Gedatolisib Triplet Shows Early Efficacy in Previously Untreated ER+/HER2– Breast Cancer


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The addition of gedatolisib to palbociclib and letrozole produced durable responses with comparable safety to that observed with palbociclib and letrozole alone in treatment-naïve patients with estrogen receptor-positive, HER2-negative advanced breast cancer.

Hope Rugo, MD, FASCO

Hope Rugo, MD, FASCO

The addition of gedatolisib to palbociclib (Ibrance) and letrozole produced durable responses with comparable safety to that observed with palbociclib and letrozole alone in treatment-naïve patients with estrogen receptor (ER)–positive, HER2-negative advanced breast cancer, according to data from a subgroup analysis of a phase 1b study (NCT02684032) presented at the 2023 ESMO Breast Cancer Annual Congress.1

In the total population of treatment-naïve patients with evaluable and measurable disease (n = 33), the triplet combination produced an objective response rate (ORR) of 78.8%; this included a partial response (PR) rate of 75.8% and a complete response (CR) rate of 3.0%. Moreover, 18.2% of patients had stable disease (SD), 9.1% of whom had durable SD, lasting for longer than 24 weeks.

Confirmed responders in this subgroup had a median duration of response (DOR) of 46.9 months (95% CI, 24.6-49.5). Six patients with measurable disease experienced a 100% reduction in the sum of target lesion diameter from baseline. Moreover, at a median follow-up of 37.8 months (range, 14.9-51.6), the median progression-free survival (PFS) was 48.6 months (95% CI, 30.4 months-not reached).

“...Efficacy results…in patients with measurable and evaluable disease, [were] very encouraging and compare favorably with published data [on] other therapies in this setting,” lead study author Hope S. Rugo, MD, FASCO, of University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, and colleagues, wrote in a poster on the data.

The study enrolled patients 18 years of age or older who were either postmenopausal, or premenopausal with medically induced menopause. Other inclusion criteria included a histologically or cytologically proven diagnosis of ER-positive, HER2-negative breast cancer with evidence of metastasis; measurable disease according to RECIST v1.1 criteria; adequate bone marrow, renal, and liver function; and an ECOG performance status of 0 or 1.2

The study included a dose-expansion and a dose-escalation portion. Patients in the dose-escalation portion (n = 35) were treated with gedatolisib, palbociclib, and letrozole (cohort A) or gedatolisib, palbociclib, and fulvestrant (Faslodex; cohort B).1 Women who were pre-/perimenopausal were administered ovarian suppression therapy.

The dose-expansion portion consisted of 4 study arms (n = 103). In arm A, patients received the letrozole combination in the first line. Those in arm B were CDK4/6 inhibitor naïve and received the fulvestrant combination in the second-line setting. Those in arm C received prior CDK4/6 inhibitors and the fulvestrant regimen weekly in the second- or third-line setting; those in arm D received the regimen on a 3-weeks-on/1-week-off schedule.

Previous data from the trial reported at the 2022 San Antonio Breast Cancer Symposium showed that the regimen was active and well tolerated, regardless of PIK3CA mutational status.3 Specifically, for those in arm D (n = 27) who had prior CDK4/6 exposure and received the triplet on the 3-weeks-on/1-week-off in the third-line setting, the overall ORR was 63%. At a median follow-up of 29 months, the median PFS was 12.9 months.

At the 2023 ESMO Breast Cancer Congress, investigators shared updated efficacy and safety data from a subgroup of treatment-naïve patients from escalation arm A (n = 11) and expansion arm A (n = 30) of this trial. For this analysis, the data cutoff date was June 29, 2022. Notably, median PFS and DOR data were updated as of March 16, 2023.1

Patients in this group received a weekly intravenous dose of 180 mg of gedatolisib in combination with a 125-mg daily dose of oral palbociclib for 21 days followed by 7 days off, and a 2.5-mg daily dose of oral letrozole.

Tumors were originally evaluated at baseline, and then every 8 weeks until disease progression or treatment discontinuation. All patients underwent this assessment every 8 weeks for the first 18 months of treatment or longer. However, protocol was adjusted 12 months after the completion of enrollment to allow for tumor assessment every 12 to 16 weeks. 

The primary end point was investigator-assessed ORR, with safety, DOR, and PFS serving as secondary end points.

The median age in the total treatment-naïve population was 54 years (range 28-78). No patients had been exposed to prior lines of therapy, but 43.9% had received prior adjuvant endocrine therapy. At the time of disease presentation, 95.1% of patients had stage IV breast cancer and 2.4% had stage III disease; disease stage was unknown in 2.4% of patients.

Measurable baseline disease was present in 92.7% of patients. The main disease site for 63.4% of patients was bone, followed by liver (36.6%), lymph node (29.3%), lung (17.1%), pleural effusion (9.8%), and skin (2.4%). The majority (85.4%) of patients had no more than 3 disease sites involved, and 14.6% had 4 or more disease sites. Regarding PIK3CA mutational status, 75.6% of patients had wild-type disease and 11% had mutated disease; this information was missing for 2.4% of patients. 

Safety analysis showed that the study regimen was well tolerated overall. Most patients (87.8%) discontinued treatment due to reasons other than an adverse effect (AE). The most common reasons for discontinuation were disease progression or relapse (36.6%) or study termination by a sponsor (22%). The percentage of patients who discontinued due to other reasons was 29.3%. This category includes withdrawal by subject, loss to follow up, global deterioration, investigator decision, or new diagnosis. Treatment-related AEs (TRAEs) led to discontinuation in 9.8% of patients; 2.4% discontinued treatment due to an unknown AE.

Nine patients continued treatment in an expanded access protocol after study termination, and 5 remained enrolled as of March 16, 2023. No TRAEs above grade 5 were observed with this regimen. Most events were grade 1 to 3, and the only grade 4 AE observed was neutropenia.

Grade 1 to 3 gastrointestinal AEs experienced by 20% or more of patients were stomatitis (grade 1, 22%; grade 2, 31.7%; grade 3, 29.3%), nausea (36.6%; 39.0%; 2.4%), diarrhea (29.3%; 12.2%; 2.4%), vomiting (31.7%, 12.2%, 0%), constipation (26.8%; 4.9%; 0%), dry mouth (24.4%; 0%; 0%).

Common blood and lymphatic system disorders included neutropenia/neutrophil count decrease (0%; 17.1%; 51.2%) and anemia (9.8%; 22%; 9.8%). Investigations showed decreased white blood cell count (2.4%; 17.1%; 12.2%), increased alanine aminotransferase (14.6%; 2.4%; 7.3%), increased aspartate aminotransferase (17.1%; 4.9%; 0%), and decreased lymphocyte count (2.4%, 9.8%, 9.8%).

Other AEs grade 3 or less included rash (26.8%; 14.6%; 36.6%), pruritus (19.5%; 7.3%; 9.8%), fatigue (24.4%; 29.3%; 9.8%), dysgeusia (46.3%; 4.9%; 0%), headache (14.6%; 12.2%; 0%), epistaxis (26.8%; 0%; 0%), arthralgia (17.1%; 4.9%; 0%), hyperglycemia (14.6%; 9.8%; 4.9%), decreased appetite (17.1%; 4.9%; 0%), hot flush (26.8%; 0%; 0%), and infusion-related reactions (12.2%; 14.6%; 0%).

“These preliminary results are very encouraging and warrant further evaluation of gedatolisib in treatment-naïve ER-positive/HER2-negative advanced breast cancer,” Rugo and colleagues concluded.

The efficacy and safety of gedatolisib and fulvestrant with or without palbociclib will be evaluated in the phase 3 VIKTORIA-1 trial (NCT05501886). The open-label, randomized, multinational 2-part trial includes patients with PIK3CA-mutated or wild-type hormone receptor–positive, HER2-negative breast cancer who progressed on a prior first-line CDK4/6 inhibitor plus a non-steroidal aromatase inhibitor.4

Disclosures: Dr Rugo reports receiving research grants or having financial or personal interests with AstraZeneca, Ayala, Boehringer Ingelheim, Daiichi Sankyo, Genentech, Gilead Sciences, Lilly, Macrogenics, Merck, Novartis, OBI Pharma, Odonate Therapeutics, Pfizer, Seattle Genetics, and Sermonix Pharmaceutical. Financial Interests, personal, or other honoraria include Blueprint, Mylan, and Puma Biotechnology.


  1. Rugo H, Wesolowski R, Stringer-reasor E, et al. Phase 1b study of gedatolisib plus palbociclib and endocrine therapy in women with hormone receptor positive advanced breast cancer: updated results in treatment naïve patients. Presented at: 2023 ESMO Breast Cancer Annual Congress; May 11-13, 2023; Berlin, Germany. Abstract 204P.
  2. A study to assess the tolerability and clinical activity of gedatolisib in combination with palbociclib/letrozole or palbociclib/fulvestrant in women with metastatic breast cancer. Updated July 27, 2022. Accessed May 31, 2023.
  3. Wesolowski R, Rugo H, Stringer-Reasor E, et al. Updated results of a phase 1b study of gedatolisib plus palbociclib and endocrine therapy in women with hormone receptor positive advanced breast cancer: subgroup analysis by PIK3CA mutation status. Cancer Res. 2023;83(suppl 5):PD13-05. doi:10.1158/1538-7445.SABCS22-PD13-05
  4. Hurvitz SA, André F, Cristofanilli F, et al. A phase 3 study of gedatolisib plus fulvestrant with and without palbociclib in patients with HR+/HER2- advanced breast cancer previously treated with a CDK4/6 inhibitor plus a non-steroidal aromatase inhibitor (VIKTORIA-1). Presented at: 2023 AACR Annual Meeting; April 14-19, 2023; Orlando, FL.
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