A Study Comparing Sotorasib With Durvalumab in People With Non-Small Cell Lung Cancer (NSCLC)

Inclusion Criteria:

Pre-Monitoring Phase

* Histologic diagnosis of NSCLC
* Locally advanced disease, defined as AJCC 8th Edition Stage III disease.
* Plan for, currently receiving, or recently completed definitive chemoradiation. Definitive radiation is defined as 56-70 Gy in 28-35 fractions concurrently with one of the following chemotherapy regimens:

  * Carboplatin + pemetrexed
  * Cisplatin + pemetrexed
  * Paclitaxel + carboplatin
  * Cisplatin + etoposide
* KRAS p.G12C mutation identified through molecular testing
* Adequate hepatic function, with adequate function defined as AST and ALT \< 2.5 x the upper limit of normal (ULN)
* Patient eligible for consolidative durvalumab therapy
* ECOG Performance status 0 - 2.
* Age ≥ 18 years.
* Patients must have decision-making capacity to consent to the study.
* Female subjects must either be of non-reproductive potential (i.e. post-menopausal by history: \>/= 55 years old and no menses for 1\> year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral salpingectomy OR history of bilateral oophorectomy) or must be willing to comply with contraception requirements.

Monitoring Phase

* Completed definitive chemoradiation. Definitive radiation is defined as 56-70 Gy in 28-35 fractions concurrently with one of the following chemotherapy regimens:

  * Carboplatin + pemetrexed
  * Cisplatin + pemetrexed
  * Paclitaxel + carboplatin
  * Cisplatin + etoposide
* Detectable ctDNA measured within 8 weeks (+2 weeks) of completing definitive chemoradiation
* No evidence of radiographic progression, as measured through SOC imaging, as deemed by principal investigator, including a CT scan of the chest
* ECOG Performance status 0 - 2.
* Plan to start or already started durvalumab consolidation

Therapeutic Phase

* No evidence of radiographic RECIST 1.1 progression, as measured through SOC imaging, as deemed by principal investigator, including a CT scan of the chest
* MRD as measured by ctDNA testing (described above)
* Candidate for sotorasib therapy
* Must have a negative pregnancy test (serum or urine) within 3 days prior to the first dose of sotorasib (if assigned to Group 2).

Exclusion Criteria:

* Serious medical co-morbidities precluding radiotherapy, determined at the discretion of the treating investigator.
* Pregnant or lactating women.
* Physical limitation to undergo radiotherapy.
* Other active malignancy (e.g. receiving active treatment) within the last year except for basal cell carcinoma of the skin and in situ malignancy even if without evidence of disease and patients on adjuvant hormonal therapies (e.g. breast, prostate), or bladder cancer with localized diseases
* Prior pneumonitis