Relapsed NSCLC - No Targetable Mutations

- Metastatic disease (stage IV) detected on imaging and histologically confirmed NSCLC as per the WHO Classification of Tumours and AJCC 8th Edition TNM Classification, without an actionable driver mutation, for whom either ICI alone or combination ICI + chemotherapy is indicated

- Oligoprogression on first-line ICI +/- chemotherapy systemic therapy after at least 3 cycles

- All sites of oligoprogression can be safely treated with SBRT or ablative radiotherapy as determined by the treating radiation oncologist, including availability and tolerability of necessary technologies (e.g. active breathing control, MRLinac, fiducial insertion, etc.) and accounting for previous radiotherapy overlap. Safety must be assessed and determined by a radiation oncologist prior to enrollment.

- Participants with treated CNS disease who have radiologic and clinical evidence of stable brain metastases, with no evidence of cavitation or hemorrhage in the brain lesion, are eligible providing that they are asymptomatic and do not require corticosteroids (must have discontinued steroids at least 1 week prior to randomization). Anticonvulsants are allowed. Participants with new or progressive brain metastases (at screening) are eligible if they are asymptomatic and do not require CNS-specific treatment.

Drugs:
Pembrolizumab was approved in the US in 2016 and is a humanized immunoglobulin G4 (IgG4)
monoclonal antibody (mAb) that inhibits PD-1 receptors thus improving an antitumor immune response
while docetaxel is an antineoplastic agent and is a second-generation chemotherapy of the taxane family.



Key Eligibility Criteria:

Pathologically confirmed stage IV NSCLC disease

Have acquired resistance to an immune checkpoint inhibitor, defined as disease progression immediately following an initial response or stable disease (≥ 6 months duration) to exactly 1 line of anti-PD-L1 or anti-CTLA-4 therapy (for Stage III, IV, or recurrent disease) that was given alone or in combination with chemotherapy.

Participants with AGA must have 1 or more documented AGA(s): EGFR, ROS1, neurotrophic tyrosine receptor kinase (NTRK), B rapidly accelerated fibrosarcoma (BRAF), mesenchymal epithelial transition (MET) exon 14 skipping, rearranged during transfection (RET), Kirsten Rat sarcoma (KRAS).

Participants with AGA must meet the following criteria for advanced or metastatic NSCLC.
Participants who have been treated with 1 or 2 prior lines of applicable targeted therapy that is locally approved (and is standard of care) for the participant's genomic alteration at the time of
screening:
a. Participants who have tumors with EGFR L858R or exon 19 deletion mutations must have received prior osimertinib.
b. Participants who received a targeted agent as adjuvant therapy for early-stage disease must have relapsed or progressed while on the treatment or within 6 months of the last dose or received at least one additional course of targeted therapy for the same genomic alteration (which may or may not be same agent used in the adjuvant setting) for relapsed/progressive disease.
c. Participants who have been treated with a prior tyrosine kinase inhibitor (TKI) must receive additional approved targeted therapy, if locally available and clinically appropriate, for the applicable genomic alteration, or the participant will not be allowed in the study.
d. Participants must meet the inclusion criteria #4 listed above.

Cohort A only: Have documented disease progression or be refractory to an anti-PD-1/PD-L1 antibody and a platinum-based chemotherapy regimen approved for NSCLC, either in combination or sequentially.

Cohort B only: Have not received prior systemic treatment for locally advanced or metastatic NSCLC and have PD-L1 ≥ 50% by local testing using an FDA-approved assay or in a Clinical Laboratory Improvement Amendments (CLIA)-approved laboratory. Note: Prior adjuvant and neoadjuvant therapy are allowed prior to the development of metastatic disease, but adjuvant treatment must have been completed at least 6 months prior to Cycle 1 Day 1 (C1D1) and neoadjuvant treatment must have been completed at least 3 months prior to C1D1. Participants must have recovered from any prior AEs to Grade 1 or lower. 3.

Cohort A only: Last dose of previous anticancer therapy (including investigational agents) ≥ 28 days, radiotherapy ≥ 14 days (targeted palliative radiotherapy is allowed for lesions not planned for injections), or surgical intervention ≥ 21 days prior to C1D1

Cohort A only: Thyroid-stimulating hormone (TSH) within normal limits. If TSH is not within normal limits at baseline, total T3 or free T3 and free T4 must be within normal limits.

Eligibility Criteria
Inclusion Criteria:
1. Single agent BCA101 - patients with the following tumor type will be eligible:
a. No prior history of treatment with anti-EGFR antibodies in the unresectable/metastatic setting (prior treatment with radiotherapy in the adjuvant setting is allowed).
2. Combination BCA101 and pembrolizumab - patients with the following tumor types will be eligible:
a. Patients must have no prior systemic therapy administered in the recurrent or metastatic setting (with the exception of systemic therapy completed >6 months prior if given as part of multimodal treatment for locally advanced disease) or prior history of immune checkpoint inhibitors with the exception of neoadjuvant therapy (>6 months prior to study drug initiation). No prior history of anti-EGFR antibodies (with the exception of radiosensitizing agents and multimodal treatment for locally advanced disease).
b. Patients must provide tissue for PD-L1 biomarker analysis from a core or excisional biopsy (fine needle aspirate is not sufficient): A newly obtained biopsy (within 90 days prior to start of study treatment) is preferred but an archival sample is acceptable.
c. Patients must have results from testing of human papillomavirus (HPV) status for oropharyngeal cancer
d. Patients must have progressed on one prior systemic therapy in the metastatic setting.
e. No prior history of treatment with anti-EGFR antibodies in the metastatic setting.
f. Expansion Cohort 6: Head and Neck Squamous Cell Carcinoma (HNSCC), metastatic or unresectable, recurrent with a Combined Positive Score (CPS) less than 1, as determined by PD-L1 IHC 22C3 pharmDx.
3. Randomized to either ficerafusp alfa alone or in combination with pembrolizumab -Expansion Cohort 9: Colorectal cancer (CRC) i. Patients must have received at least 2 and no more than 3 prior lines of systemic therapy including two standard treatment regimens.

Exclusion Criteria:
1. Prior treatment with any anti-TGFb therapy.
2. Has a history of (non-infectious) pneumonitis, radiation pneumonitis or interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease.

For pre-screening, please contact: Message Basket: VICC RESEARCH PHASE 1