A Study Evaluating the Safety, Activity, and Pharmacokinetics of Divarasib as a Single Agent or in Combination With Other Anti-Cancer Therapies in Participants With Previously Untreated Advanced or Metastatic Non-Small Cell Lung Cancer With a KRAS G12C Mutation (KRAScendo 170)

Roche

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Non-Small Cell Lung Cancer

Treatments: Drug: Pembrolizumab; Drug: Divarasib; Drug: Carboplatin; Drug: Cisplatin; Drug: Pemetrexed

Study type: Interventional

Funder types: Industry

Identifiers

NCT05789082

2022-003048-28 (EudraCT Number)

BO44426

2023-507171-22-00 (Other Identifier)

Details and patient eligibility

About

The purpose of this study is to evaluate the safety, pharmacokinetics (PK), and activity of single-agent divarasib or combined with other anti-cancer therapies in participants with previously untreated, advanced or metastatic non-small cell lung cancer (NSCLC).

Enrollment: 320 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Confirmation of Biomarker eligibility
• Pre-treatment tumor tissue along with an associated pathology report is required for all participants enrolled on study. Representative tumor specimens must be in formalin-fixed, paraffin embedded (FFPE) blocks (preferred) or 15 unstained, freshly cut, serial slides. Although 15 slides are required, if only 10 slides are available, the participant may be eligible for the study following consultation with the Sponsor.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
• Histologically or cytologically documented locally advanced unresectable or metastatic NSCLC that is not eligible for curative surgery and/or definitive chemoradiotherapy
• No prior systemic treatment for advanced unresectable or metastatic NSCLC
• Measurable disease, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Additionally, for participants in cohort D, measurable brain metastases defined as at least 5 millimeters and twice the slice thickness, but less than 20 mm, that is asymptomatic and does not require local therapy at the time of enrollment.

Exclusion criteria

• Known concomitant second oncogenic driver with available targeted treatment
• Squamous cell histology NSCLC
• Symptomatic, untreated, or actively progressing CNS metastases (Cohorts A, B, and C)
• Prior treatment with a KRAS G12C inhibitor
• Known hypersensitivity to any of the components of divarasib or pembrolizumab; or known hypersensitivity to pemetrexed, carboplatin, or cisplatin (Cohort B only)
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis, active tuberculosis, significant cardiovascular disease within 3 months prior to initiation of study treatment
• History of malignancy other than NSCLC within 5 years prior to initiation of study treatment, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate more >90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal breast carcinoma in situ, or Stage I uterine cancer
• Uncontrolled tumor related pain, pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures, uncontrolled or symptomatic hypercalcemia
• Co-morbid condition that is an absolute contraindication to treatment with corticosteroids
• Inability or unwillingness to take prophylactic treatments such as corticosteroids, anti-emetics, folic acid, or vitamin B12 supplementation.
• Participants with brain metastases for whom complete surgical resections is clinically appropriate

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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320 participants in 4 patient groups

Cohort A - Combination Dose Finding + Dose Expansion

Experimental group

Description:

Participants will be enrolled in different cohorts to receive divarasib (different dose levels will be evaluated) once a day (QD) combined with pembrolizumab 200 mg intravenous (IV) infusion every 3 weeks (Q3W). During the expansion stage, some participants are planned to be randomized to one divarasib combination dose level; other participants are planned to be randomized to another divarasib combination dose level. Divarasib will be given in combination with pembrolizumab.

Treatment:

Drug: Divarasib

Drug: Pembrolizumab

Cohort B - Combination Dose Finding + Dose Expansion

Experimental group

Description:

Participants enrolled in this cohort will receive divarasib (different dose levels will be evaluated) QD combined with pembrolizumab 200 mg IV Q3W plus investigator's choice of platinum-based chemotherapy (carboplatin or cisplatin) and pemetrexed.

Treatment:

Drug: Pemetrexed

Drug: Cisplatin

Drug: Carboplatin

Drug: Divarasib

Drug: Pembrolizumab

Cohort C - Dose Expansion

Experimental group

Description:

Participants enrolled in this cohort will receive one dose level of divarasib QD.

Treatment:

Drug: Divarasib

Cohort D - Dose Expansion

Experimental group

Description:

Participants enrolled in this cohort will receive one dose level of divarasib QD.

Treatment:

Drug: Divarasib