萝莉社

This study aims to determine the efficacy of olomorasib in combination with standard of care immunotherapy following definitive NSCLC therapy. Part A is designed to add onto existing standard of care, either a perioperative approach or adjuvant approach, in resected stage II-IIIB NSCLC. Part B is designed to add onto the existing standard of care, consolidation durvalumab after definitive chemoradiotherapy, in unresectable stage III NSCLC.

Inclusion Criteria Participants are eligible to be included in the study only if all of the following criteria apply. 5.1.1. Part A and B Age

1. Are an acceptable age to provide informed consent according to local regulations and are at least 18 years of age. Type of participant and disease characteristics
2. Have histological or cytological confirmation of NSCLC.
3. Have evidence of KRAS G12C mutation in samples from tumor or blood, as determined by molecular testing performed in a CLIA, ISO/IEC, CAP, or similarly certified laboratory per local guidelines, including, but not limited to IVDR compliance, as applicable.
4. Have known PD-L1 expression (0% to 100%) of tumor cells as determined by an IHC assay performed in a CLIA, ISO/IEC, CAP, or similarly certified laboratory as per local guidelines, including, but not limited to IVDR compliance, as applicable.
5. Have an ECOG performance status of 0 or 1.
6. Have adequate organ and marrow function as defined in the table below.

Note: Transfusions to increase a participant鈥檚 hemoglobin level or initiation of erythropoietin or G-CSF therapy to meet these criteria are not allowed in the 14 days before the first dose of study intervention. Test Result Hematology Absolute neutrophil count 鈮�1.0 脳 109 /L (鈮�1.0 脳 103 /碌L or 鈮�1.0 GI/L) Must be met without G-CSF therapy within the last 14 days Platelet count 鈮�75 脳 109 /L (鈮�75 脳 103 /碌L or 鈮�75 GI/L) Hemoglobin level 鈮�8.0 g/dL or 鈮� 5 mmol/L Must be met without erythropoietin dependency and without packed red blood cell transfusion within the last 14 days Clinical chemistry ALT and AST 鈮�2.5 脳 ULN Approved on 13 Nov 2024 GMT CONFIDENTIAL J3M-MC-JZQH 52 TBL 1.5 脳 ULN For patients with Gilbert鈥檚 syndrome, total bilirubin may be >1.5 脳 ULN, however direct bilirubin must be normal Renal Serum creatinine OR Measured creatinine clearance OR Calculated creatinine clearance or GFR or institutional standards 鈮�1.5 脳 ULN OR 鈮�30 mL/min for participant with creatinine levels >1.5 脳 institutional ULN

Note: Use Cockcroft-Gault CrCl formula to calculate creatinine clearance or institutional standards.

Abbreviations: Alt = alanine aminotransferase; Ast = aspartate aminotransferase; G-CSF = granulocyte-colony stimulating factor; GFR = glomerular filtration rate; TBL = total bilirubin level; ULN = upper limit of normal. Previous treatment

1. Have recovered from any previous surgical procedure before randomization. Contraceptive and barrier requirements
2. Contraceptive use by participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. For the contraception requirements of this protocol, see Section 10.4. Other inclusion criteria
3. Individuals assigned female at birth must have evidence of post-menopausal status, or individuals of child-bearing potential must have a negative pregnancy test (serum test is preferable) result at screening and have a negative serum or urine test result 72 hours before treatment with study intervention. See Section 10.4.1 for definitions of child[1]bearing potential and menopausal status. 10. Are able to swallow oral medication. Informed consent 11. Are capable of giving signed informed consent as described in Section 10.1.3, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol. 5.1.2. Part A Only: Stage II-IIIB Disease, Resectable Type of participant and disease characteristics 12. Have Stage II-IIIB (N2) NSCLC per AJCC 9th edition (Rami-Porta et al. 2024) including

Either:

a. Clinical Stage II-IIIB (N2) treated with presurgical chemoimmunotherapy, with residual tumor present at time of surgery. Patients with a pathologic complete response are not eligible. b. Pathologic Stage II-IIIB (N2) NSCLC treated with initial upfront resection. 13. Had curative intent resection defined as lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy. En bloc resection, for example, chest wall resection, or sub-anatomic Approved on 13 Nov 2024 GMT CONFIDENTIAL J3M-MC-JZQH 53 resection, such as wedge resection or segmentectomy, is only permitted if performed in addition to any of the previously listed curative intent resections. a. Must undergo complete resection, defined as pathologic microscopic margin free of invasive carcinoma at the parenchyma, bronchus, and vascular margins. Carcinoma in situ can be present at bronchial margin. b. A systematic complete mediastinal lymph node dissection or a lobe-specific mediastinal lymph node dissection is recommended (See Section 10.7). It is recommended that normal appearing lymph nodes, if present, be biopsied or removed. 14. Have no evidence of disease recurrence at clinical examination and baseline radiological assessment as documented by contrast enhanced chest/upper abdomen CT scan, brain CT/MRI and clinical examination within 28 days before the first dose of study intervention. Previous treatment 15. Prior treatment with chemotherapy required. Prior treatment with immune checkpoint inhibitor allowed but must be in combination with chemotherapy in the neoadjuvant setting. a. Patients treated with presurgical therapy must receive platinum-based chemotherapy with an immune checkpoint inhibitor before randomization. b. Patients treated initially with surgery must receive adjuvant platinum-based chemotherapy before randomization. These patients must begin adjuvant chemotherapy within 12 weeks of their surgery date. These patients must also be eligible to receive their first dose in this study at least 3 weeks but no more than 12 weeks from the last dose of adjuvant chemotherapy (Day 1 of last cycle). 5.1.3. Part B Only: Stage III Disease, Unresectable Type of participant and disease characteristics 16. Have clinical Stage III, unresectable NSCLC, without progression on concurrent platinum-based chemoradiotherapy. Staging is per AJCC 9th edition (Rami-Porta et al.

1. . Previous treatment 17. Have received at least 50% of planned platinum-based chemotherapy concurrent with radiation therapy, which must be completed within 1 to 42 days prior to randomization. 18. The final chemotherapy cycle must end prior to, or concurrently with, the final dose of radiation. 19. Have received a total dose of radiation of at least 54 Gy as part of the chemoradiotherapy prior to randomization. Approved on 13 Nov 2024 GMT CONFIDENTIAL J3M-MC-JZQH 54 5.2. Exclusion Criteria Participants are excluded from the study if any of the

Following criteria apply:

5.2.1. Part A and B Medical conditions 20. Have 1 of these tumor types a. large cell neuro-endocrine cancer b. mixed small cell and non-small cell lung cancer c. 2 synchronous primary invasive NSCLC in different ipsilateral or contralateral lobes. Note 鈥� Concurrent minimally invasive adenocarcinoma ( 1000 IU/mL ? patients with positive HBsAg, or anti-HBc, or detectable HBV DNA, who are unable to undergo monitoring of HBsAg, HBV DNA, and liver tests (ALT, AST, ALP, TBL, GGT) at least every 3 months. 31. Have a current infection with HCV, defined as positive for HCV RNA. 32. Have a known history of active tuberculosis. 33. Have clinically significant active cardiovascular disease or history of myocardial infarction or unstable angina within 6 months prior to planned start of study. 34. Have a 12-lead ECG QT interval corrected for heart rate using Fridericia鈥檚 formula (QTcF) >470 msec. If QTcF >470 msec on 1 ECG is obtained during the screening, obtain 2 additional measurements and use the average of the 3 measurements to determine eligibility.

Exception: Individuals with implanted pacemakers. 35. Have a serious preexisting medical condition that, in the judgment of the investigator, would preclude participation in this study, including but not limited to, substance use disorder, an unstable mental health disorder, severe dyspnea at rest or requiring oxygen therapy. Screening for chronic conditions is not required. 36. Have an active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of the study intervention. Prior and concomitant therapy 37. Have experienced any Grade 鈮�3 immune-related AE (irAE) or Grade 鈮�3 hypersensitivity while receiving any previous immunotherapy agent, or any unresolved irAE Grade >1.

Exception: Endocrinopathies on replacement hormonal therapy. 38. Have any other unresolved Grade >2 toxicities, except for alopecia, from prior therapy. 39. Received a live vaccine or live attenuated vaccines within 30 days before the first dose of study intervention.

Exception: Seasonal influenza vaccines for injection, which are generally killed virus vaccines. Prior and concurrent clinical study experience 40. Are currently enrolled in any other clinical study involving an investigational product within 4 weeks prior to the first dose of study intervention. In the case of monoclonal antibodies, 6 weeks prior to the first dose of study intervention. 41. Are currently enrolled in any type of medical research judged not to be scientifically or medically compatible with this study as determined by sponsor consult. Approved on 13 Nov 2024 GMT CONFIDENTIAL J3M-MC-JZQH 56 Other exclusion criteria 42. Are pregnant, breastfeeding, or plan on becoming pregnant or breastfeeding during the study or within 180 days after the last dose of study intervention. 5.2.2. Part A Only Prior and concomitant therapy 43. For patients treated with upfront surgical resection, have received more than 4 cycles of adjuvant chemotherapy 44. For patients treated with presurgical chemo-immunotherapy, have received any adjuvant therapy 5.2.3. Part B Only Prior and concomitant therapy 45. Have received non-standard of care treatment regimens, such as induction chemotherapy plus immunotherapy followed by concurrent chemoradiation therapy. 46. Have received sequential chemotherapy followed by radiation therapy 47. Have Grade 鈮� 2 pneumonitis from prior chemoradiation therapy 聽