Lung cancer is the leading cause of cancer deaths globally. The two main types of lung cancer are non-small cell and small cell. Non-small cell lung cancer (NSCLC) is one of the most common types of lung cancer, representing up to 84% of diagnoses. KRASG12C is the most common mutation of Kirsten rat sarcoma virus (KRAS) in NSCLC, present in approximately 14% of patients with lung adenocarcinoma, and is a biomarker of poor prognosis.

Results from the Phase 3 KRYSTAL-12 study (NCT04685135), funded by Mirati Therapeutics, a Bristol Myers Squibb company, which is designed to evaluate adagrasib* (Krazati®; Bristol Myers Squibb/BMS) compared to standard of care chemotherapy in patients with locally advanced or metastatic KRASG12C -mutated non-small cell lung cancer (NSCLC) who had previously received platinum-based chemotherapy, concurrently or sequentially with anti-PD-(L)1 therapy. [1][2][3]

The KRYSTAL-12-study is an open-label, multicenter, randomized Phase 3 study evaluating adagrasib compared to standard-of-care chemotherapy alone, in patients with KRASG12C -mutated non-small cell lung cancer. The primary endpoint of the study is progression-free survival (PFS) as assessed by Blinded Independent Central Review (BICR). Secondary endpoints included overall survival (OS), overall response rate (ORR), duration of response (DOR), and safety.

The data will be presented in a late-breaking oral presentation during the annual meeting of the American Society of Clinical Oncology (ASCO) on June 1, 2024 at 1:27 p.m. CDT (Abstract LBA8509).

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At a median follow-up of 9.4 months, adagrasib demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS), the study’s primary endpoint, as assessed by Blinded Independent Central Review (BICR) compared to docetaxel (HR: 0.58; [95% CI, 0.45-0.76]; P <0.0001). Median PFS was 5.5 months for adagrasib compared to 3.8 months for docetaxel. Overall response rate (ORR) as assessed by BICR was also significantly higher with adagrasib compared to docetaxel (32% vs 9%; odds ratio, 4.68; P < 0.0001). The median duration of response (mDOR) was 8.31 months (95% CI, 6.05–10.35) versus 5.36 months (95% CI, 2.86–8.54), respectively.

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Adagrasib demonstrated intracranial response among patients with central nervous system (CNS) metastases at baseline, with a response rate per BICR that was more than double that observed with docetaxel (24% with adagrasib vs. 11% with docetaxel).

The KRYSTAL-12 study remains ongoing to assess the additional key secondary endpoint of overall survival.[4]

The investigators did not identify new safety signals for adagrasib, and the safety data were consistent with the known safety profile. Treatment-related adverse events (TRAEs) of any grade were reported in 94% of patients treated with adagrasib and 86.4% with docetaxel. Grade ≥3 TRAEs occurred in 47% and 46% of patients, respectively.

“Approximately 14% of all patients with advanced non-small cell lung cancer carry the KRASG12C mutation, impacting thousands of people worldwide,” said Tony Mok, M.D., Chairman of the Department of Clinical Oncology and Li Shu Fan Medical Foundation Professor of Clinical Oncology of the Faculty of Medicine at The Chinese University of Hong Kong (CU Medicine).

“These results from the Phase 3 KRYSTAL-12 study reinforce adagrasib as a targeted option for patients with KRASG12C -positive lung cancer after failing standard first-line treatment.”

“The accelerated approval of adagrasib from the US Food and Drug Administration (FDA) in 2022 was welcome news for patients with KRASG12C -mutated locally advanced or metastatic NSCLC. These confirmatory results further support adagrasib as an efficacious, targeted treatment option for these patients,” explained Abderrahim Oukessou, M.D., vice president, global program lead, adagrasib, Bristol Myers Squibb/BMS.

“We look forward to further sharing these results, while also continuing to evaluate adagrasib in other advanced KRASG12C -mutated solid tumors,” Oukessou noted.

In addition to KRASG12C -mutated NSCLC, adagrasib and adagrasib-based combinations have shown encouraging, meaningful benefit in Phase 2 clinical trials across several tumors, including advanced colorectal cancer, pancreatic cancer, and other solid tumors.

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Note: * Adagrasib is a highly selective and potent oral small-molecule inhibitor of KRASG12C that is optimized to sustain target inhibition, an attribute that could be important to treat KRASG12C -mutated cancers, as the KRASG12C protein regenerates every 24-48 hours. KRASG12C mutations act as oncogenic drivers and occur in approximately 14% of non-small cell lung cancer, 3-4% of colorectal cancer, and 1-2% of several other cancers. In 2022, the U.S. Food and Drug Administration (FDA) granted adagrasib accelerated approval for treatment of adult patients with KRASG12C -mutated locally advanced or metastatic NSCLC, as determined by an FDA-approved test, who have received at least one prior systemic therapy. This indication is approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial(s). Adagrasib continues to be evaluated as a monotherapy and in combination with other anti-cancer therapies in patients with advanced KRASG12C -mutated solid tumors, including NSCLC and colorectal cancer (CRC).

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Clinical trials
Phase 3 Study of MRTX849 (Adagrasib) vs Docetaxel in Patients With Advanced Non-Small Cell Lung Cancer With KRAS G12C Mutation (KRYSTAL-12) – ClinicalTrials.gov ID NCT04685135

Highlights of Prescribing Information
Adagrasib ( ; Bristol Myers Squibb/BMS)[Prescribing Information]

Reference
[1] Dhillon S. Adagrasib: First Approval. Drugs. 2023 Feb;83(3):275-285. doi: 10.1007/s40265-023-01839-y. PMID: 36763320.
[2] Lim TKH, Skoulidis F, Kerr KM, Ahn MJ, Kapp JR, Soares FA, Yatabe Y. KRAS G12C in advanced NSCLC: Prevalence, co-mutations, and testing. Lung Cancer. 2023 Oct;184:107293. doi: 10.1016/j.lungcan.2023.107293. Epub 2023 Jul 13. PMID: 37683526.
[3] Adagrasib Response Remains Strong in NSCLC. Cancer Discov. 2022 Aug 5;12(8):OF1. doi: 10.1158/2159-8290.CD-NB2022-0042. PMID: 35666594.
[4] Gálffy G, Morócz É, Korompay R, Hécz R, Bujdosó R, Puskás R, Lovas T, Gáspár E, Yahya K, Király P, Lohinai Z. Targeted therapeutic options in early and metastatic NSCLC-overview. Pathol Oncol Res. 2024 Mar 28;30:1611715. doi: 10.3389/pore.2024.1611715. PMID: 38605928; PMCID: PMC11006988.

Featured image: Lung Cancer. Photo courtesy: © 2016 – 2024 Fotolia/Adobe. Used with permission.

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