Share Icon Health Study Area: Cardiovascular Disease Chevron Icon Health Study Area: Genitourinary For Patients Health Study Area: Lung Cancer Page Icon Phone Icon For Caregivers Health Study Area: AutoImmune Disease Health Study Area: Melanoma Location Icon Print YouTube Icon For Parents Health Study Area: Lung Cancer Print Created with Sketch. Help Icon Green Check Icon Search Icon Instagram Created with sketchtool. Direction Arrow Icon Error Icon For Parents Health Study Area: Blood Cancer Help Icon Health Study Area: NASH Gender Both Bookmark Icon Health Study Area: Melanoma Created with Sketch. Glossary Print Health Study Area: Blood Cancer Health Study Area: Genitourinary Health Study Area: Gastrointestinal Cancer Mobile Menu Icon Created with Sketch. Health Study Area: Cardiovascular Disease Health Study Area: Women's Cancer Communities Map Icon Created with Sketch. For Caregivers Health Study Area: Fibrosis Health Study Area: AutoImmune Disease FAQs Health Study Area: Head and Neck Cancer Created with Sketch. For Clinicians Chevron Right Icon Gender Female Health Study Area: Breast Cancer Direction Arrow Icon Gender Both Right Arrow Icon LinkedIn Icon Green Check Icon Gender Male Health Study Area: Fibrosis For Patients Twitter Icon Email Icon Facebook Icon Health Study Area: Gastrointestinal Cancer Health Study Area: Head and Neck Cancer For Clinicians External Link Icon

KRYSTAL - 4 Trial Information

Learn more about the KRYSTAL-4 / CA239-0004 study

High unmet need in mNSCLC despite advances with chemoimmunotherapy

- mPFS <1 year and <35% of  patients alive at 5 years;1,2

KRYSTAL-4 aims to investigate improved outcomes for patients with KRASG12C mutations, regardless of PD-L1 expression level (including 0%) by combining adagrasib with SOC (pembrolizumab + chemotherapy) in first-line treatment.

  • Pembrolizumab in combination with chemotherapy is the most widely used first-line treatment for patients with locally advanced or metastatic NSCLC without an actionable driver mutation and is a Category 1 recommendation for patients across PD-L1 expression levels per the NCCN guidelines.
  • Outcomes with pembrolizumab and chemotherapy are generally consistent in patients with and without KRAS mutations, justifying the use of this combination as standard of care in 1L locally advanced or mNSCLC patients with tumors harboring KRASG12C mutations.3
3D rendering of lung cancer cell highlighting the KRAS G12C mutation

KRYSTAL-4 is a double-blind, placebo-controlled, randomized Phase 3 study in the first-line treatment setting in patients with locally advanced or metastatic non-squamous NSCLC with KRASG12C mutation, regardless of PD-L1 expression level (including 0%). It will evaluate the efficacy and safety of

Adagrasib + Standard of Care

Adagrasib administered in combination with
pemetrexed + cis/carboplatin + pembrolizumab

VS

Placebo + Standard of Care

Placebo administered in combination with
pemetrexed + cis/carboplatin + pembrolizumab

two overlapping squares with the overlapping section filled in and the non-overlapping portions empty

Key Inclusion Criteria4

  • Age: Must be ≥18 years of age 
  • Histologically confirmed diagnosis: Histologically or cytologically confirmed diagnosis of non-squamous NSCLC
  • Disease state: Locally advanced or metastatic disease
  • Therapy candidacy: Not a candidate for definitive therapy (eg, chemoradiation or complete surgical resection)
  • Measurable disease: Measurable disease via computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST v1.1 criteria of at least 1 lesion KRASG12C and PD-L1 status:
    • Evidence of KRASG12C mutation via tumor tissue and/or ctDNA documented by Sponsor-approved laboratory testing
    • Any PD-L1 expression (0 to 100% or non-evaluable or non-quantifiable) as determined by VENTANA PD-L1 (SP263) assay, Agilent PD-L1 IHC 22C3 pharmDx, or Agilent PD-L1 IHC 28-8 pharmDx
  • Prior treatment: No prior systemic anticancer therapy given for advanced in the past 6 months or metastatic disease, including chemotherapy, immunotherapy, targeted therapy (EGFR, ALK inhibitors, etc), biologic therapy, or chemoradiation
two overlapping squares with the overlapping section empty and the non-overlapping portions filled in

Key Exclusion Criteria4

  • Additional targetable oncogenic driver mutation or alteration in genes: For which there is a standard of care treatment available
  • History of previous cancer therapy: Within the previous 2 years, except for squamous cell or basal cell carcinoma of the skin or in situ carcinoma that has been removed
  • Surgical history:
    • Major surgery within 4 weeks of randomization
    • Radiation within 2 weeks of randomization
  • Autoimmune or inflammatory disease: Active or prior documented autoimmune or inflammatory disease
  • Gastrointestinal disease or other malabsorption syndromes that would prevent absorption of oral medication
  • Participants with a condition requiring systemic treatment with corticosteroids or other immunosuppressive medications 

*Other protocol-defined inclusion-exclusion criteria may apply

References

  1. Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leal TA, Riess JW, Jensen E, Zhao B, Pietanza MC, Brahmer JR. Five-Year Outcomes With Pembrolizumab Versus Chemotherapy for Metastatic Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50. J Clin Oncol. 2021 Jul 20;39(21):2339-2349.
  2. Garassino MC, Gadgeel S, Speranza G, Felip E, Esteban E, Dómine M, Hochmair MJ, Powell SF, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Kurata T, Gray JE, Schwarzenberger P, Jensen E, Pietanza MC, Rodríguez-Abreu D. Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non-Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study. J Clin Oncol. 2023 Apr 10;41(11):1992-1998
  3. Garassino MC, Gadgeel S, Novello S, et al. Associations of Tissue Tumor Mutational Burden and Mutational Status With Clinical Outcomes With Pembrolizumab Plus Chemotherapy Versus Chemotherapy For Metastatic NSCLC. JTO Clin Res Rep 2022; 4:100431.
  4. ClinicalTrials.gov. Accessed March 2025.https://clinicaltrials.gov/study/NCT06875310

Abbreviations

mNSCLC = metastatic non-small cell lung cancer; mPFS = median progression-free survival; SOC = standard-of-care; NCCN = National Comprehensive Cancer Network; ORR = Overall Response Rate; PFS = progression-free survival; PD-L1 = programmed death-ligand 1; TPS = tumor proportion score; IHC = Immunohistochemistry; EGFR = epidermal growth factor receptor; ALK = activin receptor-like kinase

Find a clinical trial location

Explore Other KRYSTAL Studies in NSCLC Trials

This website provides general information about ongoing BMS clinical trials and a source of scientific information related to BMS investigational product adagrasib. The information included pertains to an investigational therapy that has not yet been approved for use in any country. The safety and efficacy of investigational therapies and/or uses have not been established. There is no guarantee that the agents will receive health authority approval or become commercially available in any country for the uses being investigated.

© 2025 Bristol Myers Squibb Company. All rights reserved.