Vepdegestrant Plus Palbociclib Sustains Efficacy in Advanced ER+ Breast Cancer

Erika Hamilton, MD

The combination of vepdegestrant (ARV-471) and palbociclib (Ibrance) demonstrated continued clinical efficacy and safety in patients with locally advanced or metastatic estrogen receptor (ER)–positive, HER2-negative breast cancer following prior exposure to endocrine therapy with or without a CDK4/6 inhibitor, according to updated data from a phase 1b trial (NCT04072952) that were presented at the 2024 ESMO Breast Cancer Congress.^1,2

With an additional 6 months of additional follow-up results showed that the clinical benefit rate (CBR) was 63.0% (95% CI, 47.5%-76.8%) in the overall population (n = 46), 72.4% (95% CI, 52.8%-87.3%) in the ESR1-mutant population (n = 29), and 53.3% (95% CI, 26.6%-78.7%) in the ESR1 wild-type population (n = 15). The objective response rates (ORRs) in the overall (n = 31), ESR1-mutant (n = 17), and ESR1 wild-type (n = 12) populations were 41.9% (95% CI, 24.5%-60.9%), 47.1% (95% CI, 23.0%-72.2%), and 41.7% (95% CI, 15.2%-72.3%), respectively. Among response-evaluable patients, 41.9% (n = 13) had a confirmed partial response (PR).

The median progression-free survival (PFS) was 11.2 months (95% CI, 8.2-16.5) in the overall population, 13.7 months (95% CI, 8.2–not reached [NR]) in the ESR1-mutant population, and 11.1 months (95% CI, 2.8-19.3) in the ESR1 wild-type population.

“We’re encouraged by the clinical activity and safety profile observed with vepdegestrant in combination with palbociclib in patients being treated for advanced ER-positive/HER2-negative breast cancer,” Noah Berkowitz, MD, PhD, chief medical officer at Arvinas, said in a news release. “The median PFS and duration of response data suggest a promising therapeutic benefit for these patients regardless of ESR1 mutation status.”

Vepdegestrant is an oral PROTAC degrader that produces a trimer complex with an E3 ubiquitin ligase and ER, resulting in direct ubiquitination or ER and proteasomal degradation. This differs from selective ER degraders (SERDs) in that SERDs degrade the ER following conformational changes and/or ER immobilization.

In February 2024, the FDA granted fast track designation to vepdegestrant monotherapy for patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer who previously received endocrine-based therapy.³

In preclinical models, tumor proliferation was less common with the combination of vepdegestrant and palbociclib vs the SERD fulvestrant (Faslodex) and palbociclib, serving as the basis for the combination’s ongoing evaluation in the first-in-human phase 1/2 trial.

Previous results from the study showed that vepdegestrant monotherapy was active and well tolerated in pretreated patients with advanced breast cancer, leading to the establishment of 200 mg once daily as the agent’s recommended phase 2 dose. Moreover, preliminary results from the combination arm showed evidence of heightened activity.

To be eligible for enrollment in the phase 1b combination cohort, patients needed to have histologically or cytologically confirmed ER-positive, HER2-negative advanced breast cancer with measurable or non-measurable disease per RECIST 1.1 criteria following at least 1 line of endocrine therapy and no more than 2 lines of chemotherapy in the advanced setting.²

Vepdegestrant was administered in continuous oral doses of 180 mg, 200 mg, 400 mg, and 500 mg. Palbociclib was given orally in line with the recommended starting dose of 125 mg once daily for 21 days followed by 7 days off every 28 days.

The primary end points were any dose-limiting toxicities (DLTs) in the first cycle and safety. Secondary end points included CBR (confirmed complete response, PR, or stable disease for ≥24 weeks), ORR per RECIST 1.1 criteria, PFS, and duration of response (DOR).

Between February 23, 2021, and September 21, 2022, 46 patients were enrolled and received vepdegestrant at doses of 180 mg (n = 2), 200 mg (n = 21), 400 mg (n = 3), and 500 mg (n = 20) in combination with palbociclib.

Baseline characteristics revealed that among the predominantly female population (98%) the median age was 62 years (range, 29-78). Most patients had an ECOG performance status of 0 (70%), visceral disease (72%), and ESR1 mutations (63%). Sites of metastasis included the bone (74%), liver (48%), lung (30%), and other not specified (15%). The median number of prior lines of therapy overall and in the metastatic setting was 4 (range, 1-11) and 3 (range, 0-7), respectively. Prior therapy consisted of a CDK4/6 inhibitor (87%; palbociclib, 78%), an aromatase inhibitor (98%), fulvestrant (80%), and chemotherapy (any setting, 78%; metastatic setting, 48%).

Additional efficacy results indicated that the median DOR in responders (n = 13) was 14.6 months (95% CI, 9.5-NR). At the data cutoff date of December 18, 2023, 35% (n = 16) of patients received vepdegestrant for over 12 months (≥6 to ≤12, n = 11 [24%]), with 12 patients still on treatment.

The authors also presented data on circulating tumor DNA (ctDNA) and tumor fraction, showing sustained on-treatment reductions in ESR1-mutant ctDNA from early on through later cycles of therapy in the 200-mg cohort (n = 13). Additional results showed a –98.9% median change in tumor fraction after 1 cycle of therapy in patients with quantifiable tumor fraction at the beginning of study therapy (n = 28). However, this was not definitively shown to be related to ESR1 mutation status or CBR.

Regarding safety, no DLTs or grade 5 treatment-emergent adverse effects (TEAEs) were observed. Grade 3/4 TEAEs occurred in 93% of patients, leading to vepdegestrant dose reduction and discontinuation in 11% and 15% of patients, respectively; the respective rates for palbociclib were 78% and 22%.

Treatment-related AEs included neutropenia (grade 3, 48%; grade 4, 44%), fatigue (all grade, 63%; grade 3, 7%), decreased platelet count (grade 3, 7%; grade 4, 2%), anemia (all grade, 35%; grade 3, 4%), decreased white blood cell count (grade 3, 11%; grade 4, 4%), constipation (all grade, 24%; grade 3, 0%), QT prolongation (all grade, 24%; grade 3, 4%), nausea (all grade, 24%; grade 3, 0%), diarrhea (all grade, 17%; grade 3, 0%), hot flush (all grade, 17%; grade 3, 0%), alopecia (all grade, 13%; grade 3, not applicable), arthralgia (all grade, 13%; grade 3, 0%), increased aspartate aminotransferase (all grade, 11%; grade 3, 0%), decreased appetite (all grade, 11%; grade 3, 2%), and vomiting (all grade, 11%; grade 3, 0%).

“Pfizer is focused on advancing the next generation of treatment breakthroughs for people with breast cancer,” Roger Dansey, MD, chief development officer, Oncology, Pfizer, added in a news release.¹ “With vepdegestrant, we hope to establish a new standard-of-care endocrine therapy backbone for patients with ER-positive, HER2-negative breast cancer, and the data shared at ESMO Breast Cancer continue to reinforce its potential.”

“This study evaluating vepdegestrant in combination with palbociclib among heavily pretreated patients with advanced ER-positive, HER2-negative metastatic breast cancer is consistent with the clinical activity, safety, and tolerability outcomes reported at SABCS 2023,” Erika Hamilton, MD, director of breast cancer research and executive chair of the Breast Cancer Research Executive Committee at Sarah Cannon Research Institute in Nashville, Tennessee, added. “The data show promise that vepdegestrant could be a potential addition to current treatment options for this patient population, where there are significant unmet needs.”

Vepdegestrant is also being evaluated with lower starting doses of palbociclib as frontline therapy in the lead-in phase of the phase 3 VERITAC-3 trial (NCT05909397); the combination will be compared with palbociclib and letrozole in the randomized portion in patients with advanced ER-positive, HER2-negative breast cancer.⁴

References

1. Arvinas and Pfizer announce updated clinical data from phase 1b trial of vepdegestrant in combination with Palbociclib (Ibrance). News release. Arvinas. May 16, 2024. Accessed May 16, 2024. https://ir.arvinas.com/news-releases/news-release-details/arvinas-and-pfizer-announce-updated-clinical-data-phase-1b-trial
2. Hamilton E, Hurvitz SA, McAndrew NP, et al. Vepdegestrant, a proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degrader, plus palbociclib (palbo) in ER+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer: updated phase Ib cohort results. Presented at: 2024 ESMO Breast Cancer Annual Congress; May 15-17, 2024; Berlin, Germany. Abstract 218P.
3. Arvinas and Pfizer’s vepdegestrant (ARV-471) receives FDA fast track designation for the treatment of patients with ER+/HER2- metastatic breast cancer. News release. Arvinas, Inc. February 6, 2024. Accessed May 16, 2024. https://ir.arvinas.com/news-releases/news-release-details/arvinas-and-pfizers-vepdegestrant-arv-471-receives-fda-fast
4. A study of ARV-471 (PF-07850327) plus palbociclib versus letrozole plus palbociclib in participants with estrogen receptor positive, Human Epidermal Growth factor negative advanced breast cancer (VERITAC-3). ClinicalTrials.gov. Updated April 15, 2024. Accessed May 16, 2024. https://clinicaltrials.gov/study/NCT05909397