Adagrasib, a novel agent aimed at KRAS G12C mutations, has demonstrated early signs of efficacy in patients with advanced non–small cell lung cancer and colorectal cancer whose tumors harbor the alteration, raising hopes for a new therapy against a challenging oncogenic target.
Adagrasib (MRTX849), a novel agent aimed at KRAS G12C mutations, has demonstrated early signs of efficacy in patients with advanced non–small cell lung cancer (NSCLC) and colorectal cancer (CRC) whose tumors harbor the alteration, raising hopes for a new therapy against a challenging oncogenic target.
The objective response rate (ORR) with adagrasib monotherapy was 45% and 17% in cohorts of patients with unresectable or metastatic NSCLC and CRC, respectively, who participated in the ongoing phase 1/2 KRYSTAL-1 trial (NCT03785249).1,2 The study is now enrolling patients into combination arms that will test adagrasib with pembrolizumab (Keytruda) or afatinib (Gilotrif) in NSCLC or with cetuximab (Erbitux) in CRC.3
Overall, KRAS is the single most frequently mutated oncogene in human cancers, but there are no approved therapies that directly inhibit its activity despite nearly 4 decades of research.4 Adagrasib is an oral small molecule targeted against a subset of KRAS mutations, KRAS G12C, which are associated with a poor prognosis and lack of response to standard treatments. KRAS G12C alterations occur in about 14% of lung adenocarcinomas, 3% to 4% of colorectal cancers, and 1% to 2% of several other cancers.1,2
“G12C inhibitors take advantage of novel biology that was discovered a few years ago that allows them to covalently bind to KRAS. This discovery opened up the possibility that one could develop drugs specifically for this subset of KRAS-mutant cancers, and clinically we are starting to see some activity,” Pasi A. Jänne, MD, PhD, director of the Lowe Center for Thoracic Oncology and the Belfer Center for Applied Cancer Science at Dana-Farber Cancer Institute in Boston, Massachusetts, said in an interview with OncLive®.
Specifically, investigators discovered a new binding pocket amenable to therapeutic targeting on KRAS G12C proteins, explained Melissa L. Johnson, MD, associate director, Lung Cancer Research and Drug Development, for Sarah Cannon in Nashville, Tennessee.
“It’s called the switch-II binding pocket, and it’s only on KRAS G12C proteins,” Johnson said. “Because of this discovery, a small molecule that binds covalently, selectively, and irreversibly was able to be developed which locks KRAS in an inactive configuration. In the past, because it was difficult to bind directly to the KRAS protein, the ways in which we tried to manipulate KRAS involved inhibition of downstream effectors. We’ve done that with some success but unfortunately, but we had never found a truly viable strategy.”
Additionally, KRAS mutations vary by tumor types. “Figuring out the right strategy for KRAS in lung cancer is likely different from KRAS in colon cancer. That is another reason it has been difficult in the past to find a strategy that works across the board,” Johnson said.
In the KRYSTAL-1 trial, adagrasib is being evaluated in 6 experimental arms, 3 as a single agent and 3 in combination with other therapies. After a dose escalation phase, the recommended dose for adagrasib was identified as 600 mg twice a day.
Adagrasib monotherapy is being tested in separate cohorts for patients with NSCLC, CRC, and other solid tumors. The trial includes separate arms that will assess adagrasib in combination with pembrolizumab, a PD-1–directed immunotherapy, or afatinib, a pan-HER inhibitor, in patients with NSCLC; or with cetuximab, an EGFR antagonist, in patients with CRC.
“The combination of adagrasib with pembrolizumab is intended to answer the question of whether inhibiting the tumor cell growth and causing death of the tumor cells with the KRAS G12C inhibitor and then reactivating the immune system with pembrolizumab would be an effective combination. Pembrolizumab is the standard of care in lung cancer,” said Jänne, a leading investigator for the KRYSTAL-1 lung cancer cohort.
The combinations with cetuximab and afatinib are meant to assess whether EGFR inhibitors can block other pathways the tumor uses in response to KRAS G12C inhibition. “We know if you inhibit KRAS gene G12C in some lung and colon cancers, the cancers will turn on EGFR signaling to bypass that inhibition. It’s a compensatory pathway. If you block that compensatory pathway, you can potentially have a more effective therapeutic strategy,” Jänne said.
The trial seeks to enroll 391 patients at 56 study locations throughout the United States. The primary end points are ORR, pharmacokinetics evaluation, and safety. The secondary end points are establishing a maximum tolerated dose, evaluating the safety and tolerability in combination with other therapies, and assessing the PK of adagrasib oral formulations, including when administered with food.
Enrollment is complete for the phase 2 cohort of adagrasib as a monotherapy for patients in second- and third-line NSCLC, according to Mirati Therapeutics, which is developing adagrasib. The company anticipates submitting a new drug application to the FDA for accelerated approval in the second half of 2021 for this patient population. Registrational studies also are planned for adagrasib as a monotherapy and in combinations for earlier lines of therapy for patients with NSCLC and CRC.5
Additionally, Mirati has an agreement with Strata Oncology to broaden patient identification and enrollment for KRYSTAL-1.6 The Strata NGS assay is a genomic profiling test encompassing 429 genes that analyzes DNA and RNA in tissue samples from advanced solid tumors.
In October 2020, preliminary results from KRYSTAL-1 were detailed at the virtual EORTC-NCI-AACR Symposium on Molecular Targets and Therapeutics. The findings showed that adagrasib was tolerable and elicited durable clinical activity in patients with previously treated KRAS G12C-mutant NSCLC, and demonstrated promising activity for pretreated patients with CRC and other solid tumors with the aberration.1,2
As of August 30, 2020, 79 patients with previously treated NSCLC received 600 mg twice a day in the phase 1/1b or phase 2 cohort of the study, Jänne and colleagues reported. Patients included in the analysis had undergone a median of 2 prior lines of therapy (range, 1-9); all patients had previously received platinum-based chemotherapy 92% had also been treated with a PD-1/PD-L1 inhibitor.1
Among 51 patients evaluable for clinical activity (14 from phase 1/1b; 37 from phase 2), the ORR was 45%, all partial responses (PRs), after a median follow-p of 3.6 months. Additionally, the stable disease rate was 51%, for a disease control rate (DCR) of 96.1%.
Additionally, among 14 evaluable patients in the phase 1/2b cohort who had longer-term follow-up of a median of 9.6 months, the ORR with adagrasib monotherapy was 43% (6 of 14 patients), with most patients (5 of 6) remaining on treatment at the time of data cutoff. Four of the 6 patients reported a duration of treatment of longer than 11 months although the median time on treatment was 8.2 months.
Preliminary analysis of trial participants with NSCLC with co-occurring mutations of KRAS G12C and STK11 (showed an ORR 64% (9 of 14 patients). About 30% of patients with KRAS G12C-mutant NSCLC also have an STK11 mutation, and these co-occurring alterations are significantly correlated with poor clinical outcomes to immunotherapy and platinum-based chemotherapy regimens.5
In other findings, Johnson and colleagues reported pooled data for patients with KRAS G12C-mutant CRC and other solid tumors. Patients in the CRC cohort had received a median of 4 prior lines of therapy (range, 1-9) while those with other malignancies had received a median of 2 lines (range, 1-5). Among patients with CRC, the ORR was 17% (3 of 18 patients), all PRs. An additional 14 patients had stable disease, for a DCR rate of 94%. At the time of analysis, 67% (12 of 18 patients) remained on treatment.2
Among 6 evaluable patients with other solid tumors, confirmed PRs were reported in 1 patient with endometrial cancer, 1 with pancreatic cancer, 1 with ovarian cancer, and 1 with cholangiocarcinoma. All 6 patients remain on treatment.
A safety analysis was conducted on pooled data from 110 patients who received adagrasib at the recommended dose, including participants in the NSCLC, CRC, and other tumor cohorts. Frequently reported treatment-related adverse events (TRAEs) of any grade included nausea (54%), diarrhea (51%), vomiting (35%), and fatigue (32%). Grade 5 TRAEs included pneumonitis in 1 patient and cardiac failure in 1 participant.1,2
“Across all the cohorts enrolled, the encouraging finding is that this drug is capable of resulting in responses, regardless of the tumor type,” Johnson said. “This is one of the first studies which has been able to show this for KRAS-mutant cancers. As a single agent, adagrasib appears to work well for patients with lung cancer. For patients with colorectal cancer, on the other hand, it may be part of a combination strategy.”
Johnson also pointed out that adagrasib has favorable bioavailability with a half-life of 24 hours. “All of those things are critical to developing a small molecule for effective inhibition of an oncogene,” she said. “In particular for KRAS-mutant colorectal cancer, these properties are important. We know that the KRAS protein regenerates or resynthesizes once every 24 hours and since the half-life of the drug is 24 hours, we are effectively inhibiting the KRAS protein throughout the dosing interval.”
She said this is important particularly for CRC when the KRAS-mutant protein is no longer inhibited. “That allows upregulation of the feedback signaling pathways mediated through EGFR. Colorectal cancer does tend to be the most resistant to other RAS-directed therapies in the past. And this may be part of why this experience is different.”
Moving forward, adagrasib will be evaluated in combination with pembrolizumab in patients with advanced KRAS G12C-mutant NSCLC in the phase 2 KRYSTAL-7 trial (NCT04613596). The study, which has not yet started recruiting patients, will assess the combination in patients with unresectable or metastatic disease who have not received prior systemic treatment for locally advanced or metastatic disease. Investigators are seeking to enroll 120 participants.7
Additionally, in September 2020, Mirati announced a clinical collaboration with Boehringer Ingelheim to evaluate adagrasib in combination with BI 1701963, a SOS1::pan-KRAS inhibitor that blocks KRAS independent of mutation type in patients with lung and colorectal cancers. Preclinical data suggest the drugs have complementary mechanisms of action.8