Lunresertib Plus FOLFIRI Shows Safety, Elicits Responses in CCNE1+ or FBXW7+ Advanced GI Tumors

The addition of the novel PKMYT1 inhibitor lunresertib (RP-6306) to FOLFIRI (leucovorin, fluorouracil, and irinotecan) had a safety profile consistent with that of FOLFIRI alone and elicited responses in heavily pretreated patients with locally advanced or metastatic gastrointestinal (GI) solid tumors harboring CCNE1 amplifications or deleterious FBXW7 alterations, according to data from the phase 1 MINOTAUR trial (NCT05147350).1

Findings presented at the 2024 ESMO Gastrointestinal Cancers Congress showed that patients treated at the recommended phase 2 dose (RP2D) of lunresertib at 60 mg twice per day did not experience any safety-related treatment discontinuation or grade 3 or higher treatment-related adverse effects (TRAEs). The most common grade 3 or higher TRAE was neutropenia, at 31.6%. Instances of grade 3 or higher neutropenia were consistent with the historical rate observed with FOLFIRI alone, according to presenting study author Elisa Fontana, MD, PhD, who added that these TRAEs were reversible and preventable with FOLFIRI interruptions and/or dose modifications.

Regarding efficacy, evaluable patients (n = 33) experienced an overall response rate (ORR) of 18.2% (95% CI, 7%-35.5%), which was comprised exclusively of partial responses. Notably, patients with colorectal cancer (CRC; n = 15) achieved a clinical benefit rate (CBR) of 46.7%. The CBR in patients with all other types of GI tumors (n = 18) was 55.6%.

“We have a rational, extremely well-tolerated therapy that is potentially efficacious. We observed clinical benefit in [patients with] CRC in a molecularly selected population and responses in [patients with] cancer that has not historically been responsive to FOLFIRI,” Fontana said during the presentation. Fontana is the hospital medical director of the Sarah Cannon Research Institute in London, United Kingdom.

Approximately 20% of GI cancers harbor CCNE1 amplifications or deleterious FBXW7 mutations. They are associated with poor prognosis, and no targeted therapies are available for tumors with these alterations. Lunresertib, a first-in-class PKMYT1 inhibitor, is synthetically lethal with CCNE1 amplifications or deleterious FBXW7 mutations.

MINOTAUR was a dose-escalation trial that enrolled patients at least 18 years of age with locally advanced or metastatic CRC, GI cancers, or esophageal cancers that are resistant or refractory to standard treatment. Patients were required to have radiographic evidence of progressive disease, measurable disease per RECIST 1.1 criteria, an ECOG performance status of 0 or 1, and adequate hematologic and organ function.²

Patients also needed to undergo local tissue- or plasma-based next-generation sequencing, and they were required to harbor CCNE1 amplifications or deleterious FBXW7 alterations per central review. Prior treatment with irinotecan was allowed.¹

Enrolled patients are receiving lunresertib at doses ranging from 40 mg to 240 mg per day continuously, or at 160 mg to 240 mg per day on a 3-days-on/4-days-off schedule, in combination with FOLFIRI.

The study’s primary end points were safety and tolerability, as well as establishing the RP2D and dosing schedule. Secondary and exploratory end points included pharmacokinetics, preliminary antitumor activity, pharmacodynamics, and circulating tumor DNA (ctDNA) monitoring.

Among all patients treated (n = 38), the median age was 55.5 years (range, 31-78), and 31.6% of patients were at least 65 years of age. Additionally, 55.3% of patients were male. Patients had an ECOG performance status of either 0 (47.4%) or 1 (52.6%). Notably, 55.3% of patients received 0 to 2 prior lines of therapy, and 44.7% were administered at least 3 prior lines of treatment. Prior irinotecan was given to 47.4% of patients, and 97.4% of patients received prior platinum-based chemotherapy.

RAS/BRAF wild-type disease was reported in 44.7% of patients, and 55.3% of patients harbored RAS mutations. Notably, no patients had BRAF mutations. At baseline, CCNE1 amplifications and FBXW7 mutations were reported in 31.6% and 68.4% of patients, respectively.

Additional data showed that a ctDNA major molecular response was observed in 61% of evaluable patients (n = 23).

Within the cohort of patients with CRC, a duration of treatment (DOT) of more than 9 months was reported for 40% of patients who were naive to irinotecan (n = 2 of 5) and 20% of patients who received prior irinotecan (n = 2 of 10).

Fontana also shared the case file for a 59-year-old female patient with anal carcinoma harboring an FBXW7 mutation and high cyclin E. This patient received 3 prior lines of therapy but was naive to irinotecan. DOT during the study was 9 months and consisted of lunresertib at 120 mg twice per day for 3 days on and 4 days off plus FOLFIRI. This patient achieved a PR at 6 weeks, a best target lesion decrease from baseline of –65.2%, and a molecular response at 4 weeks of –98%.

Additionally, Fontana detailed the treatment and outcomes for a 67-year-old male patient with CRC harboring KRAS and FBXW7 mutations. This patient received prior perioperative CAPOX with primary tumor and liver resection, prior FOLFIRI, and prior trifluridine/tipiracil (Lonsurf). During the study, patient received 240 mg of continuous lunresertib plus FOLFIRI with a DOT of 46 weeks, and he experienced stable disease with a best target lesion decrease of –1.3% from baseline. His molecular response at 2 weeks was –74%.

Additional safety data showed that the most common TRAEs reported in at least 15% of patients included nausea/vomiting (any-grade, 55.3%; grade ≥3, 2.6%), neutropenia (42.1%; 31.6%), diarrhea (39.5%; 5.3%), mucosal inflammation (39.5%; 5.3%) fatigue (34.2%; 0%), rash (31.6%; 0%), alopecia (21.1%; 2.6%), leukopenia (21.1%; 13.2%), anemia (18.4%; 5.3%), palmar-plantar erythrodysesthesia syndrome (18.4%; 2.6%), stomatitis (18.4%; 7.9%), and taste disorder (15.8%; 0%).

Fontana concluded her presentation by saying the addition of lunresertib to FOLFIRI warrants further exploration in a randomized phase 2 study for patients with high-risk GI tumors harboring CCNE1 amplifications or FBXW7 mutations.

Disclosures:Dr Fontana reported receiving honoraria from Repare Therapeutics, CARIS Life Science, Seagen, Sapience, BicycleTx Ltd, Astellas, and Pfizer; serving in leadership roles with the European Organisation for Research and Treatment of Cancer, the Gastrointestinal Tactical Coordinating Group, and the ASCO Annual Meeting Scientific Programme Committee: GI Cancers, Colorectal, and Anal Track.

References

1. Wainberg ZA, Bent AH, Moreno V, et al. Phase 1 study of the PKMYT1 inhibitor lunresertib (lunre) in combination with FOLFIRI in advanced gastrointestinal cancers (MINOTAUR study). Presented at: 2024 ESMO Gastrointestinal Cancers Congress; June 26-29, 2024; Munich, Germany. Abstract 504MO.
2. Study of RP-6306 with FOLFIRI in advanced solid tumors (MINOTAUR). Updated March 12, 2024. Accessed June 26, 2024. https://clinicaltrials.gov/study/NCT05147350