Lumakras Plus Vectibix Improves PFS in Colorectal Cancer

Treatment with combinations using Lumakras (sotorasib) at multiple dose levels and Vectibix (panitumumab) improved progression-free survival (PFS; the time from random assignment in a clinical trial to disease progression or death) compared to standard of care (SOC) in patients with chemorefractory metastatic colorectal cancer (mCRC) harboring KRAS G12C mutations, according to findings from the primary analysis of the phase 3 CodeBreaK 300 trial, which were presented at the 2023 ESMO Congress and published within the New England Journal of Medicine.

The multicenter, open-label, CodeBreaK 300 trial randomly assigned patients with chemorefractory KRAS G12C–positive, metastatic CRC who were naïve to prior KRAS G12C inhibitors to one of three groups: 960 mg of the KRAS G12C inhibitor, Lumakras, once daily plus the EGFR inhibitor Vectibix (53 patients); 240 mg of Lumakras once daily plus Vectibix (53 patients); or investigator’s choice of standard trifluridine/tipiracil (37 patients) or Stivarga ([regorafenib];14 patients).

At a median follow-up of 7.8 months and a data cutoff cate of June 19, 2023, patients in the 960-mg Lumakras/Vectibix, 240-mg Lumakras/Vectibix, and SOC arms achieved a median PFS of 5.6 months, 3.9 months and 2.2 months, respectively.

“With these new data, Lumakras plus Vectibix showed consistent efficacy across key subgroups at both doses and supports the biologic rationale of combining these two biomarker-directed therapies,” presenting author Dr. Filippo Pietrantonio, of the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy, said in a press release.

Previously, the phase 1b CodeBreaK 101 trial demonstrated that Lumakras plus Vectibix elicited a confirmed ORR of 30% in patients with chemorefractory mCRC.

CodeBreaK 300 included adult patients with disease progression or recurrence after at least one prior line of therapy for metastatic disease, which must have included fluoropyrimidine, oxaliplatin and irinotecan; however, patients who experienced unacceptable side effects and were eligible to receive TAS-102 or Stivarga as their next line of therapy if deemed appropriate by the investigator and medical monitor, were also allowed to enroll.Patients also needed to have a KRAS G12C mutation as confirmed by prospective central molecular testing, an ECOG performance status (PS) of 0 to 2, and adequate organ function.

The trial’s primary end point was PFS per blinded independent central review (BICR) per RECIST v1.1 criteria. Key secondary end points included overall survival (OS) and overall response rate (ORR) per RECIST v1.1 criteria, duration of response (DOR), time to response, disease control rate (DCR) per BICR, safety, quality of life and pharmacokinetics.

The median duration of treatment in the 960-mg Lumakras /Vectibix, 240-mg Lumakras / Vectibix, and SOC arms was 5.8 months (range, 1.0-13.2), 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% (five patients) of patients in the 960-mg Lumakras /Vectibix, 240-mg Lumakras /Vectibix and SOC arms, respectively, continued to receive treatment after the data cutoff date.

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

Moreover, 3.8% (two patients), 1.9% (one patient) and 20.4% (11 patients) of patients in the 960-mg Lumakras /Vectibix, 240-mg Lumakras/Vectibix and SOC arms, respectively, were not assessed, and one patient each in the 960-mg Lumakras /Vectibix and 240-mg Lumakras/Vectibix arms had no assessable disease at baseline.

The median DOR was 4.4 months in the 960-mg Lumakras/Vectibix arm and not evaluable in the other arms because of insufficient responses. The median time to response in the 960-mg Lumakras/Vectibix and 240-mg Lumakras/Vectibix arms was 2.1 months and 1.8 months, respectively. The DCR in the 960-mg Lumakras/Vectibix, 240-mg Lumakras/Vectibix, and SOC arms was 71.7%, 67.9 and 46.3%, respectively.

At the data cutoff date, the OS data were not mature, and 34.4% (55 patients) had died. However, trends were observed favoring both the 960-mg Lumakras/Vectibix arm and the 240-mg Lumakras Vectibix arm vs the SOC arm.

In total, treatment-related side effects occurred in 94.3% (50 patients), 96.2% (51 patients) and 82.4% (42 patients) of patients in the 960-mg Lumakras/Vectibix, 240-mg Lumakras/Vectibix and SOC arms, respectively. Grade 3 or higher treatment-related side effects occurred in 35.8%, 30.2% and 43.1% of patients in the 960-mg Lumakras/Vectibix, 240-mg Lumakras/Vectibix and SOC arms, respectively, and grade 4 or higher side effects 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 Lumakras/Vectibix arm, 7.8% of patients in the SOC arm, and no patients in the 240-mg Lumakras/Vectibix. Furthermore, no side effects leading to death were reported.

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

In the 960-mg Lumakras/Vectibix, 240-mg Lumakras/Vectibix, and SOC arms, treatment-related side effects led to discontinuation of any treatment occurred in 3.8%, 1.9% and 2.0% of patients, respectively. Additionally, 18.9%, 17.0% and 17.6% of patients required dose reductions, respectively. Dose interruptions 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 Lumakras/Vectibix, 240-mg Lumakras/Vectibix and SOC arms, respectively.

In the 960-mg Lumakras/Vectibix arm, the most common side effects were anemia (any-grade, 1.9%; grade 3 or higher, 1.9%), diarrhea (20.8%; 3.8%), 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%), inflamed hair follicles (15.1%; 0%), paronychia (5.7%; 0%), decreased weight (1.9%; 0%), hypomagnesemia (28.3%; 5.7%), decreased appetite (5.7%; 0%), hypocalcemia (5.7%; 1.9%), rash (28.3%; 5.7%), dermatitis acneiform (22.6%; 11.3%), dry skin (18.9%; 0%), pruritis (15.1%; 0%), skin fissures (13.2%; 0%), skin-related toxic effects (9.4%; 3.8%), palmar-plantar erythrodysesthesia (7.5%; 0%), nail cuticle fissures (5.7%; 0%) and maculopapular rash (3.8%; 0%).

In the 240-mg Lumakras/Vectibix arm, the most common side effects were anemia (any-grade, 7.5%; grade 3 or higher, 1.9%), thrombocytopenia (3.8%; 0%), diarrhea (18.9%; 5.7%), nausea (17.0%; 3.8%), vomiting (11.3%; 0%), stomatitis (7.5%; 0%), fatigue (5.7%; 0%), weakness/fatigue (5.7%; 0%), malaise (3.8%; 1.9%), inflamed hair folllicles (3.8%; 1.9%), infection near the nails (11.3%; 1.9%), decreased weight (1.9%; 0%), decreased neutrophil counts (3.8%; 0%), hypomagnesemia (30.2%; 7.5%), decreased appetite (5.7%; 1.9%), hypocalcemia (3.8%; 0%), rash (24.5%; 1.9%), dermatitis acneiform (37.7%; 3.8%), dry skin (22.6%; 0%), pruritis (13.2%; 0%), skin fissures (7.5%; 0%), skin-related toxic effects (7.5%; 1.9%), palmar-plantar erythrodysesthesia (5.7%; 0%), maculopapular rash (5.7%; 1.9%), hair loss (1.9%; 0%) and hypertension (1.9%; 0%).

In the SOC arm, the most common side effectswere anemia, thrombocytopenia (7.8%; 2.0%), leukopenia (7.8%; 2.0%), neutropenia (31.4%; 23.5%), 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%), decreased weight (5.9%; 0%), decreased neutrophil counts (7.8%; 3.9%), hypomagnesemia (2.0%; 0%), decreased appetite (11.8%; 2.0%), rash (2.0%; 0%), dermatitis acneiform (2.0%; 0%), pruritis (3.9%; 0%), skin-related toxic effects (2.0%; 2.0%), palmar-plantar erythrodysesthesia (9.8%; 3.9%), maculopapular rash (2.0%; 0%), alopecia (5.9%; 0%) and hypertension (13.7%; 5.9%).

The investigators reported that the pharmacokinetics of Lumakras and Vectibix were consistent with those observed in prior studies, and that similar drug exposures were seen with the two Lumakras dose levels. Additionally, investigators reported no pharmacokinetic drug-to-drug interactions between Lumakras and Vectibix.

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