Sotorasib helps curtail pancreatic cancer with manageable side effects in patients who have KRAS p.G12C-mutated advanced pancreatic cancer and have undergone previous treatment, according to a recent study.
Pancreatic cancer accounts for approximately 3 percent of all cancers, ranking eighth among common cancers in women and 10th among most common cancers in men, according to The Cancer Network. Moreover, it remains one of the deadliest of cancers, accounting for 7 percent of all cancer deaths-a rate that has increased in 0.2 percent increments in men since the late 1990s. In 2020 alone, it accounted for nearly half a million new cases of cancer (n=495,773) and claimed almost as many lives (n=466,003) (N Engl J Med 2023; doi: 10.1056/NEJMoa2208470).
Historically, standard treatment protocols consisted of surgery with or without a chemotherapy regimen, including fluorouracil, leucovorin, irinotecan, and oxaliplatin, an anticancer cocktail commonly known as FOLFIRINOX. Although usually aggressive in nature, these treatment regimens only offer meager survival and quality-of-life benefits at best. In addition, these therapies have a toxicity profile that few patients can tolerate due to various factors such as age, performance status, and disease-related frailty.
The toxicity of these therapeutic options has triggered the exploration of other therapies offering similar if not greater benefits without the unpleasant side effects. To that end, additional treatments approved for pancreatic cancer include the following:
* olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, indicated as maintenance therapy for metastatic pancreatic ductal adenocarcinoma carrying a germline BRCA mutation;
* pembrolizumab for unresectable or metastatic, microsatellite instability-high, or defective DNA mismatch repair-deficient solid tumors; and
* tropomyosin receptor kinase inhibitors larotrectinib and entrectinib that target solid tumors with an NTRK gene fusion.
The most prevalent historical type of pancreatic cancer is pancreatic ductal carcinoma with a mutation in the Kirsten rat sarcoma viral oncogene homolog (KRAS). In fact, KRAS falls among the most commonly mutated isoforms found in pancreatic cancers in the RAS family of genes. In addition, this malignancy is found in approximately 90 percent of all pancreatic ductal carcinoma cases. However, the KRAS p.G12C, or glycine-to-cysteine substitution at codon 12, occurs in about 1-2 percent of the patient population.
A small molecule, sotorasib specifically and irreversibly inhibits KRAS G12C. Recently, the drug gained accelerated approval from the FDA for patients who have KRAS p.G12C-mutated non-small cell lung cancer and received at least one systemic treatment. This study explores the effects of patients who are heavily pretreated with KRAS p. G12C-mutated pancreatic cancer from the Phase I/II portions of the CodeBreaK 100 trial.
Study Details
Investigators designed this study as an international, multicenter, open-label, Phase I/II trial to assess the safety and efficacy of sotorasib as monotherapy in patients with KRAS p.G12C-mutated pancreatic cancer. In Phase I, evaluating the drug's safety and side effect profile was the primary objective. Meanwhile, Phase II focused on determining the recommended dose, which researchers defined as 960 mg daily. Patients in both phases received sotorasib treatment until their cancer progressed, unacceptable side effects developed, or they withdrew consent.
The study's investigators evaluated the following efficacy endpoints: objective response, duration of response, time to objective response, disease control (defined as an objective response or stable disease), progression-free survival, and overall survival. Blinded independent central reviewers examined tumor response in both phases based on the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1).
Researchers enrolled candidates in the study if they were a minimum of 18 years of age; had a pathologically documented, locally advanced, or metastatic pancreatic cancer with KRAS p.G12C mutation confirmed by local performance molecular testing; and received treatment with at least one previous systemic therapy. However, a therapeutic exception was given to patients deemed ineligible for available therapies with previously established clinical benefits or that would have caused unacceptable adverse events. Lastly, enrollees must have had an Eastern Cooperative Oncology Group (ECOG) performance status score of 2 or less on a scale of 0-5, with higher scores indicative of a greater degree of disability.
The trial began on July 3, 2019, and concluded on January 25, 2021, with investigators following 38 patients with KRAS p.G12C-mutated pancreatic cancer at 25 centers in seven countries. Phase I had 12 enrollees, while Phase II had 26 enrollees. All patients received 960 mg doses of oral sotorasib each day. With a median treatment duration of 18 weeks (range: 1-48), 66 percent of patients (n=25) received treatment for at least 3 months. Meanwhile, 21 percent (n=8) received treatment for 6 months or longer. Although the protocol originally specified treatment would be discontinued if the disease progressed, two patients (5%) continued receiving treatment following the progression of their disease, as their investigator determined the patients would benefit clinically.
By the November 1, 2021, cutoff date, the remaining 95 percent of patients (n=36) had discontinued treatment, with disease progression serving as the most common reason (84%, n=32). It is worth noting that 72 percent of the patients (n=26) died or withdrew from the trial without receiving additional anticancer treatment. Most of the remaining patients received some form of chemotherapy.
The vast majority of patients were men (n=29) with a median age of 65.6 (ranging 45-81) years of age. More than half (55%) of patients had Stage IV pancreatic cancer when initially diagnosed, and all patients had metastatic involvement upon enrollment. Similarly, the majority of cancers had metastasized to the liver (n=31, 82%). However, 14 patients (37%) had a history of pancreatic retention, with one patient having Stage IV pancreatic cancer at the initial diagnosis. In addition, trial enrollees previously received a median of two lines of therapy (range: 1-8). Thirty of those patients (79%) received at least two previous lines of therapy.
Patient Responses
The blinded independent central review assessed enrollees' responses to determine efficacy. To that end, no patients experienced a complete response. Meanwhile, eight of the 38 patients enrolled in the trial (21%; 95% CI: 10-37) had a confirmed partial response. The median time to achieve partial response was 1.5 months (1.3-5.6). The duration of response was 5.7 months (95% CI: 1.6-nonevaluable). Investigators observed a partial response in 62 percent (n=5) of the enrollees approximately at Week 6-the time at which they conducted the first tumor assessment. At the time of the data cutoff date, two of the eight patients who received a partial response were continuing to receive treatment. The ongoing treatment lasted approximately 10 months. Researchers observed tumor shrinkage of any magnitude in 79 percent of patients (n=30). In addition, the median progression-free survival was 4.0 months (95% CI: 2.8-5.6), as assessed by blinded independent central review.
As for safety, the study authors noted that sotorasib shares a profile similar to that observed in the Phase I (12 patients) and Phase II (26 patients) cohorts. All patients (100%) experienced some sort of adverse event. The most commonly reported adverse events were abdominal pain (n=14, 37%), diarrhea and nausea (n=9, 24%), and vomiting and pyrexia (n=8, 21%). More than half of trial participants experienced adverse events that were at least Grade 3, if not higher (n=24, 63%).
Across all grades, investigators deemed the following adverse events to be treatment-related in 16 patients or 42 percent of the participants. Six patients (16%) experienced Grade 3 adverse events, the most common being diarrhea and fatigue (n=2, 5% each). No Grade 4/5 treatment-related events were reported, while three patients (8%) reported treatment-related serious adverse events. In addition, researchers did not consider any of the 14 fatalities (37%) to be treatment-related.
Overall, the study authors expressed optimistic views of the trial's potential benefits regarding approved regimens of second-line treatment for advanced pancreatic cancer. Furthermore, while patient responses in this trial mirrored those observed in the POLO trial, it is important to note that the POLO study differed in trial design.
Unlike this trial, which is a nonrandomized, single-group, Phase I/II trial, the POLO trial was a randomized, placebo-control, Phase III trial with eligibility restricted to patients who experienced no disease progression following 4 months of first-line platinum-based treatment. This distinction bears additional emphasis because such a response (or lack thereof) increased the likelihood the patients would respond to PARP inhibitors.
On the other hand, nearly 80 percent of the patients enrolled in the current trial had been heavily pretreated with at least two lines of anticancer therapies. Additional studies specifically exploring the safety and efficacy of sotorasib administered concomitantly with other anticancer therapies are in the works.
Frieda Wiley is a contributing writer.