Changes made to ineligibility criteria regarding pneumonitis following new information received from drug company. The new iRECIST guidelines for immune-oncology trials have been incorporated into the response section of the protocol in order to implement these changes in response assessment.

Increasingly, Canadian sites are only routinely measuring lipase (and not amylase). Footnote #4 was added to clarify that either lipase or amylase is acceptable. Clarification that the substitution (not only discontinuation) of carboplatin for cisplatin in cases where cisplatin is contraindicated may be allowed on case-by-case basis Central pathology review added as histology is a stratification factor on the study, and epithelioid vs sarcomatoid is difficult to verify based on local pathology reports.

Study redesigned to a phase 3 study : phase 2 reported separately and all analysed patients were excluded from the phase 3 trial. Clarification added to include future participation of UK sites. Addition of Health Economics Assessment to align with phase III objectives/ design. Patient evaluations updated to include Health Economics, and other updates reflect changes made elsewhere in the protocol with respect to lab and follow up requirements, confirmation of need for iRECIST response evaluations/PD for patients on one of the IO containing arm. Also urinalysis, ECG and electrolytes test frequency has been decreased to ensure consistency with other similar phase III trials; more intensive testing was only planned for the early phase II patients. Section 7.3 updated to reflect additional data/information presented in updated investigators brochures. Changes made to the Dose Modification Guidelines section of the protocol, are largely restructuring (ie to include other new expected events such as myocarditis), in keeping with new information and guidance provided in updated investigator brochures. Statistical analysis updated to reflect phase III objectives and analysis of the increases sample size. Health Utilities Assessment (introduction and copy of questionnaire) now included as new phase III objectives.

Clarification added to include future participation of France and UK sites. Study schema updated to align with phase III objectives/design. Objectives updated : clarification added to protocol that RECIST 1.1 being used for primary and secondary objective, while iRECIST will be used for exploratory analyses. Standard interim analysis added as now a phase III design. Sample size (n value for phase II vs phase III) clarification added in section 12.3. Treatment and Dose Modification Guidelines updated to reflect additional data/information presented in updated investigators brochure. Changes made to the Dose Modification Guidelines section of the protocol, are largely restructuring (ie discontinue treatment after recurrent grade 3 diarrhea), in keeping with new information and guidance provided in updated investigator brochure. Wording deleted from page 35 as duplicate (monitoring guideline already in Table 2). Update to Eligibility/Ineligibility Criteria : wording updated to reflect CCTG standard of practice. 4.2.11 added to ensure patients receive palliative radiation therapy prior to enrollment, to ensure patient safety with no concurrent radiation on trial and to minimize inevaluability and or the need for censoring for response based endpoints because of other anticancer therapy. Update to Patient Treatment and Follow-up : reference to maximum 6 cycles of chemotherapy added per American Society of Clinical Oncology Clinical Practice Guideline 2018. Clarification added regarding Day 1 re-treatment requirements including steroid taper. Follow-up wording update made to comply with changes to CCTG standard template . Clarification added regarding when central radiology and pathology review will be carried out.

CCTG to check intent of previous chemo (if any given) prior enrollment to ensure eligibility. CCTG to check extent of previous radiation (if any given to thorax) prior enrollment to ensure eligibility. Clarification added to include LVEF testing for patients with history of hypertension. Rewarding to clarify. Patients with arrhythmias controlled on medication, or with a pacemaker are considered to be eligible. Alignment on updated guidelines from 2018 for Modified RECIST for Mesothelioma. mRecist reference added as clarification. SAE definition with pembrolizumab overdose. Emerging data from other trials with immune checkpoint inhibitors and chemotherapy suggested that a hazard ratio of 0.65 is overly optimistic so revised to align with more commonly used hazard ratio of 0.7. That HR would still demonstrate significant benefit to patients in terms of improvement in survival.

Clarification that collection of all data , including assessments and questionnaires such as QOL cease when the patients withdraws consent to do so. Patients are having delays for the next cycles when on pembrolizumab alone for minor reduction in CrCL likely related to platinum for earlier (combination) cycles. Provide additional information and ensure compliance with GDPR (General Data Protection Regulation). Clarification that BICR will be used for the primary response based analyses, while CCTG will conduct and publish investigator assessed per their SOPs. Some patients on the study have PD assigned based on new dermal lesions. Updated statistical methodology. Updated statistical methodology to reflect alpha spending for multiple endpoints. Clarification that ORR and PFS will also be analysed in the interim analysis. Change in the item used for pain in QOL (from pain to chest pain) to be consistent with prior Merck analyses.

PD-L1 as a stratification factor has been removed from the protocol and study objective moved from secondary to exploratory. Dose Modification Guidelines for Drug-Related Adverse Events according to the pembrolizumab product monograph dated 2021Mar04.