Results of a 129-patient phase I trial of sotorasib, an investigational small molecule agent that “selectively and irreversibly” targets KRASG12C, produced responses in patients with KRAS-mutation solid tumors, according to results reported at the European Society for Clinical Oncology virtual congress (ESMO).
But KRAS mutation tumors have consistently proven to be resistant to targeted therapies, so it is not surprising that the activity demonstrated in this phase I trial was limited as David S. Hong, MD, of University of Texas, MD Anderson Cancer Center, in Houston and colleagues, wrote in a paper posted online by The New England Journal of Medicine concurrently with the ESMO presentation.
“Despite the fact that the cancers in our patient population had been refractory to previous treatments, 32.2% of the patients with NSCLC had a confirmed response, and the majority (88.1%) had disease control for a few months or more with sotorasib, leading to a median progression-free survival of 6.3 months. Similarly, most patients in the colorectal cancer subgroup had disease control, with a median duration of stable disease of 5.4 months and median progression-free survival of 4.0 months,” they wrote. “With current therapies, approximately 9 to 18% of patients with NSCLC have a response to second- or third-line therapies, with median progression-free survival of 2.5 to 4.0 months, and approximately 1.0 to 1.6% of patients with previously treated colorectal cancer have a response to standard therapies, with median progression-free survival of 1.9 to 2.1 months Thus, the treatment outcome in patients with NSCLC or colorectal cancer similar to patients in our study is generally poor. Responses and disease stability associated with sotorasib in these patients are encouraging.”
Most of the patients in the trial had non-small-cell lung cancer (n=59) or colorectal cancer (n=42), and less than a third (n=28) had other cancers. All had received a median of 3 previous lines of treatment for metastatic disease. “The trial consisted of dose escalation and expansion cohorts. Sotorasib was administered orally once daily. The planned dose levels for the escalation cohorts (1 through 4) were 180, 360, 720, and 960 mg, with two to four patients receiving treatment in each cohort.”
Among the findings:
- 73 patients reported treatment-related adverse events.
- Confirmed objected response (complete or partial) was observed in 19 (32.2%) of the NSCLC patients.
- 88.1% of NSCLC patients had disease control.
- Median progression-free survival in NSCLC patients was 6.3 months.
- Median progression-free survival among colorectal cancer patients was 4.0 months.
Hong and colleagues noted that in the NSCLC subgroup they observed a 35.3% response at the 960 mg dose, which they found “particularly promising”, and as a result the 960 mg dose is advancing to confirmatory studies. Moreover, the response to sotorasib was rapid—observed at first assessment (6 weeks)—and durable, “ongoing for a median follow-up of nearly a year.… The median duration of response among all patients who had a response was 10.9 months.” But there were patients who progressed soon after an initial response.
“Overall, the results of this trial are very encouraging, showing the first step in ’drugging the undruggable,’” wrote Patricia M. LoRusso, DO, of the Yale Cancer Center, and Judith S. Sebolt-Leopold, PhD, of the University of Michigan Rogel Cancer Center, Ann Arbor in an editorial. “Tumor responses were much better than those seen with the current standard of care for patients with similar disease profiles. Despite these encouraging results, no complete responses were observed, perhaps because tumors harboring KRAS mutations often have multiple oncogenic drivers. Neither serial biopsy data nor serial circulating tumor DNA (ctDNA) data were presented, leaving key questions unanswered — namely, can particular differences in the mutational signatures of KRASG12C NSCLC and colorectal cancers explain the substantial differences in response of these two tumor types, and could other driver mutations have contributed to the lack of complete responses?”
The inconsistency in response was acknowledged by Hong and colleagues who hypothesized that the difference in response between NSCLC patients and colorectal cancer patients “the poor prognosis in patients with metastatic disease and the lack of effective treatments in this population, controlling the tumor burden with an oral therapy for a few months may be meaningful.suggests either that KRAS p.G12C is not the dominant oncogenic driver for colorectal cancer or that other pathways, such as Wnt or EGFR pathways, mediate oncogenic signaling beyond KRAS, a hypothesis supported by recently published preclinical evidence. Therefore, combining sotorasib with therapies that block additional pathways may be a viable option, as shown by studies in BRAF V600E–mutant colorectal cancer.”
LoRusso and Sebolt-Leopold concluded the “article by Hong, et al shows that, through meaningful scientific collaborations, clinical inhibition of this previously untouchable target is now possible. The early development of KRASG12C-targeted agents is just the beginning, lending hope that the ability to target not only other KRAS mutations but also other targets previously thought to be undruggable may be within reach.”
Note that sotorasib is an investigational agent that is not FDA approved for clinical use.
Be aware that the results reported by Hong et al are from a phase I, open-label study which demonstrated sotorasib’s activity. Confirmatory trials of the 960 mg dose are ongoing.
Peggy Peck, Editor-in-Chief, BreakingMED™
Supported by Amgen; also supported in part by a Cancer Prevention Research Institute of Texas Precision Oncology Decision Support Core grant (RP150535)and Comprehensive Cancer Center Core Grants (P30 CA016672 and P30 CA008748) at Memorial Sloan Kettering Cancer Center from the National Institutes of Health (NIH). Denlinger is supported in part by a Comprehensive Cancer Center Core Grant (P30 CA006927) at Fox Chase Cancer Center from the NIH, and Lito is supported in part by grants (1R01CA23074501 and 1R01CA23026701A1) from the NIH National Cancer Institute, by the Pew Charitable Trusts, and by the Damon Runyon Cancer Research Foundation.
Hong reported grants or consultant work for AbbViee, Adaptimmune, Aldi-Norte, Alpha Insights, American Society of Clinical Oncology, Amgen, Inc., AstraZeneca, AxioMed, LLC, Baxter Healthcare, Bayer HealthCare Pharmceuticals Inc., Bristol-Myers Squibb Company, Daiichi Sankyo Company, Eisai Inc., Eli Lilly Company, Fate Therapeutics, Genentech USA, Inc., Genmab, GlaxoSmithKline, GLG Group, Group H, Guidepost Global, Ignyta, Infinity, Kite, Kyowa Kirin, Inc., Loxo Oncology, Medimmune, Medscape, Merck, Mirati, MiRNA, Molecular Templates, MolecularMatch, Mologen, NCI-CTEP, Novartis, Numab, Oncology Education Project Association, OncoResponse, Pfizer, PrimeOncology, Seattle Genetics, Society of Imunotherapy in Cancer, ST-Cube, Takeda Oncology, Trieza Therapeutics, Turning Point Therapeutics, and WebMD.
LoRusso reported personal fees from AbbVie, Agios , Five Prime, GenMab, Halozyme, CytomX, Takeda, SOTIO, Cybrexa, Agenus, Tyme, IQVIA, TRIGR, Pfizer, ImmunoMet, Glaxo-Smith Kline, QED Therapeutics, AstraZeneca, EMD Serono, Shattuck, Astellas, Salarius, Silverback, MacroGenics, Kyowa Kirin Pharmaceutical Development, Kineta, Genentech, Zentalis Pharmaceuticals , Molecular Templates, and other compensation from Black Diamond outside the submitted work.
Sebolt-Leopold had nothing to disclose.
Cat ID: 120
Topic ID: 78,120,120,697,935,192,925,696