Rollover Study for Participants Who Have Been Treated With and Are Continuing to Benefit From Opnurasib as a Single Agent or in Combination With Other Study Treatments

Screening occurs on the same day as the parent study's End of Treatment visit, with informed consent and eligibility confirmation required before enrollment. Eligible participants start treatment within seven days and return for scheduled visits for drug resupply, safety monitoring, and confirmation of clinical benefit. Sites are expected to follow their local practice regarding the method and frequency of the assessments used to assess clinical benefit for the patient. Treatment continues until disease progression or other discontinuation criteria, and safety follow-up lasts 30-150 days depending on the last drug received. The study will remain open for up to three years from first participant visit or until all participants discontinue.

• Opnurasib (Drug), also known as JDQ443: Eligible participants will receive the same starting dose and regimen of opnurasib as the last dose and regimen administered before completing the parent protocol at the time of transition to the rollover study.
• TNO155 (Drug): Eligible participants will receive the same starting dose and regimen of any applicable combination drug as the last dose and regimen administered before completing the parent protocol at the time of transition to the rollover study.
• trametinib (Drug), also known as TMT212: Eligible participants will receive the same starting dose and regimen of any applicable combination drug as the last dose and regimen administered before completing the parent protocol at the time of transition to the rollover study.
• cetuximab (Biological): Eligible participants will receive the same starting dose and regimen of any applicable combination drug as the last dose and regimen administered before completing the parent protocol at the time of transition to the rollover study.
• tislelizumab (Biological), also known as VDT482: Eligible participants will receive the same starting dose and regimen of any applicable combination drug as the last dose and regimen administered before completing the parent protocol at the time of transition to the rollover study.

Primary outcomes

• Number of participants receiving opnurasib as single agent or in combination with other study treatments [Assessed up to approximately 3 years]: The number of participants enrolled and receiving opnurasib as single agent or in combination with other study treatments under the rollover study, will be summarized by treatment arm.
• Duration of exposure to study treatment [Assessed up to approximately 3 years]: The duration of exposure in months to opnurasib and the combination partner will be summarized by means of descriptive statistics using the SAS.

Secondary outcomes

• Incidence rate of Adverse Events (AEs) [Assessed up to approximately 3 years]: The distribution of adverse events will be evaluated by analyzing the frequencies of treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs). In this study, TEAEs are defined as AEs with an onset date after the start of the treatment period, or events that were present before the treatment period but subsequently increased in severity, changed from not suspected to suspected of being related to study treatment, or evolved into SAEs after the start of the treatment period. The safety follow-up period will extend from the first administration of study treatment until: 1. 30 days after the last dose for participants receiving opnurasib as monotherapy or in combination with TNO155 or trametinib, 2. 60 days after the last dose for participants receiving opnurasib in combination with cetuximab, and 3. 150 days after the last dose for participants receiving opnurasib in combination with tislelizumab.
• Number of participants with dose adjustments [Assessed up to approximately 3 years]: The number of participants with dose adjustments (reductions, interruption, or permanent discontinuation) will be summarized by treatment arm.

Sex: All, ages: 18 Years to 100 Years

Key Inclusion Criteria:

* Participant is currently enrolled in a pre-defined Novartis-sponsored study and is receiving opnurasib as single agent or in combination with other study treatment.
* Participant has received at least 6 cycles of opnurasib in a parent study.
* Participant is currently deriving clinical benefit from the study treatment, as determined by the Investigator.
* Participants currently receiving treatment in one of the KontRASt studies, including those who have not experienced disease progression or who are continuing treatment beyond initial disease progression, may be eligible to enroll in the rollover study if, in the Investigator's judgment, they are expected to continue deriving clinical benefit from treatment with opnurasib (alone or in combination). Clinical benefit, as assessed by the Investigator, may be reflected by delayed disease progression, improvement in disease-related symptoms, improvement in overall quality of life, or a combination of these factors.

Key Exclusion Criteria:

* Participant has been permanently discontinued from opnurasib in the parent protocol for any reason other than enrollment in the CJDQ443B12105B study.
* Participant is not willing to comply with the contraception requirements outlined in the exclusion criteria of the parent protocol.
* Participant currently has unresolved toxicities for which opnurasib dosing has been interrupted in the parent study.
* Participant has known actionable mutations, such as EGFR-sensitizing mutation, ALK rearrangement, or others, identified during the participation in the parent trial for which there are available treatment options.

Other protocol-defined inclusion/exclusion criteria may apply.

• Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals

NIH grants: 2025