Researchers reported a 100% disease control rate in 27 evaluable patients with KRASG12C-mutant pancreatic ductal adenocarcinoma and other gastrointestinal tumors, not including colorectal cancer, who received adagrasib monotherapy. These preliminary data come from the phase II portion of the KRYSTAL-1 study, which is assessing the safety and efficacy of the KRASG12C inhibitor.

Previously reported data from the KRYSTAL-1 study demonstrated that the KRASG12C inhibitor adagrasib (MRTX849; Mirati Therapeutics) offers clinical benefit in a variety of malignancies, including colorectal and non–small cell lung cancers. Now, preliminary data from the phase II portion of the trial shows a disease control rate of 100% in patients with pancreatic and other gastrointestinal (GI) cancers.

The findings were reported by Tanios Bekaii-Saab, MD, of the Mayo Clinic in Scottsdale, AZ, at the American Society of Clinical Oncology 2022 Gastrointestinal Cancers Symposium, held January 20–22.

KRAS cycles between “GTP on” and “GDP off.” Adagrasib irreversibly and selectively binds KRASG12C, locking it in its GDP-bound state, explained Bekaii-Saab. This suppresses MAPK signaling—and tumor growth—in KRASG12C-mutant cancers.

Bekaii-Saab and his team enrolled 30 patients with previously treated, inoperable or metastatic KRASG12C-mutant GI cancers other than colorectal cancer to receive adagrasib as a monotherapy: Twelve patients had pancreatic ductal adenocarcinoma (PDAC) and 18 had other GI cancers, including eight with biliary tract, five with appendiceal, two with gastroesophageal junction (GEJ), two with small bowel, and one with esophageal cancer.

Among 10 evaluable patients with PDAC, 50% experienced a partial response (PR) after a median of 8.1 months, Bekaii-Saab reported. The rest of the patients developed stable disease, for a disease control rate (DCR) of 100%. The median duration of response (DOR) and median progression-free survival (PFS) were 7 months and 6.6 months, respectively. As of the September 10, 2021, data cutoff, five patients were still receiving adagrasib.

In addition, after a median of 6.3 months, four of the eight patients with biliary tract cancer experienced a PR; one patient with GEJ cancer and one with small bowel cancer also had PRs, for an objective response rate of 35%. All other evaluable patients with GI cancers developed stable disease, for a DCR of 100%. The median DOR and median PFS were both 7.9 months, and 65% of patients were still taking adagrasib at the time of data cutoff.

Among all 30 patients, 87% experienced treatment-related adverse events (TRAE)—most commonly nausea, vomiting, diarrhea, and fatigue. However, Bekaii-Saab noted that there were no grade 4 or 5 TRAEs, and no patients discontinued treatment due to a TRAE, a sign that adagrasib monotherapy is “well tolerated and has a manageable safety profile.”

“The results are very impressive,” said Michael Pishvaian, MD, PhD, of Johns Hopkins University School of Medicine in Baltimore, MD. “The fact that the responses were seen across cancer types points to this drug being a very molecularly targeted therapy—irrespective of the underlying cancer type.” Similar results, he noted, led to tumor-agnostic approvals of the PD-1 inhibitor pembrolizumab (Keytruda; Merck) for microsatellite instability–high cancers, and the NTRK inhibitors larotrectinib (Vitrakvi; Bayer) and entrectinib (Rozlytrek; Genentech) for any cancer with an NTRK fusion.

Relaying questions from conference-goers, session co-chair Mandana Kamgar, MD, MPH, of the Medical College of Wisconsin in Milwaukee, asked about the possibility of a phase III trial. “Obviously, that's a challenge with these rare subtypes” of disease, she said.

Bekaii-Saab agreed but added that “as long as we can continue with the enrollment [of patients with noncolorectal GI tumors in the phase II trial] and continue to see these signals, there are certainly multiple paths to get this to the clinic.”

Because KRASG12C mutations are uncommon in pancreatic and other noncolorectal GI tumors, researchers are assessing agents to suppress other oncoproteins. “Ongoing preclinical work supports the development of KRAS inhibitors that can modulate the more common G12D and G12V oncoproteins in PDAC,” said David Tuveson, MD, PhD, of Cold Spring Harbor Laboratory in New York, noting that investigational trials will begin “in the near future.”

“It's a very exciting time for KRAS targeting,” Bekaii-Saab said. –Suzanne Rose