Part 1 of this first-in-human, two-part Phase I/IIa trial involved a dose-escalation study. In part 1A, which aimed to determine the maximum tolerated dose or recommended dose for expansion, patients with solid tumors, including breast cancer and other tumors with CDK4/CCND1 amplification, received twice-daily doses of PF-07220060 monotherapy ranging from 100 mg to 500 mg. In parts 1B and 1C, PF-07220060 was evaluated at twice-daily doses of 300 mg and 400 mg, respectively, in combination with letrozole and fulvestrant (Faslodex), in patients with HR-positive, HER2-negative metastatic breast cancer who had progressed on prior CDK4/6 inhibitors and endocrine therapy.

The updated safety results of this novel CDK4-selective inhibitor will be showcased at ASCO 2024, highlighting its potential to further improve treatment options for patients with HR+/HER2− breast cancer. 

Conclusion: The combination of PF-07220060 with endocrine therapy has demonstrated promising outcomes in heavily pretreated patients with HR+/HER2− breast cancer, even post-progression on prior CDK4/6 inhibitors. If PF-07220060 continues to showcase promising results at ASCO 2024, it could signify a significant advancement in the treatment paradigm for this cancer subtype.