KRYSTAL-12 Investigators Seek to Confirm Adagrasib’s Role in KRAS G12C–Mutant NSCLC

Alexander I. Spira, MD, PhD, FACP

Efforts to unlock treatment modalities targeting KRAS mutations have ebbed and flowed for patients with non–small cell lung (NSCLC) as investigators face resistance, intolerable toxicity profiles, and a lack of available binding pockets to guide treatment development.¹ A rise in the identification of actionable genetic biomarkers have illuminated the prevalence of KRAS G12C point mutations in patients with adenocarcinomas (13%) and up to 4% of patients with squamous NSCLC.^1,2

The development of direct inhibitors which form covalent bonds with cysteine 12 in the switch II binding pocket of the KRAS G12C protein have demonstrated the ability to irreversibly and selectively bind KRAS G12C in an inactive state.^1,2 Sotorasib (Lumakras) demonstrated early efficacy for patients with KRAS G12C–mutant disease and was granted accelerated approval in 2021. Another agent, adagrasib, has demonstrated preclinical and early phase efficacy in patients with previously treated NSCLC with encouraging activity in patients with brain metastases.^2-4

“Adagrasib is a small molecule KRAS G12C inhibitor and it [has evidence of efficacy] in NSCLC; there has been a lot of excitement about this agent for various reasons,” Alexander I. Spira, MD, PhD, FACP, codirector of Virginia Cancer Specialists Research Institute, director of the Thoracic and Phase I Program, and clinical assistant professor at Johns Hopkins School of Medicine, in Baltimore, Maryland, said in an interview with OncologyLive^®.

“We know that KRAS G12C mutations act as oncogenic drivers and occur in approximately 14% of patients with NSCLC, predominantly adenocarcinomas,” Spira explained. “[Approximately] 27% to 42% of these patients will have CNS metastases at diagnosis. Adagrasib…was optimized for desired properties of a KRAS G12C inhibitor, including a long half-life, a [approximately] 23 hours, and dose-dependent pharmacokinetics,” he said adding that the agent “was designed with several things in mind, most notably it was designed to penetrate the central nervous system [CNS].”

CNS metastases are present in up to 42% of patients with KRAS G12C-mutated NSCLC. With a median overall survival (OS) of approximately 5 months, patients with active, untreated CNS metastases represent a portion of patients with an unmet need.⁵

Investigators recently published findings from the phase 2 cohort of the KRYSTAL-1 trial (NCT03785249) at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, which were simultaneously published in the New England Journal of Medicine.^2,3 These data demonstrated that adagrasib administered at 600 mg orally twice daily was safe and effective for patients who had received prior treatment with platinum-based chemotherapy and immunotherapy.^2,3

After a median follow-up of 12.9 months, the objective response rate (ORR) was 43% (95% CI, 33.5%-52.6%) among the 112 patients with measurable disease at baseline, which included 1 complete response (CR; 1%) and 47 partial responses (PRs; 42%). There were 41 patients with stable disease (SD; 37%) and 6 with progressive disease (5%) for a DCR of 80% (n = 89; 95% CI, 70.8%-86.5%).^2,3

“Responses appear to be deep, with 75% of responders having a greater than 50% tumor reduction,” Spira said.

Moreover, the median time to response with the KRAS G12C inhibitor was 1.4 months (range, 0.9-7.2) and median duration of response was 8.5 months (95% CI, 6.2-13.8). Spira noted that as of the data cut-off, treatment was ongoing in half of patients who experienced a response (n = 24) and 33% (n = 16) have maintained their response.^2,3

The median progression-free survival (PFS) was 6.5 months (95% CI, 4.7-8.4), with 6- and 12-month PFS rates of 52% and 29%, respectively. After a median follow-up of 15.6 months, median overall survival (OS) was 12.6 months (95% CI, 9.2-19.2), with 6- and 12-month OS rates of 71% and 51%, respectively.^2,3

The investigators further evaluated intracranial activity among 33 patients with adequately treated, stable central nervous system (CNS) metastases. The intracranial ORR was 33% (n = 11; 95% CI, 18%-52%), which included 5 CRs (15%) and 6 PRs (18%). There were 17 patients with SD (52%) for a DCR of 85% (n = 28; 95% CI, 68%-95%). The median intracranial PFS was 5.4 months (95% CI, 3.3-11.6).^2,3

“We saw some patients with pretreated brain metastases continue to have some response,” Spira said noting that there were patients who received no prior radiation therapy and that brain metastases were treated with just chemotherapy or immunotherapy. These patients were defined by investigators as those who had asymptomatic, neurologically stable brain lesions, including focal leptomeningeal disease and cerebellar metastases, but excluding patients with brainstem lesions.⁵

In terms of safety, Spira noted that overall, the agent was well-tolerated and that adverse effects (AEs) were manageable with dose reductions. “There were significant number of patients that got dose reductions but only 16% of patients discontinued, so if [patients] don’t tolerate it dose reducing seems to work,” he said.

In the overall population of patients who received adagrasib in KRYSTAL-1, treatment-related AEs (TRAEs) of any grade occurred in 113 patients (97%), of which 50 (43%) were grade 3/4 in severity. The most frequent any-grade TRAEs were diarrhea (63%), nausea (62%), vomiting (47%), fatigue (41%), ALT increase (28%), blood creatinine increase (26%), AST increase (25%), and decreased appetite (24%). Among patients with grade 3/4 TRAEs, the most common reported events were elevated lipase levels (6.0%) and anemia (5.2%). Two grade 5 events occurred: cardiac failure and pulmonary hemorrhage.2,3 TRAEs led to dose reductions in 60 patients (52%), interruptions in 71 (61%), and discontinuation in 8 (7%).³

An analysis of patients in the phase 1b cohort of KRYSTAL-1 with active, untreated CNS metastases at baseline (n = 25), also presented the 2022 ASCO Annual Meeting, showed that patients who received adagrasib 600 mg twice daily had durable CNS-specific activity. At a median follow-up of 6.6 months, 19 patients had radiographically evaluable disease for intracranial ORR—15 with target lesions and 4 with nontarget lesions only.⁴ Patients were assessed using modified Response Assessment in Neuro-Oncology Brain Metastases (mRANO-BM) criteria via blinded independent central review.

Among all evaluable patients, intracranial ORR was 32% (95% CI, 12.6%-56.6%) comprising a 16% CR rate and a 16% partial response (PR) rate.4 Moreover, 53% of patients had stable disease and disease control rate (DCR) was 84% (95% CI, 60.4%-96.6%). Among the 15 patients with target lesions, intracranial ORR was 27%, with a CR rate of 7%, a PR rate of 20%, and a DCR of 80%. Finally, among patients with nontarget lesions, 2 patients had a CR for an intracranial ORR of 50%. The remaining 2 patients in this cohort had stable disease for a DCR of 100%.

Median OS in this population was not reached.4 Investigators reported that intracranial DOR was not reached (95% CI, 4.1-not estimable [NE]), and median intracranial PFS was 4.2 months (95% CI, 3.8-NE) in this patient population.

Further, investigators reported the concordance between systemic and intracranial disease control was 88% (14 of 16 patients evaluable).4 Systemic ORR, using RECIST 1.1 criteria, was 37% (95% CI, 16.3%-61.6%), and systemic DCR was 79% (95% CI, 54.4%-93.9%).4 Median systemic DOR was 9.6 months (95% CI, 2.7-9.6), and median systemic PFS was 5.6 months (95% CI, 3.8-11.0).

The safety profile of adagrasib in this cohort was consistent with the overall population and no new safety signals were observed.4 Any grade TRAEs were observed in 96%. The most frequent TRAEs (any grade ≥ 40%) included nausea (80%), diarrhea (80%), vomiting (44%), and AST increase (40%). Grade 1/2 TRAEs occurred in 60% of patients; no grade 4/5 TRAEs were reported. TRAEs led to dose reduction or interruption in 12 (48%) patients and discontinuation in 1 (4%) patient. The CNS-specific TRAEs included dizziness (all grade, 20%; grade 3, 8%) and grade 1/2 aphasia and insomnia reported in 1 patient.⁴

KRYSTAL-12 Pushes Adagrasib Into the Spotlight

Building on the foundation of observations gained from the phase 1/2 study, investigators are comparing single-agent adagrasib head-to-head with standard-of-care docetaxel in the phase 3 KRYSTAL-12 trial (NCT04685135).^5,6

Investigators plan to enroll approximately 340 participants with previously treated unresectable locally advanced or metastatic KRAS G12C–mutant NSCLC.^5,6 Prior treatment must include a platinum-containing regimen and a checkpoint inhibitor for advanced or metastatic disease and may not include prior treatment with a KRAS G12C inhibitor, such as sotorasib. Patients are also ineligible if they have active brain metastases.

Specimens from either the primary or metastatic tumors must be available—either archival or newly obtained—for central laboratory testing of KRAS G12C mutations and for additional correlative gene alterations.

Participants will be randomly assigned 2:1 to either adagrasib 600 mg twice daily administered orally or docetaxel 75 mg/m² every 3 weeks. Stratification factors include region (US/Canada vs other countries) and administration or prior platinum-based chemotherapy and anti–PD-1/PD-L1 therapy (sequential vs concurrent).

The primary end point of the study is PFS. Secondary end points include OS, safety, ORR, and 1-year OS rates. Additionally, patient-reported outcomes using the lung cancer symptom scale and quality-of-life assessments using the European Quality of Life 5 Dimensions Questionnaire will be administered.

As the treatment landscape for patients with NSCLC with actionable oncogenic driver mutations continues to expand exponentially, Spira noted that integrating these therapies into practice will rely on testing. A new drug application was submitted by Mirati Therapeutics, Inc based on data from KRYSTAL-1. The FDA is expected to make a decision on the application in December 2022.⁷

“There is a currently an FDA-approved agent, sotorasib, so [if adagrasib is approved] will have 2 [agents] in our armamentarium and that’s great,” Spira said. “I think a lot of the information that will come out [will help us determine] which [may be] better for certain patients [and determine] how important the CNS activity is, which [could] be a differentiator for adagrasib.”

Continued enrollment on clinical trials and increasing testing for actionable mutations are the key to continued successes for this patient population. “We can’t make better drugs without patients enrolling in studies,” Spira said. “We have all these [actionable] mutations and we’re still only testing approximately 75% of patients for EGFR and that has been around for [approximately] 10 years. [Testing rates are] even less for KRAS. The bottom line is we need to test all our patients for all mutations but include KRAS G12C,” Spira said.

References

1. de la Fuente EC, Garcia MEO, Rueda AG, Lage Y, Garrido P.Targeting KRAS in non-small cell lung cancer. Front Oncol. 2022;11:792635. doi:10.3389/fonc.2021.792635
2. Spira AI, Riely GJ, Gadgeel SM, et al. KRYSTAL-1: activity and safety of adagrasib (MRTX849) in patients with advanced/metastatic non-small cell lung cancer (NSCLC) harboring a KRAS G12C mutation. J Clin Oncol. 2022;40(suppl 16):9002 doi:10.1200/JCO.2022.40.16_suppl.9002
3. Jänne PA, Riely G, Gadgee SM, et al. Adagrasib in non–small-cell lung cancer harboring a KRASG12C mutation. N Engl J Med. Published online ahead of print June 3, 2022. doi:10.1056/NEJMoa2204619
4. Sabari JK, Spira AI, Heist RS, et al. Activity of adagrasib (MRTX849) in patients with KRASG12C-mutated NSCLC and active, untreated CNS metastases in the KRYSTAL-1 trial. J Clin Oncol. 2022;40(suppl 17):LBA9009. doi:10.1200/JCO.2022.40.17_suppl.LBA9009
5. 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. Updated June 9, 2022. Accessed June 17, 2022. https://clinicaltrials.gov/ct2/show/NCT04685135
6. Mok TSK, Lawler WE, Shum MK, et al. KRYSTAL-12: a randomized phase 3 study of adagrasib (MRTX849) versus docetaxel in patients (pts) with previously treated non-small-cell lung cancer (NSCLC) with KRASG12C mutation. J Clin Oncol. 2021;39(suppl 15):TPS9129. doi:10.1200/JCO.2021.39.15_suppl.TPS9129
7. U.S. Food and Drug Administration (FDA) accepts Mirati Therapeutics’ new drug application for adagrasib as treatment of previously treated KRASG12C-mutated non-small cell lung cancer. News release. Mirati Therapeutics, Inc. February 15, 2022. Accessed June 17, 2022. bit.ly/3xEn1ya