Elena Garralda, MD, MSc, Director of Early Drug Development at Vall d’Hebron University Hospital and Director of the Phase I Unit at NEXT Oncology, Barcelona, was invited to discuss the KRYSTAL-1 findings.
“In KRYSTAL-1, adagrasib monotherapy has demonstrated clinically meaningful activity in a variety of KRAS G12C–mutated tumors, particularly biliary tract and pancreatic tumors. This is the largest tumor-agnostic data set to evaluate KRAS G12C–mutated solid tumors and the first to present data on a biliary tract cohort.”
Elena Garralda, MD, MSc
According to Dr. Garralda, one of seven persons with cancer has a KRAS mutation. These mutations occur across tumor types, making KRAS one of the top oncogenic drivers. Until recently, KRAS was considered undruggable. Covalent inhibitors are now emerging that not only target KRAS, but specifically target KRAS G12C, offering effective treatment to about 13% of KRAS-driven cancers, she said.
Data supporting the KRAS G12C inhibitor adagrasib has followed on the heels of sotorasib, which yielded an objective response rate of 41%, a disease control rate of 84%, median progression-free survival of 6.3 months, and median overall survival of 12.5 months in CodeBreaK100 in KRAS G12C–positive non–small cell lung cancer (NSCLC).1 Both drugs are approved for treatment of NSCLC.
Commenting on the response rates to single-agent adagrasib in KRYSTAL-1, Dr. Garralda noted benefit in all tumor types except appendiceal; none of those patients responded to this treatment. She was most impressed with the overall disease control rate of 86% and the strong activity in pancreatic and biliary tract cancers, where disease control rates were 81% and 91%, respectively. This aligns with the disease control rate of 84% in 38 patients with pancreatic cancer treated with sotorasib in CodeBreaK1001 and with emerging data for another KRAS G12C inhibitor in development, GDC-6036.2
“Histologic context seems to matter in the activity of KRAS G12C inhibitors, at least with monotherapy,” she said, adding that longer follow-up of the data is needed to show the relative efficacy of one inhibitor over another in the various tumor types.
No new toxicity signals emerged in the updated analysis, and most adverse events were low-grade. However, Dr. Garralda noted that 40% did require dose reduction, and 44% required dose interruptions, “so there is still room for improvement there,” she said.
Comparisons With Other Targeted Agents
There is also room for improvement in efficacy, if one compares these outcomes with those achieved with some other novel targeted agents, she pointed out. “We are still far from the overall response rates we’ve seen in other tumor-agnostic indications,” including for larotrectinib in TRK fusion–positive cancers (79%)3 and selpercatinib in RET fusion–positive tumors (44%).4 There are probably different intrinsic mechanisms of resistance at play among these agents, she acknowledged, but “there are still things we need to do to match these overall response rates.”
Next Steps
Outcomes with KRAS G12C inhibitors are further improved when these drugs are given in combination, as was shown by a more than doubling in response rates among patients with colorectal cancer receiving adagrasib plus cetuximab or sotorasib plus panitumumab. “Combinations can be the way forward to increase responses with these inhibitors, at least in some tumor types,” maintained Dr. Garralda.
“The next steps in targeting KRAS in the years to come are going to be very exciting,” she predicted. Here are some of these steps:
- Develop drugs with alternative modes of binding.
- Address and harness the redundancy of the pathway and tap into the biologic rationale for combination therapies.
- Optimize the development of combinatorial therapies and patient selection based on molecular background.
More than a dozen other KRAS-off inhibitors, in addition to adagrasib and sotorasib, are in development, along with pan-KRAS inhibitors, KRAS degraders, KRAS-on inhibitors and others. “Multiple KRAS drugs will be tested in the clinic in the next few years,” she said.
DISCLOSURE: Dr. Garralda has served as a consultant or advisor to Roche, Ellipses Pharma, Janssen, Boehringer Ingelheim, Seattle Genetics, Alkermes, Thermo Fisher Scientific, MabDiscovery, Anaveon, F-Star Therapeutics, Hengrui Therapeutics, Sanofi, and Incyte and is on the speakers bureau of MSD, Roche, Thermo Fisher Scientific, Eli Lilly, Novartis, and Seagen. She is employed by NEXT Oncology and has been the recipient of numerous institutional research grants.
REFERENCES
1. Hong DS, Fakih MG, Strickler JH, et al: KRAS G12C inhibition with sotorasib in advanced solid tumors. N Engl J Med 383:1207-1217, 2020.
2. Patel M, Lee J, de Miguel MJ, et al: Phase Ia study to evaluate GDC-6036 monotherapy in patients with solid tumors with a KRAS G12C mutation. ESMO Congress 2022. Abstract 459MO. Presented September 12, 2022.
3. Hong DS, DuBois SG, Kummar S, et al: Larotrectinib in patients with TRK fusion-positive solid tumours: A pooled analysis of three phase 1/2 clinical trials. Lancet Oncol 21:531-540, 2020.
4. Subbiah V, Wolf J, Konda B, et al: Tumour-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid tumours (LIBRETTO-001): A phase 1/2, open-label, basket trial. Lancet Oncol 23:1261-1273, 2022.
