A Study to Investigate the Efficacy of Durvalumab Plus Tremelimumab in Combination With Chemotherapy Compared With Pembrolizumab in Combination With Chemotherapy in Metastatic NSCLC Patients With Non-squamous Histology Who Have Mutations and/or Co-mutations in STK11, KEAP1, or KRAS

Inclusion Criteria:

• Histologically or cytologically documented Stage IV non-squamous NSCLC not amenableto curative surgery or radiation.

• Participants must have tumors with STK11 or KEAP1 or KRAS mutations. Co-mutationsare also allowed.

• Participants must have tumors that lack activating epidermal growth factor receptormutations and ALK fusions.

• No prior chemotherapy or any other systemic therapy for metastatic NSCLC.Participants who have received prior platinum-containing adjuvant, neoadjuvant, ordefinitive chemoradiation for advanced disease are eligible, provided thatprogression has occurred > 6 months from end of last therapy.

• No prior exposure to immune-mediated therapy excluding therapeutic anti-cancervaccines, within 6 months of randomization.

• WHO/ECOG performance status of 0 or 1 at enrollment and randomization.

• Minimum life expectancy ≥ 12 weeks at randomization.

• At least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 targetlesion at baseline and can be accurately measured at baseline as ≥ 10 mm in thelongest diameter with Computed Tomography (CT)/CT- Positron Emission Tomography orMagnetic Resonance Imaging and that is suitable for accurate repeated measurementsas per RECIST 1.1 guidelines.

• Adequate organ and bone marrow function.

• Negative pregnancy test (urine or serum) for women of child-bearing potential

• Female participants must be 1 year post-menopausal, surgically sterile, or using onehighly effective form of birth control

• Male and Female participants and their partners must use an acceptable method ofcontraception.

• Body weight of > 30 kg

Exclusion Criteria:

• Any evidence of acute or uncontrolled diseases or history of allogeneic organtransplant.

• Mixed small cell lung cancer and NSCLC histology.

• Major surgical procedure within 28 days prior to the first dose of the studyintervention or an anticipated need for major surgery during the study.

• Active or prior documented autoimmune or inflammatory disorders (includinginflammatory bowel disease [eg, colitis or Crohn's disease], systemic lupuserythematosus, sarcoidosis, granulomatosis with polyangiitis, Graves' disease,rheumatoid arthritis [requiring immunosuppressive systemic therapy, eg,methotrexate, steroids], hypophysitis, uveitis, etc), autoimmune pneumonitis andautoimmune myocarditis. The following are exceptions to this criterion:

• Participants with vitiligo or alopecia.

• Participants with hypothyroidism (eg, following Hashimoto syndrome) stable onhormone replacement.

• Any chronic skin condition that does not require systemic therapy.

• Participants without active disease in the last 5 years may be included butonly after consultation with the Study Clinical Lead.

• Participants with celiac disease controlled by diet alone.

• Medical contraindication to platinum-based doublet chemotherapy.

• History of another primary malignancy except:

• Malignancy treated with curative intent with no known active disease ≥ 2 yearsbefore the first dose of study intervention and of low potential risk forrecurrence

• Adequately resected non-melanoma skin cancer and curatively treated in situdisease.

• Persistent toxicities (Common Terminology Criteria for Adverse Events [CTCAE] Grade ≥ 2) caused by previous anti-cancer therapy, alopecia and vitiligo are excludedtoxicities.

• Participants with Grade ≤ 2 neuropathy can be considered based on Investigator'sjudgement. Participants with irreversible toxicity that is not reasonably expectedto be exacerbated by treatment with study intervention in the opinion of theInvestigator may be included (eg, hearing loss).

• Spinal cord compression unless asymptomatic and stable.

• Participant meets the following:

• Symptomatic congestive heart failure, unstable angina pectoris, uncontrolledcardiac arrhythmia (multifocal premature ventricular contractions, bigeminy,trigeminy, ventricular tachycardia), which requires treatment (CTCAE Grade 3),symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomaticsustained ventricular tachycardia. Participants with atrial fibrillation controlledby medication or arrhythmias controlled by pacemakers may be permitted based on theInvestigator judgement with cardiologist consultation recommended.

• Any concurrent chemotherapy, investigational product, biologic, or hormonal therapyfor cancer treatment. Concurrent use of hormonal therapy for non-cancer-relatedconditions (eg, hormone replacement therapy) is acceptable.

• No radiation therapy is allowed, unless it is 1) definitive radiation that had beenadministered at least 6 months prior, 2) palliative radiation to brain, withassociated criteria for stability or lack of symptoms, or 3) palliative radiation topainful bony lesions (this must comprise less than 30% of the bone marrow)

• Patients with suspected brain metastases at screening should have an IVcontrast-enhanced MRI (preferred) or IV contrast-enhanced CT/CT-PET of the brainprior to study entry. If brain metastases are detected patients must be treatedbefore randomization. Randomization is only permitted if patients with brainmetastases have:

• Confirmed stable condition

• Returned neurologically to baseline Brain metastases will not be recorded asRECIST target lesions at baseline.

• Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [eg, colitis or Crohn's disease], systemic lupus
erythematosus, sarcoidosis, granulomatosis with polyangiitis, Graves' disease,
rheumatoid arthritis [requiring immunosuppressive systemic therapy, eg,
methotrexate, steroids], hypophysitis, uveitis, etc), autoimmune pneumonitis and
autoimmune myocarditis. The following are exceptions to this criterion:
 

• Participants with vitiligo or alopecia.
 

• Participants with hypothyroidism (eg, following Hashimoto syndrome) stable on
hormone replacement.
 

• Any chronic skin condition that does not require systemic therapy.
 

• Participants without active disease in the last 5 years may be included but
only after consultation with the Study Clinical Lead.
 

• Participants with celiac disease controlled by diet alone.
 

• Medical contraindication to platinum-based doublet chemotherapy.
 

• History of another primary malignancy except:
 

• Malignancy treated with curative intent with no known active disease ≥ 2 years
before the first dose of study intervention and of low potential risk for
recurrence
 

• Adequately resected non-melanoma skin cancer and curatively treated in situ
disease.
 

• Persistent toxicities (Common Terminology Criteria for Adverse Events [CTCAE] Grade
 ≥ 2) caused by previous anti-cancer therapy, alopecia and vitiligo are excluded
toxicities.
 

• Participants with Grade ≤ 2 neuropathy can be considered based on Investigator's
judgement. Participants with irreversible toxicity that is not reasonably expected
to be exacerbated by treatment with study intervention in the opinion of the
Investigator may be included (eg, hearing loss).
 

• Spinal cord compression unless asymptomatic and stable.
 

• Participant meets the following:
 

• Symptomatic congestive heart failure, unstable angina pectoris, uncontrolled
cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy,
trigeminy, ventricular tachycardia), which requires treatment (CTCAE Grade 3),
symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic
sustained ventricular tachycardia. Participants with atrial fibrillation controlled
by medication or arrhythmias controlled by pacemakers may be permitted based on the
Investigator judgement with cardiologist consultation recommended.
 

• Any concurrent chemotherapy, investigational product, biologic, or hormonal therapy
for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related
conditions (eg, hormone replacement therapy) is acceptable.
 

• No radiation therapy is allowed, unless it is 1) definitive radiation that had been
administered at least 6 months prior, 2) palliative radiation to brain, with
associated criteria for stability or lack of symptoms, or 3) palliative radiation to
painful bony lesions (this must comprise less than 30% of the bone marrow)
 

• Patients with suspected brain metastases at screening should have an IV
contrast-enhanced MRI (preferred) or IV contrast-enhanced CT/CT-PET of the brain
prior to study entry. If brain metastases are detected patients must be treated
before randomization. Randomization is only permitted if patients with brain
metastases have:
 

• Confirmed stable condition
 

• Returned neurologically to baseline Brain metastases will not be recorded as
RECIST target lesions at baseline.
 

• History of leptomeningeal carcinomatosis.

• Known to have tested positive for active tuberculosis infection

• Known active hepatitis infection, positive HCV antibody, HBsAg, or anti-HBc, atscreening. Participants with a past or resolved HBV infection (defined as thepresence of anti-HBc and absence of HBsAg) are eligible. Participants positive forHCV antibody are eligible only if PCR is negative for HCV RNA. Participantsco-infected with HBV and HCV, or co-infected with HBV and HDV, namely: HBV positive (presence of HBsAg and/or anti-HBcAb with detectable HBV DNA); AND

• HCV positive (presence of anti-HCV antibodies); OR

• HDV positive (presence of anti-HDV antibodies).

• Known human immunodeficiency virus (HIV) infection that is not well controlled.

• Current or prior use of immunosuppressive medication within 14 days before the firstdose of study intervention. The following are exceptions to this criterion:

• Intranasal, inhaled, topical steroids or local steroid injections (eg,intra-articular injection).

• Systemic corticosteroids at physiologic doses not to exceed 10 mg/day ofprednisone or its equivalent.

• Steroids as premedication for hypersensitivity reactions (eg, CT scanpremedication, premedication for chemotherapy) or a single dose for palliativepurpose (eg, pain control).

• Receipt of live attenuated vaccine within 30 days prior to the first dose of studyintervention.

• Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up period of an interventionalstudy.

• Participants with a known hypersensitivity to any of the study interventions or anyof the excipients of the products.

• For females only: Currently pregnant (confirmed with positive pregnancy test) orbreastfeeding, or who are planning to become pregnant.

Female participants should refrain from breastfeeding from enrolment throughout the study and until up to 14 months after the last dose of cisplatin or 180 days after pemetrexed or 90 days after tremelimumab or durvalumab or pembrolizumab, whichever is longer; and during treatment with carboplatin.