Molecular Testing in Advanced NSCLC

Videos

Benjamin Levy, MD, discusses the role of molecular testing in patients with advanced NSCLC.

Shirish M. Gadgeel, MD, division lead, Hematology/Oncology, associate director, patient experience and clinical care, Henry Ford Cancer Institute, discusses 2-year follow-up data from the phase 1/2 KRYSTAL-1 trial (NCT03785249) in patients with advanced or metastatic non–small cell lung cancer (NSCLC) harboring 

 G12C mutations, which he presented at the 2023 IASLC World Conference on Lung Cancer.

KRYSTAL-1 is evaluating adagrasib (Krazati) in patients with 

 G12C–mutated NSCLC at 600 mg twice daily. These 2-year follow-up data are comprised of pooled datasets from the phase 1/1b dose escalation and expansion cohorts, as well as data from phase 2 cohort A.

At a median follow-up of 26.9 months, the median overall survival (OS) was 14.1 months (95% CI, 9.2-18.7), with a 1-year OS rate of 52.8% and a 2-year OS rate of 31.3%. The median progression-free survival (PFS) was 6.9 months (95% CI, 5.4-8.7), with 1- and 2-year PFS rates of 35.0% and 13.9%, respectively. The overall response rate was 43%, and the median duration of response was 12.4 months (95% CI, 7.0-15.1).

No additional safety signals were identified with this long-term follow-up, Gadgeel says. Furthermore, no patients who received adagrasib within 30 days of receiving immunotherapy experienced grade 3 or higher hepatotoxicity, an adverse effect (AE) that is associated with other 

 G12C inhibitors that are administered after immunotherapy, Gadgeel notes. Additionally, among the patients who received adagrasib for at least 1 year, the incidence of new-onset treatment-related AEs (TRAEs) after 1 year of therapy was low, Gadgeel emphasizes. The most common new-onset TRAEs included gastrointestinal toxicities, fatigue, and increased serum creatinine levels.

This 2-year analysis also assessed the effects of dose modification, defined as either dose interruption or dose reduction, on the efficacy of adagrasib. Among the patients who responded, 60% (n = 33) received adagrasib for more than 1 year, and 22% (n = 12) received the agent for more than 2 years, all of whom underwent dose modifications. Of the patients who underwent dose modifications, the 2-year OS rate was 32.1%. These data demonstrate that dose modification does not affect the efficacy of adagrasib, Gadgeel concludes.

Shirish M. Gadgeel, MD, discusses 2-year follow-up data from the phase 1/2 KRYSTAL-1 trial in patients with advanced or metastatic non–small cell lung cancer harboring KRAS G12C mutations. 

Dr Gadgeel on Adagrasib Monotherapy in KRAS G12C–Mutated NSCLC

Shirish M. Gadgeel, MD, head, the Division of Hematology/Oncology, associate director, Patient Experience and Clinical Care, the Henry Ford Cancer Institute, discusses the efficacy of adagrasib in patients with 

 G12C–mutated non–small cell lung cancer (NSCLC) and central nervous system (CNS) metastases. 

The phase 1/2 KRYSTAL-1 trial (NCT03785249) examined the use of adagrasib in patients with advanced solid tumors, including NSCLC, whose tumors harbored 

The phase 1b cohort included 19 patients who had 

 G12C–mutant NSCLC and CNS metastases that had not been previously treated with local approaches such as radiation or surgery, Gadgeel says. Data presented during the 2022 ASCO Annual Meeting showed that in this patient population, adagrasib produced an intracranial overall response rate (ORR) of 32%; the median intracranial duration of response (DOR) was not yet reached, Gadgeel adds.

Cohort A of the phase 2 portion of the trial included 33 patients with treated, stable CNS metastases. In this population, the intracranial ORR achieved with adagrasib was 33%, and the median intracranial DOR was 11.2 months. In the full cohort of patients with previously treated 

 G12C–mutated disease (n = 112), the ORR with adagrasib was 43%.

Because adagrasib demonstrated activity both inside and outside of the CNS, the drug has a clear advantage, Gadgeel concludes.

Shirish M. Gadgeel, MD, discusses the efficacy of adagrasib in patients with KRAS G12C–mutated non–small cell lung cancer and central nervous system metastases. 

Dr. Gadgeel on CNS Activity Achieved With Adagrasib in KRAS G12C+ NSCLC

Shirish Gadgeel, MD, medical oncologist, leader of the Thoracic Oncology Multidisciplinary Team at Karmanos Cancer Institute, Wayne State University, discusses the KEYNOTE-021 study, which is examining the combination of pembrolizumab (Keytruda) and chemotherapy as a potential treatment for patients with non—small cell lung cancer (NSCLC).

In this phase I multicenter trial, pembrolizumab was combined with 3 cytotoxic chemotherapy regimens. Recently, findings from the first 3 cohorts were presented. Cohort A was comprised of pembrolizumab in combination with carboplatin/paclitaxel, while cohort B was pembrolizumab plus carboplatin/paclitaxel/bevacizumab (Avastin). Cohort C was pembrolizumab added to carboplatin/pemtrexed. Safety was the trial's primary endpoint.

Results showed that the combination was found to be fairly tolerable in all 3 cohorts, with approximately 25 patients in each arm. There was one case of a dose-limiting toxicity, Gadgeel adds. The overall response rate across 3 cohorts was 55%. The median progression-free survival was 10.5 months, and the median overall survival has not yet been observed.

Shirish Gadgeel, MD, medical oncologist, leader of the Thoracic Oncology Multidisciplinary Team at Karmanos Cancer Institute, Wayne State University, discusses the KEYNOTE-021 study, which is examining the combination of pembrolizumab (Keytruda) and chemotherapy as a potential treatment for patients with non–small cell lung cancer.

Shirish Gadgeel, MD

Articles

Molecular Testing in Advanced NSCLC

Dr Gadgeel on Adagrasib Monotherapy in KRAS G12C–Mutated NSCLC

Dr. Gadgeel on CNS Activity Achieved With Adagrasib in KRAS G12C+ NSCLC

Dr. Gadgeel on Pembrolizumab/Chemo Combo in NSCLC