A Phase II Study of Neoadjuvant Sotorasib in Combination With Cisplatin or Carboplatin and Pemetrexed for Surgically Resectable Stage IIA-IIIB Non-Squamous Non-Small Cell Lung Cancer With a KRAS p.G12C Mutation

Phase 2

Recruiting

• Conditions: Lung Cancer
• Interventions: Drug: AMG 510; Drug: Cisplatin; Drug: Carboplatin; Drug: Pemetrexed

• Registration Number: NCT05118854
• Lead Sponsor: M.D. Anderson Cancer Center

Brief Summary

This is a phase II, single-arm, open-label study evaluating the efficacy, safety and tolerability of neoadjuvant sotorasib in combination with cisplatin (or carboplatin) and pemetrexed chemotherapy for patients with surgically resectable stage IIA - IIIB (T3-T4/N2) (based on AJCC 8th edition), non-squamous NSCLC with a KRAS p.G12C mutation. The primary objective of the study is to determine whether neoadjuvant therapy with 4 cycles of at least one dose of sotorasib plus cisplatin (or carboplatin) and pemetrexed can be administered safely and result in improved MPR rate in patients with KRAS p.G12C-mutant non-squamous NSCLC compared with the historical control MPR rate for platinum-based chemotherapy alone.

Detailed Description

Objectives

Primary:

* To evaluate the efficacy of induction with sotorasib (AMG 510) in combination with cisplatin (or carboplatin) and pemetrexed in patients with surgically resectable KRAS p.G12C-mutant non-squamous NSCLC as assessed by major pathologic response rate in resected tumor specimens.

* To determine the safety, tolerability and RP2D of sotorasib in combination with cisplatin (or carboplatin) and pemetrexed as induction therapy in patients with surgically resectable KRAS p.G12C-mutant nonsquamous NSCLC

Secondary:

* To evaluate the efficacy of induction sotorasib in combination with cisplatin (or carboplatin) and pemetrexed in patients with surgically resectable KRAS p.G12C mutant non-squamous NSCLC as assessed by : Objective response rate (ORR), Eventfree survival, Recurrence-free survival, Overall Survival (OS), Complete Resection (R0) and Pathologic complete response rate (pCR)

* To determine the safety and tolerability of sotorasib in combination with cisplatin (or carboplatin) and pemetrexed as induction therapy in patients with surgically resectable KRAS p.G12C-mutant nonsquamous NSCLC.

Exploratory:

* To evaluate biomarkers of response to induction sotorasib in combination with cisplatin (or carboplatin) and pemetrexed in surgically resectable KRAS p.G12C-mutant non-squamous NSCLC.

* To assess modulation of tissue and/or blood markers in response to induction with sotorasib in combination with cisplatin (or carboplatin) and pemetrexed in surgically resectable KRAS p.G12C-mutant nonsquamous NSCLC.

* To evaluate mechanisms of adaptation and/or resistance to sotorasib in combination with cisplatin (or carboplatin) and pemetrexed in surgically resectable KRAS p.G12C-mutant non-squamous NSCLC.

* To evaluate immune modulation in tissue and the periphery in response to induction sotorasib in combination with cisplatin (or carboplatin) and pemetrexed in surgically resectable KRAS p.G12C-mutant nonsquamous NSCLC.

Study Timeline

• Study First Submitted: 2021-09-28
• Study First Submitted QC: 2021-11-03
• Study First Posted: 2021-11-12
• Study Start: 2022-03-30
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-22
• Last Update Posted: 2025-04-25
• Primary Completion: 2025-10-20
• Study Completion: 2025-10-20

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 27

Inclusion Criteria

Not provided

Exclusion Criteria

1. [*]Current or prior systemic anticancer therapy (chemotherapy, immunotherapy, biological therapy, hormonal therapyor other investigational anti-cancer drug) or radiation therapy for treatment of the current lung cancer. Concurrent use of hormonal therapy for non-cancer-related conditions (such as hormone replacement therapy) is allowed.

2. [*]Pure squamous or predominantly squamous cardinoma histology NSCLC. Mixed tumors with be categorized by the predominant cell type. Subjects with mixed small cell lung cancer and NSCLC histology or large cell neuroendocrine carcinoma histology are ineligible. Subjects with sarcomatoid carcinoma are ineligible.

3. The subject is deemed to have unresectable NSCLC by multidisciplinary evaluation that must include a thoracic surgeon who performs lung cancer surgery as a significant part of their practice.

4. Stage IIIB N3 and Stages IIIC, IVA and IVB NSCLC.

5. [*]History or presence of hematological malignancies unless curatively treated with no evidence of disease ≥ 2 years.

6. [*]History of other malignancy with the following exceptions:

   • Treated malignancy with no known active disease present for ≥ 2 years before enrollment and felt to be at low risk for recurrence by the treating physician.
   • Adequately treated non-melanoma skin cancer (basal or squamous cell cancer) or lentigo maligna without evidence of disease.
   • Adequately treated cervical carcinoma in situ without evidence of disease.
   • Adequately treated breast ductal carcinoma in situ without evidence of disease.
   • Prostatic intraepithelial neoplasia without evidence of prostate cancer.
   • Adequately treated urothelial papillary non-invasive carcinoma or carcinoma in situ.

7. Major surgery within 28 days of cycle 1 day 1. In addition, patients with ongoing clinically relevant complications from prior surgery are not eligible and they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.

8. [*]Significant cardiovascular disease, such as New York Heart Association cardiac disease (> Class II), myocardial infarction within 6 months prior to cycle 1 day 1, unstable angina or unstable/uncontrolled cardiac arrhythmias. Patients with cardiac arrhythmias that are adequately controlled with medication (for example chronic, rate controlled atrial fibrillation) are potentially eligible if they are deemed to be surgical candidates and do not meet other exclusion criteria. Patients with 1st degree atrioventricular [AV] block or asymptomatic left anterior fascicular block [LAFB/right bundle branch block [RBBB] are eligible.

9. [*]Gastrointestinal (GI ) tract disease causing inability to take oral medication, refractory nausea and vomiting, uncontrolled diarrhea, significant small bowel resection or gastric bypass surgery, use of feeding tubes, malabsorption syndrome, requirement for intravenous alimentation, or uncontrolled inflammatory GI disease (for example Crohn's disease, ulcerative colitis).

10. Infections requiring more than 5 days of parenteral antibiotics, antivirals, or antifungals within 2 weeks prior to cycle 1 day 1. Anti-infective therapy must be completed at least 7 days before cycle 1 day 1. Prophylactic antibiotics are allowed following approval by the trial PI.

11. Previous history of interstitial lung disease or drug-induced pneumonitis.

12. [*]Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results.

13. [*]Serious illness or concomitant non-oncological disease such as neurologic, psychiatric, infectious disease or laboratory abnormality that may increase the risk associated with study participation or study drug administration and in the judgment of the treating physician (local principal investigator or sub-investigator)would make the patient inappropriate for entry into the study.

14. Patients with newly diagnosed (as documented by an audiology assessment performed prior to study enrollment) or pre-existing moderate or severe sensorineural hearing loss are not eligible to receive cisplatin but may be treated with carboplatin following discussion of the risks and benefits at the discretion of the treating physician.

15. [*]Current CTCAE version 5.0 grade ≥ 2 peripheral neuropathy.

16. [*]Unwillingness or inability to follow the procedures required in the protocol.

17. [*]Psychological,familial,sociological or geographicalfactors potentially hampering compliance with the study protocol and follow-up schedule.

18. Positive test for hepatitis B virus surface antigen (HBsAg). If the patient is negative for HBsAg) but has positive hepatitis B core antibody, then hepatitis B surface antibody [Anti-HBs] testing is necessary (Hepatitis B core antibody testing is not required for screening but if this is done and is positive, then anti-HBs testing is necessary). Undetectable anti-HBs in this setting would suggest unclear and possible infecition and needs exclusion. Patients receiving antiviral therapy for Hepatitis B or C are not eligible.

19. Positive Hepatitis C virus antibody. In this case hepatitis C virus ribonucleic acid [HCV RNA] is necessary. Detectable HCV RNA indicating acute or chronic infection renders the subject ineligible.

20. [*]Known history of testing positive for human immunodeficiency virus or known acquired immunodeficiencysyndrome.

21. Subject has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmetter-Guerin (BCG) and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg FluMist®) are live attenuated vaccines and are not allowed. Patients who enroll in the clinical protocol should not receive a live vaccine while receiving investigational product and up to 30 days after the last dose of investigational product. 34

22. [*]Regular use of illicit drugs or history (within the past year) of substance abuse (including alcohol).

23. [*]Subject is unwilling to take corticosteroid premedication for pemetrexed.

24. [*]Subject is unwilling or unable to take folic acid or vitamin B12 (intramuscular injection per label) supplementation.

25. [*]Subject is unable or unwilling to interrupt aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs), other than aspirin dose ≤ 1.3gr per day, for a 5-day period (8-day period for long-acting agents, such as piroxicam).

26. Use of known cytochrome P450 (CYP) 3A4 sensitive substrates (with a narrow therapeutic window) or P-gp sensitive substrates (with a narrow therapeutic window) within 14 days or 5 half-lives of the drug or its major active metabolite, whichever is longer, prior to study day 1 that was not reviewed and approved by the principal investigator.

27. Use of strong inducers of CYP3A4 (including herbal supplements such as St. John's wort) within 14 days or 5 half-lives (whichever is longer) prior to study day 1 that was not reviewed and approved by the principal investigator.

28. Use of warfarin. Other anticoagulation may be allowed with PI approval.

29. [*]History of severe hypersensitivity reaction to any component of the study drug treatment (cisplatin/carboplatinpemetrexed, sotorasib).

30. [*]Brain metastatic disease cannot be confidently excluded due to inability to receive both iodinated contrast for CT scans and gadolinium contrast for MRI scans.

31. [*]Female subject who is pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment with:

    • Sotorasib and for an additional 7 days after the last dose of sotorasib
    • Cisplatin (or Carboplatin) and Pemetrexed and for an additional 6 months after the last dose of cisplatin/carboplatin or pemetrexed.

32. [*]Female subjects of childbearing potential unwilling to use one highly effective method of contraception (such as implants, injectables, combined oral contraceptives, some intrauterine devices or vasectomized partner). during treatment with:

    • Sotorasib and for an additional 7 days after the last dose of sotorasib
    • Cisplatin (or Carboplatin) and Pemetrexed and for an additional 6 months after the last dose of cisplatin/carboplatin or pemetrexed.

33. [*]Female subjects of childbearing potential unwilling to use one highly effective method of contraception (such as implants, injectables, combined oral contraceptives, some intrauterine devices or vasectomized partner). during treatment with:

    • Sotorasib and for an additional 7 days after the last dose of sotorasib.
    • Cisplatin (or Carboplatin) and Pemetrexed and for an additional 6 months after the last dose of cisplatin/carboplatin or pemetrexed. Female subject of childbearing potential is defined as any female who has experienced menarche and who has not undergone surgicalsterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes

34. [*]Female subjects of childbearing potential with a positive pregnancy test assessed at screening or day 1 by a serum pregnancy test and/or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG).

35. [*]Male subjects with a female partner of childbearing potential who are unwilling to practice sexual abstinence (refrain from heterosexual intercourse) or use contraception during treatment with:

    • Sotorasib and for an additional 7 days after the last dose of sotorasib.
    • Cisplatin (or Carboplatin) and Pemetrexed and for an additional 3 months after the last dose of cisplatin (or carboplatin) and pemetrexed.

36. [*]Male subjects with a pregnant partner who are unwilling to practice sexual abstinence or use a condom during heterosexual intercourse during treatment with:

    • Sotorasib and for an additional 7 days after the last dose of sotorasib.
    • Cisplatin (or Carboplatin) plus pemetrexed and for an additional 6 months after the last dose of cisplatin (or carboplatin) plus pemetrexed

37. [*]Male subjects unwilling to abstain from donating sperm during treatment and for an additional 6 months after the last dose of cisplatin (or carboplatin) and pemetrexed.

38. Vulnerable populations including prisoners and cognitively impaired adults.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Sotorasib in Combination with Cisplatin/Carboplatin and Pemetrexed	Carboplatin	4 cycles of at least one dose of sotorasib plus cisplatin (or carboplatin) and pemetrexed can be administered safely
Sotorasib in Combination with Cisplatin/Carboplatin and Pemetrexed	AMG 510	4 cycles of at least one dose of sotorasib plus cisplatin (or carboplatin) and pemetrexed can be administered safely
Sotorasib in Combination with Cisplatin/Carboplatin and Pemetrexed	Cisplatin	4 cycles of at least one dose of sotorasib plus cisplatin (or carboplatin) and pemetrexed can be administered safely
Sotorasib in Combination with Cisplatin/Carboplatin and Pemetrexed	Pemetrexed	4 cycles of at least one dose of sotorasib plus cisplatin (or carboplatin) and pemetrexed can be administered safely

Primary Outcome Measures

Name	Time	Method
Patients with surgically resectable KRAS p.G12C-mutant non-squamous NSCLC as assessed by major pathologic response rate in resected tumor specimens	through study completion, an average of 1 year

Trial Locations

Locations (2)

Memorial Sloan Kettering Cancer Center; 🇺🇸 New York, New York, United States

M D Anderson Cancer Center; 🇺🇸 Houston, Texas, United States