Sotorasib Shows Early Promise in Heavily Pretreated KRAS G12C–Mutated Advanced Pancreatic Cancer

Pipeline Report | <b>Pipeline Report: February 2022</b>

Sotorasib had clinically meaningful activity in heavily pretreated patients with KRAS G12C–mutated advanced pancreatic cancer, according to findings from the phase 1/2 CodeBreaK 100 trial.

Sotorasib (Lumakras) had clinically meaningful activity in heavily pretreated patients with KRAS G12C–mutated advanced pancreatic cancer, according to findings from the phase 1/2 CodeBreaK 100 trial (NCT03600883) presented during the February 2022 ASCO Plenary Series.

At a median follow-up of 16.8 months (range, 0.6-16.8), the KRAS G12C inhibitor elicited a confirmed objective response rate (ORR) of 21.1% (95% CI, 9.55%-37.32%) per blinded independent central review (BICR) and RECIST v1.1 criteria among 38 patients evaluated in both the phase 1 and 2 portions of the trial.

“The is the largest dataset evaluating efficacy and safety of a KRAS G12C inhibitor in patients with pretreated KRAS G12C–mutated pancreatic cancer,” lead study author John H. Strickler, MD, of Duke University Medical Center, said in a presentation on the data. “These data support the further exploration of sotorasib in this patient population with a high unmet medical need.”

Second-line treatment options that have received regulatory approval for use in patients with pancreatic ductal adenocarcinoma (PDAC) have been found to result in a survival benefit of approximately 6 months and a response rate of about 16%. Notably, those who experience disease progression on first- or second-line chemotherapy do not have any options available to them that have a demonstrated improved survival, according to Strickler.

About 90% of patients with PDAC have tumors that harbor a KRAS mutation with KRAS G12C detected in approximately 1% to 2% of patients. No targeted therapies are currently approved for patients with KRAS G12C–mutated PDAC.

In the global, open-label, phase 1/2 CodeBreaK 100 trial, investigators set out to examine the use of sotorasib in patients with advanced solid tumors harboring KRAS G12C. To be eligible for enrollment to the pancreatic cancer cohort, patients needed to have locally advanced or metastatic disease harboring a KRAS p.G12C mutation and have received 1 or more prior systemic therapies or be intolerant or ineligible for available therapies.

The trial was comprised of 2 phases. In the phase 1 dose-escalation and -expansion phase, 12 patients received the agent until progressive disease or the end of the study. The primary end point was safety and tolerability, and secondary end points included pharmacokinetics, ORR, duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and duration of stable disease.

In the phase 2 portion of the research, the agent was evaluated in 26 patients. The primary end point for this phase of the trial was ORR per BICR and RECIST v1.1 criteria, and key secondary end points comprised DOR, DCR, PFS, OS, time to response (TTR), and safety.

All 38 patients in the combined phase 1/2 population were given oral sotorasib at a once-daily dose of 960 mg.

Among these patients, the median age was 65.5 years (range, 45-81), 76.3% were male, 57.9% had an ECOG performance status of 1, and 97.4% had adenocarcinoma. At the time of enrollment, all patients had stage IV disease; however, 7.9% had stage I disease at initial diagnosis, 28.9% had stage II disease, 7.9% had stage III disease, and 55.3% had stage IV disease. Additionally, 44.7% of patients had metastatic disease in 1 body site, 39.5% had it in 2 sites, and 15.8% had it in 3 or more sites. The most common site of metastases was the liver (81.6%), followed by the lung (42.1%), the bone (10.5%), and the brain (2.6%).

Notably, 44.7% of patients had received 3 or more prior lines of therapy, 34.2% had received 2 prior lines, and 21.1% had received 1 prior line. The median number of previous lines of treatment was 2 (range, 1-8). The most common prior therapies received was chemotherapy (100.0%) in the form of fluoropyrimidine (89.5%), irinotecan (86.8%), oxaliplatin or cisplatin (84.2%), gemcitabine (73.7%), nab-paclitaxel (Abraxane; 65.8%), and liposomal irinotecan (13.2%). Just under 3% (3.6%) of patients received prior erlotinib (Tarceva).

Additionally, 76.3% of patients received FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin), 65.8% received gemcitabine plus nab-paclitaxel, and 13.2% had 5-fluororacil plus liposomal irinotecan.

Additional data showed that the Kaplan-Meier estimated median DOR with sotorasib was 5.7 months (95% CI, 1.6–not evaluable). Moreover, the KRAS G12C inhibitor resulted in a DCR of 84.2% (95% CI, 68.75%-93.98%) per BICR.

“Thirty out of 38 patients experienced a decrease in the sum of diameters of RECIST lesions compared with baseline,” Strickler noted.

The Kaplan-Meier estimate for median PFS with sotorasib was 4.0 months (95% CI, 2.8-5.6) and the estimated median OS was 6.9 months (95% CI, 5.0-9.1).

Safety was evaluated in all 38 patients who received at least 1 dose of sotorasib. Any-grade treatment-related adverse effects (TRAEs) were experienced by 42.1% of patients; these effects were grade 2 or higher in 31.6% of patients and grade 3 or higher in 15.8% of patients. Notable grade 3 or higher TRAEs included diarrhea (5.3%), fatigue (5.3%), abdominal pain (2.6%), alanine aminotransferase increased (2.6%), pleural effusion (2.6%), and pulmonary embolism (2.6%).

Toxicities resulting in dose reduction or interruption were experienced by 13.2% of patients. Moreover, serious toxicities occurred in 7.9%. Notably, no TRAEs were fatal or resulted in treatment discontinuation.

Strickler shared an example of female patient enrolled to the trial who experienced a partial response with sotorasib. The patient was 64 years of age and had stage IV pancreatic cancer at the time of diagnosis. Moreover, she had metastatic lesions in the liver, lymph nodes, lung, and peritoneum. She had received FOLFIRINOX as first-line treatment and experienced disease progression on the regimen.

In this patient, the TTR with sotorasib was 1.3 months, the DOR was 5.8 months, the PFS was 7.1 months, and the OS was 7.1 months. “[The patient had] a target lesion with a baseline diameter of 2.2 centimeters,” Stricker said. “At 18 weeks post-baseline, the diameter had decreased to 0.8 centimeters. By week 18 scan, she had a 42% reduction in tumor volume [per] RECIST criteria.”


Strickler JH, Satake H, Hollebecque A, et al. First data for sotorasib in patients with pancreatic cancer with KRAS p.G12C mutation: a phase 1/2 study evaluating efficacy and safety. J Clin Oncol. 2022;40(36):360490-360490. doi:10.1200/JCO.2022.40.36_suppl.360490