Sotorasib Combo Yields PFS Benefit in KRAS G12C+ Metastatic CRC

"With these new data, sotorasib plus panitumumab showed consistent efficacy across key subgroups at both doses and supports the biologic rationale of combining these two biomarker-directed therapies," according to Filippo Pietrantonio, MD.

Patients with KRAS G12C-mutated chemorefractory metastatic colorectal cancer (mCRC) experienced improvements in progression-free survival (PFS) with sotorasib (Lumakras) plus panitumumab (Vectibix) compared with standard of care (SOC), according to primary analysis findings from the phase 3 CodeBreaK 300 trial (NCT05198934) presented at the 2023 European Society for Medical Oncology Congress (ESMO) and published in New England Journal of Medicine.^1,2

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 1:1:1 to receive 960 mg of the KRAS G12C inhibitor sotorasib once daily plus the EGFR inhibitor panitumumab (n = 53), 240 mg of sotorasib once daily plus panitumumab (n = 53), or investigator’s choice of standard trifluridine/tipiracil (TAS-102; n = 37) or regorafenib (n = 14).

At a median follow-up of 7.8 months (range, 0.1-13.9) and a data cutoff cate of June 19, 2023, patients in the 960-mg sotorasib/panitumumab, 240-mg sotorasib/panitumumab, and SOC arms achieved a median PFS of 5.6 months (95% CI, 4.2-6.3), 3.9 months (95% CI, 3.7-5.8), and 2.2 months (95% CI, 1.9-3.9), respectively. The hazard ratio (HR) for disease progression or death in the 960-mg sotorasib/panitumumab arm vs the SOC arm was 0.49 (95% CI, 0.30-0.80; P = .006). The HR for disease progression or death in the 240-mg sotorasib/panitumumab arm vs the SOC arm was 0.58 (95% CI, 0.36-0.93; P = .03).

“With these new data, sotorasib plus panitumumab showed consistent efficacy across key subgroups at both doses and supports the biologic rationale of combining these two biomarker-directed therapies,” presenting author Filippo Pietrantonio, MD, of the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy, said in a press release.³

Previously, the phase 1b CodeBreaK 101 trial (NCT04185883) demonstrated that sotorasib plus panitumumab elicited a confirmed ORR of 30% (95% CI, 16.6%-46.5%) in patients with chemorefractory mCRC.⁴

CodeBreaK 300 included adult patients with disease progression or recurrence after at least 1 prior line of therapy for metastatic disease, which must have included fluoropyrimidine, oxaliplatin, and irinotecan; however, patients who experienced unacceptable adverse effects (AEs) and were eligible to receive TAS-102 or regorafenib as their next line of therapy if deemed appropriate by the investigator and medical monitor, were also allowed to enroll.2 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.

Between April 19, 2022, and March 14, 2023, 219 patients were screened at 76 sites across 12 countries. A total of 160 eligible patients were enrolled in Europe (65.6%), Asia (22.5%), North America (10.6%), and other regions (1.2%). Three patients in the SOC arm did not receive the assigned treatment and were not included in the safety population.

Sotorasib was administered orally once a day. Panitumumab was administered IV at 6 mg/kg every 2 weeks. Each treatment cycle lasted 28 days. TAS-102 was administered orally twice a day at a starting dose of 75 mg/m2 up to a maximum of 80 mg/m2, or a maximum of 75 mg/m2 for patients in Japan, on the basis of the trifluridine component, on days 1 through 5 and 8 through 12 in 28-day cycles. Regorafenib was administered orally once a day on days 1 through 21 every 28 days.

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.

In the overall population, the median age was 62.0 years (range, 34-82), and 49.4% of the patients were male. In total, 60.0%, 36.9%, and 3.1% of patients had an ECOG PS of 0, 1, and 2, respectively. Fifteen percent of patients had received 1 prior line of therapy, and 85.0% of patients had received at least 2 prior lines of therapy. Right-sided tumors were present in 45.3%, 32.1%, and 29.6% of patients in the 960-mg sotorasib/panitumumab, 240-mg sotorasib/panitumumab, and SOC arms, respectively.

The median duration of treatment in the 960-mg sotorasib/panitumumab, 240-mg sotorasib/panitumumab, 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% (n = 23), 35.8% (n = 19), and 9.3% (n = 5) of patients in the 960-mg sotorasib/panitumumab, 240-mg sotorasib/panitumumab, and SOC arms, respectively, continued to receive treatment after the data cutoff date.

In the 960-mg sotorasib/panitumumab, 240-mg sotorasib/panitumumab, and SOC arms, the ORRs were 26.4% (95% CI, 15.3%-40.3%), 5.7% (95% CI, 1.2%-15.7%), and 0.0% (95% CI, 0.0%-6.6%), respectively. One patient (1.9%) in the 960-mg sotorasib/panitumumab arm achieved a complete response. Additionally, in the 960-mg sotorasib/panitumumab arm, 24.5% (n = 13), 45.3% (n = 24), and 22.6% (n = 12), of patients had a partial response (PR), stable disease (SD), or progressive disease (PD), respectively. In the 240-mg sotorasib/panitumumab arm, 5.7% (n = 3), 62.3% (n = 33), and 24.5% (n = 13), and 3.8% (n = 2) of patients had a PR, SD, PD, or noncomplete response/nonprogressive disease, respectively. In the SOC arm, 46.3% (n = 25), 31.5% (n = 17), and 1.9% (n = 1) of patients had SD, PD, or noncomplete response/nonprogressive disease, respectively.

Moreover, 3.8% (n = 2), 1.9% (n = 1), and 20.4% (n = 11) of patients in the 960-mg sotorasib/panitumumab, 240-mg sotorasib/panitumumab, and SOC arms, respectively, were not assessed, and 1 patient each in the 960-mg sotorasib/panitumumab and 240-mg sotorasib/panitumumab arms had no assessable disease at baseline.

The median DOR was 4.4 months (95% CI, 3.6–not reached) in the 960-mg sotorasib/panitumumab arm and not evaluable in the other arms because of insufficient responses. The median time to response in the 960-mg sotorasib/panitumumab and 240-mg sotorasib/panitumumab arms was 2.1 months (range, 1.9-3.9) and 1.8 months (range, 1.7-1.9) months, respectively. The DCR in the 960-mg sotorasib/panitumumab, 240-mg sotorasib/panitumumab, and SOC arms was 71.7% (95% CI, 57.7%-83.2%), 67.9% (95% CI, 53.7%-80.1%), and 46.3% (95% CI, 32.6%-60.4%), respectively.

At the data cutoff date, the OS data were not mature, and 34.4% (n = 55) of patients had died. However, trends were observed favoring both the 960-mg sotorasib/panitumumab arm (HR, 0.77; 95% CI, 0.40-1.45) and the 240-mg sotorasib/panitumumab arm (HR, 0.91; 95% CI, 0.48-1.71) vs the SOC arm.

In total, treatment-related AEs (TRAEs) occurred in 94.3% (n = 50), 96.2% (n = 51), and 82.4% (n = 42) of patients in the 960-mg sotorasib/panitumumab, 240-mg sotorasib/panitumumab, and SOC arms, respectively. Grade 3 or higher TRAEs occurred in 35.8%, 30.2%, and 43.1% of patients in the 960-mg sotorasib/panitumumab, 240-mg sotorasib/panitumumab, and SOC arms, respectively, and grade 4 or higher TRAEs occurred in 3.8%, 0%, and 3.9% of patients, respectively. Additionally, serious AEs occurred in 5.7% of patients in the 960-mg sotorasib/panitumumab arm, 7.8% of patients in the SOC arm, and no patients in the 240-mg sotorasib/panitumumab. Furthermore, no AEs leading to death were reported.

In the 960-mg sotorasib/panitumumab arm, sotorasib- and panitumumab-related AEs occurred in 60.4% and 92.5% of patients, respectively. In the 240-mg sotorasib/panitumumab arm, sotorasib- and panitumumab-related AEs occurred in 64.2% and 94.3% of patients, respectively.

In the 960-mg sotorasib/panitumumab, 240-mg sotorasib/panitumumab, and SOC arms, TRAEs 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 sotorasib/panitumumab, 240-mg sotorasib/panitumumab, and SOC arms, respectively.

In the 960-mg sotorasib/panitumumab arm, the most common AEs were anemia (any-grade, 1.9%; grade ≥3, 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%), asthenia (5.7%; 0%), xerosis (5.7%, 0%), folliculitis (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 sotorasib/panitumumab arm, the most common AEs were anemia (any-grade, 7.5%; grade ≥3, 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%), asthenia (5.7%; 0%), malaise (3.8%; 1.9%), folliculitis (3.8%; 1.9%), paronychia (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%), alopecia (1.9%; 0%), and hypertension (1.9%; 0%).

In the SOC arm, the most common AEs were anemia (any-grade, 19.6%; grade ≥3, 5.9%), 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%), pyrexia (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 sotorasib and panitumumab were consistent with those observed in prior studies, and that similar drug exposures were seen with the 2 sotorasib dose levels. Additionally, investigators reported no pharmacokinetic drug-to-drug interactions between sotorasib and panitumumab.

Editor's note: Pietrantonio reports financial interests, personal interests, or advisory board participation with Amgen, Merck-Serono, MSD, Bayer, Organon, and Astellas; financial interests, personal interests, or invited speaker participation with Amgen, Merck-Serono, BMS, Lilly, Servier, Bayer, Pierre-Fabre, AstraZeneca, and Astellas; and financial interests, institutional funding, or research grants from BMS, AstraZeneca, and Incyte.

References

1. Pietrantonio F, Salvatore L, Esaki T, et al. LBA10 sotorasib plus panitumumab versus standard-of-care for chemorefractory KRAS G12C-mutated metastatic colorectal cancer (mCRC): CodeBreak 300 phase III study. Ann Oncol. 2023;34(suppl 2):S1266. doi:10.1016/j.annonc.2023.20.016
2. Fakih MG, Salvatore L, Esaki T, et al. Sotorasib plus panitumumab in refractory colorectal cancer with mutated KRAS G12C. New Engl J Med. Published online October 22, 2023. doi:10.1056/NEJMoa2308795
3. Amgen presents new Lumakras (sotorasib) plus Vectibix (panitumumab) data in patients with KRAS G12C-mutated metastatic colorectal cancer. News Release. Amgen. October 22, 2023. Accessed October 22, 2023. https://www.prnewswire.com/news-releases/amgen-presents-new-lumakras-sotorasib-plus-vectibix-panitumumab-data-in-patients-with-kras-g12c-mutated-metastatic-colorectal-cancer-301963791.html
4. Kuboki Y, Yaeger R, Fakih MG, et al. 315O Sotorasib in combination with panitumumab in refractory KRAS G12C-mutated colorectal cancer: safety and efficacy for phase Ib full expansion cohort. Ann Oncol. 2022;33(suppl 7):S680-S681. doi:10.1016/j.annonc.2022.07.453