MK-2870

A Phase 3 Randomized Open-Label Study of Adjuvant Pembrolizumab With or Without MK-2870 in Participants With Resectable Stage II to IIIB (N2) NSCLC not Achieving pCR After Receiving Neoadjuvant Pembrolizumab With Platinum-based Doublet Chemotherapy Followed by Surgery

Criteria 1 through 5 apply to screening for the neoadjuvant and adjuvant periods:
1. Has histological or cytological confirmation of squamous or nonsquamous NSCLC, resectable clinical Stage II, IIIA or IIIB (with nodal involvement [N2]) per AJCC eighth edition guidelines (Appendix 8). No restaging is required at the time of randomization.
Note: Lymph node disease requires histological or cytological confirmation if it will affect stage grouping stratification, otherwise imaging can act as a surrogate for pathological staging. If a lymph node biopsy result is negative for malignancy but the investigator believes this result to be a false negative, then clinical staging is at the investigator’s discretion. If performing a lymph node biopsy is considered high risk or a
lymph node is not readily accessible by minimally invasive techniques, then lymph node biopsy confirmation is not required.
2. Confirmation that either EGFR-directed or ALK-directed therapy is not indicated as primary therapy (historical data with respect to the index NSCLC under study of absence of tumor-activating EGFR mutations [eg, DEL19 or L858R] or ALK mutations, as determined by local laboratory).
Note: If participant’s tumor has a predominantly squamous histology, molecular testing for EGFR or ALK mutation is not required.
3. Able to undergo surgery based on opinion of investigator after consultation with surgeon.
4. Able to receive neoadjuvant pembrolizumab and platinum-based doublet chemotherapy.
Note: Participants with resectable NSCLC (Criterion 1) previously treated outside the study with 1 to 4 cycles of neoadjuvant pembrolizumab and platinum-based chemotherapy and who successfully completed surgery with surgical tumor tissue sample available, may advance to screening for the pre-randomization period (see Section 1.3.1 and Section 1.3.3). Refer to Section 8.1.8.2 regarding timing of surgery relative to first dose of neoadjuvant therapy.

5. An ECOG performance status of 0 to 1 assessed within 10 days before first dose of study treatment.
Criteria 6 through 11 apply to screening for the adjuvant period only, before randomization:
6. Achieved R0 or R1 resection status (see Section 8.1.8.3 for definitions).
7. Has not achieved pCR at surgery by local review of pathology. See Section 4.1 for definition of pCR.
8. Tumor tissue sample from surgical resection has been provided for determination of PD-L1 and TROP2 status by central vendor before randomization into the adjuvant period. Submission of additional tumor specimen from surgical resection may be required before randomization if initial tumor tissue submitted was not evaluable. Details pertaining to tumor tissue submission can be found in the Central Laboratory Manual.
9. Confirmed to be disease-free based on re-baseline radiological assessment as documented by contrast-enhanced chest/abdomen/pelvis CT (or MRI) within 28 days before randomization.
Note: Participants may not be randomized without BICR verification of disease-free
status.
10. Is able to continue on adjuvant pembrolizumab.
11. An ECOG performance status of 0 to 1 assessed within 10 days before randomization.

All remaining inclusion criteria apply to screening for both the neoadjuvant and adjuvant periods.
Demographics
12. Is an individual of any sex/gender, from at least 18 years of age at the time of providing the informed consent.
Assigned Male Sex at Birth
13. If capable of producing sperm, the participant agrees to the following during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception for each study intervention is:

-MK-2870: 120 days

-Pembrolizumab: no requirements

-Chemotherapy: 100 days

-Radiation therapy: 90 days

• Refrains from donating sperm
  PLUS either:
• Abstains from penile-vaginal intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agrees to remain abstinent  OR
  • Uses contraception as detailed below unless confirmed to be azoospermic (vasectomized or secondary to medical cause, documented from the site personnel’s review of the participant’s medical records, medical examination, or medical history interview) as detailed below:

– Uses a penile/external condom when having penile-vaginal intercourse with a nonparticipant of childbearing potential who is not currently pregnant PLUS partner use of an additional contraceptive method, as a condom may break or leak.
Note: Participants capable of producing ejaculate whose partner is pregnant or breastfeeding must agree to use a penile/external condom during each episode of sexual activity in which the partner is at risk of drug exposure via ejaculate.

– Contraceptive use by participants capable of producing sperm should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions are more stringent than the requirements above, the local label requirements are to be followed.
Assigned Female Sex at Birth
14. A participant assigned female sex at birth is eligible to participate if not pregnant or breastfeeding, and at least one of the following conditions applies:
• Is not a POCBP
OR
• Is a POCBP and:

– Uses a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or is abstinent from penile-vaginal intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), as described in Appendix 5 during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention.
The participant agrees not to donate eggs (ova, oocytes) to others or freeze/store eggs during this period for the purpose of reproduction. The length of time required to continue contraception for each study intervention is:
o MK-2870: 210 days
o Pembrolizumab: 120 days
o Chemotherapy: 190 days
o Radiation therapy: 180 days

– The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention. Contraceptive use by POCBPs should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions are more stringent than the requirements above, the local label requirements are to be followed.

– Has a negative highly sensitive pregnancy test (urine or serum) as required by local regulations within 24 hours (for a urine test) or 72 hours (for a serum test) before the first dose of study intervention. If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
Additional requirements for pregnancy testing during and after study intervention are in Section 8.3.6.

– Abstains from breastfeeding during the study intervention period and for at least 120 days after study intervention.

– Medical history, menstrual history, and recent sexual activity has been reviewed by the investigator to decrease the risk for inclusion of a POCBP with an early undetected pregnancy.
Informed Consent
15. The participant has provided documented informed consent for the study.
Note: References to “legally acceptable representative” for consenting purposes are not applicable in the EEA. Individuals in EEA countries who require a legally designated representative, as defined by the European Regulation, for informed consent are not eligible to participate.
Individuals in EEA countries who are legally able to consent for themselves but require an Impartial Witness to the consenting process (eg, individuals who are blind, unable to read or write, or unable to sign due to a physical disability) may be enrolled. Investigators must follow local regulations and processes for using an Impartial Witness.
Additional Categories
16. Participants who have AEs due to previous anticancer therapies must have recovered to ≤Grade 1 or baseline. Participants with endocrine-related AEs who are adequately treated with hormone replacement are eligible.
17. HIV-infected participants must have well controlled HIV on ART, defined as:
a. Participants on ART must have a CD4+ T-cell count ≥350 cells/mm3 at the time of screening
b. Participants on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 or the LLOQ (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks before screening
c. It is advised that participants must not have had any AIDS-defining opportunistic infections within the past 12 months
d. Participants on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks before study entry (Day 1) and agree to continue ART throughout the study

e. The combination ART regimen must not contain any antiretroviral medications that interact with CYP3A4 inhibitors/inducers/substrates (https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug interactions-table-substrates-inhibitors-and-inducers)
18. Adequate organ function as defined in the following table (Table 8). Specimens must be collected within 10 days before the start of study intervention.

19. Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks, and have undetectable HBV viral load at screening.
Note: Participants should remain on antiviral therapy throughout study intervention and follow local guidelines for HBV antiviral therapy post completion of study intervention.
Hepatitis B screening tests are not required unless:

– Known history of HBV infection

– As mandated by local health authority

20. Participants with history of HCV infection are eligible if HCV viral load is undetectable at least 4 weeks before the start of study intervention.
Note: Participants must have completed curative antiviral therapy at least 4 weeks before start of study intervention.
Hepatitis C screening tests are not required unless:

– Known history of HCV infection

– As mandated by local health authority

An individual must be excluded from the study if the individual meets any of the following criteria:
Medical Conditions
1. Has one of the following tumor locations/types:
• NSCLC involving the superior sulcus
• Large cell neuro-endocrine cancer (LCNEC)
• Sarcomatoid tumor
• Diagnosis of SCLC or, for mixed tumors, presence of small cell elements
2. Has Grade ≥2 peripheral neuropathy.
3. Has history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or corneal disease that prevents/delays corneal healing.
4. Has active inflammatory bowel disease requiring immunosuppressive medication or previous history of inflammatory bowel disease (eg, Crohn’s disease, ulcerative colitis, or chronic diarrhea).
5. Has uncontrolled, significant cardiovascular disease or cerebrovascular disease, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, uncontrolled symptomatic arrhythmia, prolongation of QTcF interval to >480 ms, and/or other serious cardiovascular and cerebrovascular diseases within the 6 months preceding study intervention.
Prior/Concomitant Therapy
Exclusion Criteria #6, 10, and 11 do not apply to participants entering screening during the adjuvant period after receiving neoadjuvant therapy and surgery outside the study.
6. Received prior neoadjuvant therapy for their current NSCLC diagnosis.
7. Received prior treatment with a TROP2-targeted ADC.
8. Received prior treatment with a topoisomerase I inhibitor-containing ADC.
9. Requires treatment with a strong inhibitor or inducer of CYP3A4 at least 14 days before the first dose of study intervention and throughout the study

Note: A list of strong inhibitors or inducers of CYP3A4 can be found at the following website:
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers
10. Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137).
11. Received prior systemic anticancer therapy including investigational agents within 4 weeks before the first dose of study intervention.
12. Received prior radiotherapy within 2 weeks of start of study intervention, or radiation-related toxicities, requiring corticosteroids.
13. Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.
Refer to Section 6.5 for information on COVID-19 vaccines.
Prior/Concurrent Clinical Study Experience
14. Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.
Diagnostic Assessments
15. Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study medication.
16. Known additional malignancy that is progressing or has required active treatment within the past 5 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded. Participants with low-risk early stage prostate cancer (T1-T2a, Gleason score ≤6, and PSA <10 ng/mL) either treated with definitive intent or untreated in active surveillance with stable disease are not excluded.
17. Severe hypersensitivity (≥Grade 3) to study intervention, any of its excipients, and/or to another biologic therapy.
18. Active autoimmune disease that has required systemic treatment in the past 2 years.
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid) is allowed.
19. History of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
20. Active infection requiring systemic therapy.
21. HIV-infected participants with a history of Kaposi’s sarcoma and/or Multicentric Castleman’s Disease

22. Concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV DNA) and Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection.
Note: Hepatitis B and C screening tests are not required unless:

– Known history of HBV and HCV infection

– As mandated by local health authority

23. History or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound the results of the study, interfere with the individual’s ability to cooperate with the requirements of the study, or interfere with the participant’s participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator.
Other Exclusions
24. History of allogeneic tissue/solid organ transplant.
25. Participants who have not adequately recovered from major surgery or have ongoing surgical complications.