Phase One Study Shows Novel KRAS Inhibitor Well Tolerated by Patients with Adenocarcinoma and Non-Small Cell Lung Cancer

BARCELONA, Spain, Sept. 8, 2019 /PRNewswire/ -- A clinical trial testing the toxicity of a KRAS inhibitor demonstrated early promising antitumor activity and few adverse side effects in patients with advanced non-small cell lung cancer harboring KRAS G12C mutation, according to Ramaswamy Govindan, M.D., from the Siteman Cancer Center at Washington University School of Medicine, St. Louis.

The KRAS G12C mutation is found in approximately 14 percent of patients with lung adenocarcinoma and 11 percent of patients with non-small cell lung cancer but there are no therapies approved that target this mutation. KRAS G12C mutation has been identified as an oncogenic driver of tumorigenesis. KRAS is a guanine-nucleotide-binding protein that acts as a molecular switch inside cells and links to receptor tyrosine kinase activation to intracellular signaling.

To test this therapy, AMG 510, for safety and toxicity, Dr. Govindan and his colleagues enrolled 76 patients with locally advanced or metastatic malignancies who had received previous standard therapy. The research group's primary endpoint was toxicity and secondary research endpoints were objective response rate, duration of response, disease control rate, progression-free survival and duration of stable disease.

Patients were enrolled in four dose cohorts: 180 mg, 360 mg, 720 mg and 960 mg, taken orally once a day for 21 days and followed up with radiographs and examinations. Initial data from the Phase One study were presented at the 55th Annual Meeting of the American Society of Clinical Oncology earlier this year. The additional follow-up in a larger group of patients being presented at the WCLC includes a subset of 34 NSCLC patients enrolled, with 23 of the patients being evaluable for efficacy. Thirteen of the evaluable patients received the target dose of 960 mg once daily, with seven (54 percent) achieving a partial response at one or more timepoints and six (46 percent) achieving stable disease, for a disease control rate of 100 percent. 

There were no dose-limiting toxicities and no adverse events leading to discontinuation in the 34 NSCLC patients enrolled. Twenty-seven of these patients remain on treatment. Of the 34 patients, only nine (26.5 percent) reported treatment-related adverse events of grade one or two. Three patients reported grade three treatment-related adverse effects (anemia and diarrhea). There were no grade four or higher TRAEs.

"KRAS G12C mutant lung adenocarcinoma is one of the largest subsets of NSCLC potentially amenable to targeted therapies. I am pleased that we have a promising new oral therapy for this group of patients," Govindan said. "These data continue to show encouraging anti-tumor activity with AMG 510, underscoring the potential to close the treatment gap for non-small cell lung cancer patients with previously treated KRAS G12C-mutated NSCLC."

Mutations Associated with Sensitivity or Resistance to Immunotherapy in mNSCLC: Analysis from the MYSTIC Trial

The relationship between gene alterations and response to anti-PD-L1 with and without anti-CTLA-4 are not well characterized. Dr. N. Rizvi from Columbia University Medical Center in New York today presented an update from the Phase Three MYSTIC study that showed poorer outcomes across treatment arms in patients with metastatic non-small cell lung cancer and mutations in STK11 or KEAP1 genes compared with those without the corresponding mutations. In patients receiving durvalumab with tremelimumab, ARID1Am was associated with survival benefits compared with ARID1Awt.

The MYSTIC trial is a randomized, open-label, multi-center, global Phase Three trial of durvalumab monotherapy or durvalumab in combination with tremelimumab versus chemotherapy in the 1st-line treatment of patients with epidermal growth-factor receptor and anaplastic lymphoma kinase wild-type, locally advanced or metastatic non-small cell lung cancer.

In the mutation-evaluable population (n=943), STK11 mutation, KEAP1 mutation, and ARID1A mutation frequencies were 16 percent, 18 percent and 12 percent, respectively (19 percent, 20 percent and 11 percent [nonsquamous]; 7 percent, 13 percent and 15 percent [squamous]).

Across treatment arms, patients with STK11m or KEAP1m had a shorter median overall survival than patients with STK11wt or KEAP1wt metastatic NSCLC. In the durvalumab + tremelimumab arm, patients with ARID1A mutations had a longer median overall survival rate than patients with ARID1A without mNSCLC.

Nivolumab Combined with Ipilimumab Safe as First-Line Therapy for Lung Cancer Patients With Comorbid Diseases

Combining the PD-1 immune checkpoint inhibitor nivolumab with the monoclonal antibody ipilimumab showed a consistent safety profile in special populations with advanced non-small cell lung cancer, according to research presented by Dr. Fabrice Barlesi from Aix-Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France.

Ipilimumab is a monoclonal antibody that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system. 

CheckMate 817 was started because data are limited on safety and efficacy of immunotherapy in patients with advanced NSCLC with other comorbidities such as brain metastases, kidney and renal disease and HIV.

Dr. Barlesi and researchers at other sites involved in CheckMate 817 tested two groups of patients who had previously untreated advanced NSCLC. Cohort A1 consisted of 198 patients with an Eastern Cooperative Oncology Group score of PS 2 or ECOG PS 0–1 with asymptomatic untreated brain metastases, hepatic or renal impairment, or HIV.

The other group of patients (Cohort A) totaled 391 and had an ECOG of PS 0–1. Patients with known EGFR mutations or ALK translocations sensitive to available targeted therapy were excluded from both cohorts. Each group received nivolumab flat dose plus ipilimumab weight-based low dose for two years or until the patients achieved disease progression or unacceptable toxicity.

Both groups of patients experienced similar rates of treatment-related adverse events, but ORR was 25 percent in cohort A1 and 35 percent in cohort A.  Progression-free survival was shorter in cohort A1 than cohort A.

"First-line flat-dose nivolumab plus weight-based ipilimumab showed a consistent safety profile in special populations with advanced NSCLC, including those with ECOG PS 2. Patients with either high TMB or higher tumor PD-L1 expression appeared to exhibit improved efficacy," Barlesi reported.

KEYNOTE 189: Tumor Mutational Burden Not Significantly Associated with Efficacy of Pembrolizumab

Tumor mutational burden was not significantly associated with efficacy of pembrolizumab plus chemotherapy or placebo plus chemotherapy as first-line therapy for metastatic nonsquamous non-small cell lung cancer, according to research reported today by Dr. M. Garassino from the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 

Tumor mutational burden is a measurement of mutations carried by tumor cells and is a predictive biomarker being studied to evaluate its association with response to immunotherapy. TMB, in concert with PD-L1 expression, has been demonstrated to be a useful biomarker across some cancer types.

To test this notion, Dr. Garassino and her colleagues randomized 616 patients 2:1 to pembrolizumab plus chemotherapy or placebo plus chemotherapy. TMB was determined by whole-exome sequencing of tumor and matched normal DNA. The clinical utility of TMB on outcomes was assessed using prespecified TMB cut points of 175 and 150 Mut/.

Of the 616 patients enrolled, 293 (48.3 percent) had evaluable TMB data: 207 for pembrolizumab plus chemotherapy, 86 for placebo plus chemotherapy. Baseline characteristics and outcomes were generally similar in the TMB-evaluable and total populations. TMB as a continuous variable was not significantly associated with overall survival, progression-free survival or objective response rate for pembrolizumab plus chemotherapy or placebo plus chemotherapy. Pembrolizumab plus chemotherapy improved overall survival, progression-free survival and objective response rate.

"Tumor mutational burden was not significantly associated with efficacy of pembrolizumab plus chemotherapy or placebo plus chemotherapy as first-line therapy for metastatic nonsquamous NSCLC," said Dr. Garassino. "Pembrolizumab plus chemotherapy had a similar overall survival benefit in the TMB-high and low subgroups."

New KEYNOTE 021 Data Shows No Association with Tumor Mutational Burden

Researchers had previously reported data from the KEYNOTE 021 trial that showed antitumor activity for pembrolizumab plus platinum-based chemotherapy in untreated advanced nonsquamous non-small cell lung cancer patients. 

The researchers, led by Corey Langer from Abramson Cancer Center of the University of Pennsylvania in Philadelphia, created two new groups. Patients in cohort C received pembrolizumab plus carboplatin and pemetrexed. Patients in cohort G were randomized 1:1 to pembrolizumab plus carboplatin and pemetrexed or carboplatin and pemetrexed alone. Tumor mutational burden was determined by whole-exome sequencing of tumor and matched normal DNA.

Langer and the KEYNOTE 021 researchers were able to evaluate TMB data for 70 patients: 12/24 (50 percent) in cohort C, 32/60 (53.3 percent) in the cohort G pembrolizumab plus chemotherapy arm, and 26/63 (41.3 percent) in the cohort G chemotherapy-only arm.

TMB as a continuous variable was not significantly associated with objective response rate, progression-free survival or overall survival for pembrolizumab plus chemotherapy or chemotherapy alone. There was no significant correlation between TMB and Tissue Polypeptide-specific Antigen in patients treated with pembrolizumab plus.  

"In this exploratory analysis, TMB was not significantly associated with efficacy of pembrolizumab plus carboplatin and pemetrexed or carboplatin and pemetrexed alone as first-line therapy for metastatic nonsquamous NSCLC," Langer reported. "TMB was also not significantly correlated with PD-L1 expression. Among pembrolizumab plus chemotherapy-treated patients, ORR was high in both the TMB low and high subgroups." 

Journal of Thoracic Oncology Announces New Journal at World Conference on Lung Cancer

The Journal of Thoracic Oncology today announced that a new open access journal, JTO Clinical and Research Reports, will debut during the first quarter of 2020. The announcement was made at the International Association for the Study of Lung Cancer World Conference on Lung Cancer in Barcelona, Spain by JTO editor Dr. Alex Adjei.

JTO Clinical and Research Reports will be the official open access journal of the IASLC. Its goal is to complement the JTO by providing authors a gold open access publication option.

The current JTO management and oversight team, along with select members of the JTO Editorial Board, will serve as the JTO Clinical and Research Reports editorial board to ensure the roll out for this new publication is seamless, said Adjei. An editorial board dedicated to the JTO Clinical and Research Reports will be established after the first year of publication is completed.

The inaugural year of JTO Clinical and Research Reports will print quarterly. The new journal will publish the following categories of articles:

Phase I trials Well performed single-arm phase II trials Subset analyses of published trials Impactful retrospective Studies Database analysis Large institutional series High-quality case reports Region-specific clinical trials  Subspecialty thoracic oncology studies Selected high-quality meeting reports

The Journal of Thoracic Oncology (JTO) remains the official journal of the IASLC. It is the primary educational and informational publication for topics relevant to the prevention, detection, diagnosis, and treatment of all thoracic malignancies.