Lumakras Plus Vectibix improves PFS in colorectal cancer

Treatment with Lumaclas (sotorasib) in combination with Vectibix (panitumumab) at multiple dose levels significantly increases patient progression-free survival (PFS) and disease progression from random assignment in clinical trials compared to standard of care (SOC). (time to progression or death).Have chemotherapy-resistant metastatic colorectal cancer (mCRC) class G12C mutation, according to primary analysis results from the phase 3 CodeBreaK 300 trial. 2023 ESMO Conference and was published in New England Medical Journal.

The multicenter, open-label CodeBreaK 300 trial randomly assigned chemotherapy-resistant patients class Patients with G12C-positive metastatic colorectal cancer without a history of prior KRAS G12C inhibitors in one of three groups: KRAS G12C inhibitor Lumakras 960 mg once daily plus EGFR inhibitor Vectibix (53 patients). Lumaclas and Vectibix 240 mg once daily (53 patients). or standard trifluridine/tipiracil (37 patients) or Stivarga ([regorafenib]; 14 patients).

At a median follow-up of 7.8 months and a data cutoff date of June 19, 2023, patients in the 960 mg Lumaclas/Vectibix, 240 mg Lumaclas/Vectibix, and SOC groups had a median PFS of 5.6 months; Achieved 3.9 months. 2.2 months each.

“With these new data, Lumakras and Vectibix demonstrate consistent efficacy across key subgroups at both doses, supporting the biological rationale for combining these two biomarker-directed therapies.” Dr. Filippo Pietrantonio, author of the National Institute of Oncology Fondazione IRCCS in Milan, announced. , Italy said in a press release.

Previously, the phase 1b CodeBreaK 101 trial demonstrated that the combination of Lumakras and Vectibix induced a confirmed ORR of 30% in patients with chemotherapy-resistant mCRC.

CodeBreaK 300 included adult patients whose disease progressed or recurred after receiving at least one treatment for metastatic disease, including a fluoropyrimidine, oxaliplatin, or irinotecan. However, patients who experienced unacceptable side effects and were eligible to receive TAS-102 or Stivarga as a next line of treatment were also allowed to enroll if the investigator and medical monitor deemed it appropriate. The patient also class G12C mutation confirmed by prospective central molecular testing, ECOG performance status (PS) of 0-2, and adequate organ function.

The primary endpoint of this study was PFS by blinded independent central review (BICR) according to RECIST v1.1 criteria. Key secondary endpoints include overall survival (OS) and overall response rate (ORR) based on RECIST v1.1 criteria, duration of response (DOR), time to response, and disease control rate (DCR) based on BICR. , safety, quality of life, and pharmacokinetics.

Median treatment duration in the 960 mg Lumaclas/Vectibix, 240 mg Lumaclas/Vectibix, and SOC groups was 5.8 months (range, 1.0-13.2) and 4.1 months (range, 0.9-10.1). , and 2.2 months (range, 0.8–10.3), respectively. In total, 43.4% (23 patients), 35.8% (19 patients), and 9.3% (5 patients) of patients in the 960 mg Lumaclas/Vectibix group, 240 mg Lumaclas/Vectibix group, and SOC group, respectively, received treatment. Continued. Treatment after data cutoff date.

ORRs for the 960 mg Lumaclas/Vectibix, 240 mg Lumaclas/Vectibix, and SOC groups were 26.4%, 5.7, and 0.0%, respectively. Her 1 patient (1.9%) in the Lumakras/Vectibix 960 mg group achieved a complete response. Additionally, in the 960 mg Lumaclas/Vectibix arm, 24.5% (13 patients), 45.3% (24 patients), and 22.6% (12 patients) of patients had partial response (PR), stable disease (SD) or progressive disease (PD), respectively. In the Lumakras/Vectibix 240 mg group, 5.7% (3 patients), 62.3% (33 patients), and 24.5% (13 patients) and 3.8% (2 patients) of patients had PR, SD, PD, or incomplete response. was shown. /non-progressive disease, respectively. In the SOC group, 46.3% (25 patients), 31.5% (17 patients), and 1.9% (1 patient) of patients had SD, PD, or incomplete response/nonprogressive disease, respectively. .

Additionally, 3.8% (2 patients), 1.9% (1 patient), and 20.4% (11 patients) of patients in the 960 mg Lumakras/Vectibix, 240 mg Lumakras/Vectibix, and SOC groups, respectively, were evaluated. did not. One patient each in the Lumakras/Vectibix 960 mg and Lumakras/Vectibix 240 mg groups had no evaluable disease at baseline.

The median DOR for the Lumaclas/Vectibix 960 mg group was 4.4 months; other groups could not be evaluated due to insufficient response. Median time to response was 2.1 months and 1.8 months in the Lumakras/Vectibix 960 mg and Lumakras/Vectibix 240 mg groups, respectively. DCRs for the 960 mg Lumaclas/Vectibix, 240 mg Lumaclas/Vectibix, and SOC groups were 71.7%, 67.9, and 46.3%, respectively.

As of the data cutoff date, OS data were not mature and 34.4% (55 patients) had died. However, a trend in favor of both the 960 mg Lumaclas/Vectibix and 240 mg Lumaclas Vectibix groups was observed compared to the SOC group.

In total, treatment-related side effects occurred in 94.3% (50 patients), 96.2% (51 patients), and It occurred in 82.4% (42 patients). , Each. Treatment-related adverse reactions of grade 3 or higher occurred in 35.8%, 30.2%, and 43.1% of patients in the Lumaclas/Vectibix 960 mg group, Lumaclas/Vectibix 240 mg group, and SOC group, respectively; did. They occurred in 3.8%, 0%, and 3.9% of patients, respectively. Additionally, serious side effects occurred in 5.7% of patients in the 960 mg Lumaclas/Vectibix group, 7.8% of patients in the SOC group, but no patients in the 240 mg Lumaclas/Vectibix group. did. Additionally, no side effects leading to death have been reported.

In the Lumakras/Vectibix 960 mg group, Lumakras- and Vectibix-related side effects occurred in 60.4% and 92.5% of patients, respectively. In the Lumakras/Vectibix 240 mg group, Lumakras- and Vectibix-related side effects occurred in 64.2% and 94.3% of patients, respectively.

Treatment-related side effects led to treatment discontinuation in 3.8%, 1.9%, and 2.0% of patients in the Lumaclas/Vectibix 960 mg, Lumaclas/Vectibix 240 mg, and SOC groups, respectively. . Additionally, 18.9%, 17.0%, and 17.6% of patients required dose reduction, respectively. Discontinuation of any treatment occurred in 35.8%, 30.2%, and 39.2% of patients, respectively.

Skin and subcutaneous tissue disorders occurred in 83.0%, 84.9%, and 21.6% of patients in the 960 mg Lumaclas/Vectibix, 240 mg Lumaclas/Vectibix, and SOC groups, respectively.

The most common side effects in the Lumakras/Vectibix 960 mg group were anemia (any grade, 1.9%; grade 3 or higher, 1.9%), diarrhea (20.8%, 3.8%), and nausea (11.3%, 1.9%). ), vomiting (5.7%; 0%), stomatitis (5.7%; 0%), fatigue (7.5%; 0%), mucosal inflammation (7.5%; 0%), weakness or lack of energy (5.7%; 0%) ), dry skin (5.7%, 0%), hair follicle inflammation (15.1%, 0%), paronychia (5.7%, 0%), weight loss (1.9%, 0%), low magnesium blood symptoms (28.3%, 5.7%), decreased appetite (5.7%; 0%), hypocalcemia (5.7%; 1.9%), rash (28.3%; 5.7%), acneiform dermatitis (22.6%; 11.3 %), dry skin (18.9%; 0%), pruritus (15.1%; 0%), skin fissures (13.2%; 0%), skin-related toxic effects (9.4%; 3.8%), palmar and sole Red blood cell paresthesia (7.5%; 0%), nail cuticle fissures (5.7%; 0%) and maculopapular rash (3.8%; 0%).

The most common side effects in the Lumaclas/Vectibix 240 mg group were anemia (any grade, 7.5%; grade 3 or higher, 1.9%), thrombocytopenia (3.8%, 0%), and diarrhea (18.9%, 5.7%). ) was. ), nausea (17.0%; 3.8%), vomiting (11.3%; 0%), stomatitis (7.5%; 0%), fatigue (5.7%; 0%), weakness/malaise (5.7%; 0%) , fatigue (3.8%; 1.9%), inflammation of hair follicles (3.8%; 1.9%), infection near the nails (11.3%; 1.9%), weight loss (1.9%; 0%), neutrophils (3.8%; 0%)), hypomagnesemia (30.2%; 7.5%), decreased appetite (5.7%; 1.9%), hypocalcemia (3.8%; 0%), rash (24.5%) ; 1.9%), acneiform dermatitis (37.7%; 3.8%), dry skin (22.6%; 0%), pruritus (13.2%; 0%), skin fissures (7.5%; 0%), skin-related toxic effects (7.5%; 1.9%), palmar-plantar red blood cell dysesthesia (5.7%; 0%), maculopapular rash (5.7%; 1.9%), hair loss (1.9%; 0%) and hypertension (1.9%). %; 0%).

The most common side effects in the SOC group were anemia, thrombocytopenia (7.8%; 2.0%), leukopenia (7.8%; 2.0%), neutropenia (31.4%; 23.5%), and diarrhea (19.6%). %; 0%), nausea (29.4%; 2.0%), vomiting (7.8%; 0%), stomatitis (9.8%; 0%), fatigue (11.8%; 0%), mucosal inflammation (3.9%; 0%) ), asthenia (13.7%; 2.0 %), malaise (5.9%; 0%), fever (5.9%; 0%), weight loss (5.9%; 0%), decreased neutrophil count (7.8%) ; 3.9%), hypomagnesemia (2.0%; 0%), decreased appetite (11.8%; 2.0%), rash (2.0%; 0%), dermatitis acneiformis (2.0%; 0%), pruritus (3.9%; 0%), skin-related toxic effects (2.0%; 2.0%)), palmar and plantar erythrodysesthesia (9.8%; 3.9%), maculopapular rash (2.0%; 0%), alopecia (5.9%; 0%) and hypertension (13.7%; 5.9%).

The researchers reported that the pharmacokinetics of Lumakras and Vectibix were consistent with those observed in previous studies, with similar drug exposure seen at the two Lumakras dose levels. Additionally, the researchers reported no pharmacokinetic drug-drug interactions between Lumakras and Vectibix.

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