Lung Cancer

Title: A Phase III, Randomized, Open-label Study of Izalontamab Brengitecan (BMS-986507) in Combination with Osimertinib versus Osimertinib Monotherapy or Osimertinib in Combination with Platinum based Chemotherapy as First-Line Therapy in Patients with EGFR Mutant Locally Advanced or Metastatic Non-small Cell Lung Cancer

MOA: Izalontamab Brengitecan (BMS 986507) is an ADC that targets both EGFR and HER3 while delivering a topoisomerase I payload

Key Eligibility:

• Histologically or cytologically confirmed non-squamous NSCLC, newly diagnosed locally
  advanced (Stage IIIB or IIIC) or metastatic (Stage IVA or IVB), or recurrent disease not
  amenable to curative surgery or definitive radiotherapy and requiring systemic treatment
  • Tumors with mixed adenosquamous histology may be eligible if the predominant histology is
    non-squamous and the patient is considered appropriate for EGFR-TKI-based therapy, and
    where applicable, pemetrexed-based therapy
• Documented evidence of an EGFR-TKI-sensitizing mutation (exon 19 deletion or exon 21 L858R
  substitution) determined by local testing
  • For patients without prior EGFR mutation results, central testing must confirm eligibility prior to
    randomization
• Fresh or FFPE tumor tissue (FFPE block or slides) must be submitted for retrospective
  confirmation or prospective (if local isn't available) central testing of EGFR mutation status
• Pt must have measurable extracranial disease per RECIST v1.1
• Prior neoadjuvant/adjuvant plt-based chemo (administered ≥ 4 weeks before randomization) and
  immunotherapy (administered ≥ 8 weeks before randomization) are allowed; however, for
  patients with recurrence 12 months after completion of plt therapy are not eligible for plt-based
  treatment in the control arm
• Pts with unstable, symptomatic, or uncontrolled CNS metastases, including brain leptomeningeal
  disease, and/or spinal cord compression are excluded
• Pts with prior treatment with an EGFR-TKI, or with iza-bren, or any antibody and/or any ADC
  targeting EGFR and/or HER3, or any drug containing a topoisomerase I inhibitor are excluded

Beamion LUNG-3: A randomized, controlled, multi-center trial evaluating zongertinib as an adjuvant monotherapy compared with standard of care in patients with early-stage, resectable non-small cell lung cancer (Stage II-IIIB) harboring tyrosine kinase domain activating HER2 mutations

MOA: Zongertinib is an oral, selective HER2 TKI

Key Eligibility:

• Confirmed diagnosis of Stage II-IIIB (up to T4, max N2) Non-squamous (NSq) NSCLC who underwent complete surgical resection
  • Must use open/VATS techniques
  • Must be performed either as lobectomy, sleeve lobectomy, bi-lobectomy, or pneumonectomy, including systematic ipsilateral lymph node dissection
  • Unresectable T4 and/or N3 disease and/or M1 disease is excluded
  • Incomplete or aborted surgical resection (R1 or greater) are excluded
• Documented TKD activating HER2 mutation (preferably by NGS)
• Archival tumor tissue must be submitted to central lab to confirm HER2 status
  (FFPE block is preferred, 20-25 FFPE slides are acceptable)
• Prior to randomization, pts must have completed either 3-4 cycles of
  neoadjuvant plt-based chemo + immunotherapy or 4 cycles of adjuvant plt-based
  chemo tx
• Pre- or post-op radiation tx for the primary NSCLC diagnosis are excluded
• Any prior anticancer tx other than SoC neoadjuvant plt-based immunochemo tx
  or adjuvant plt-based chemo tx are excluded
• Pts with presence of co-occurring AGAs with approved targeted tx in the
  (neo)adjuvant setting (e.g. EGFR or ALK) are excluded
• Pts with non-activating EGFR mutations are eligible

A Global, Phase 3, Randomized, Multicenter, Open-label Study To
Evaluate The Efficacy And Safety Of Firmonertinib Compared With
Investigator’s Choice Of Osimertinib Or Afatinib As First-line Treatment In
Participants Who Have Locally Advanced Or Metastatic Non-small-cell
Lung Cancer With Epidermal Growth Factor Receptor P-loop And Alpha
C-helix Compressing (PACC) Uncommon Mutations (ALPACCA)

MOA: Firmonertinib is an oral EGFR inhibitor with activity against EGFR classical and uncommon mutations, and HER2 mutations.

Key Eligibility

• Cyto/histologically documented locally advanced or metastatic
  NSCLC not amenable to curative surgery or radiotherapy
• Measurable disease per RECIST v1.1 (non irradiated and preferably
  not used for biopsy)
• Documented EGFR PACC mutation in tumor tissue or blood from
  local testing via validated NGS or PCR assay
  • NOTE: PACC mutations may not be identified as “PACC” on NGS
    reports. Please see the protocol for specific included mutations.
• EGFR mutations like exon 19 del, L858R or C797S are excluded
• Archival tumor tissue must be provided (15 unstained slides)
• At least 12 months since completion of prior (neo)adjuvant or
  chemoradiation tx
  • Prior tx with EGFR-targeted agent is excluded
  • Prior systemic anti-cancer tx for advanced NSCLC is excluded

A Phase 3 Multicenter Double-blind Randomized Study Of Taletrectinib Versus Placebo In Patients With ROS1-fusion Positive Stage IB-IIIA Non-small Cell Lung Cancer Who Have Undergone Complete Tumor Resection (TRUST-IV)

MOA: Taletrectinib (AB-106 or DS-6051b) is a ROS1 tyrosine kinase inhibitor (TKI) effective against ROS1 and acquired resistance mutations.

Key Eligibility:

• Histologically confirmed stage IB, II, or IIIA NSCLC that underwent locoregional curative surgery
  • Randomization should happen within 4-16 weeks after surgery if no adjuvant chemo was given (or 4-30 weeks if adjuvant chemo was given)
• Documented ROS1 rearrangement in primary tumor tissue or liquid-base sample (local)
• Co-mutations of EGFR or ALK fusion are excluded
• Archival tumor tissue (blocks or slides) must be provided
• Postoperative radiation therapy is excluded
  • Radiotherapy in the neoadjuvant setting is allowed and must be completed at least 4 weeks prior to randomization
• Prior adjuvant anticancer therapy for treatment of NSCLC, other than standard postoperative platinum-based chem, are excluded
  • Up to 4 cycles of adjuvant ICI is allowed (at least 12 weeks of washout needed before randomization)
  • Neoadjuvant chemo +/- prior ICI is allowed

A Phase 1b Clinical Study of NXP900 in Combination with Osimertinib in Subjects with Advanced, EGFRMut+ Non-Small Cell Lung Cancer (NXP900-103)

MOA: NXP900 is an orally bioavailable small molecular and potent inhibitor of kinases from the SRC family of kinases (SFK).

Key Eligibility:

• Unresectable, met/LA EGFRMut+ NSCLC
• Plasma or tissue may be used for ctDNA, NGS, RT-PCR, or other methods performed by a CLIA certified lab for detection of EGFRMut+
• Pt must have had prior treatment with osimertinib as 1L or 2L, as single agent or in combination with chemotherapy, in the met/LA setting
  • Up to 3 prior systemic therapies, including in combination with osimertinib are allowed
• Pts who had progression within the first 6 months of treatment with osimertinib are excluded
• Pts who had no response to prior treatment with osimertinib after a minimum of 6 months, defined as stable disease are excluded
• Pts with known oncogenic driver alterations other than EGFR are excluded
  • Pts with known EGFR mutations that cause resistance to Osimertinib (C797S, L718Q, G796, and G724S) are excluded
  • Pts with known HER2 overexpression (>2+ on IHC) are excluded
• Pts with progressive CNS disease such as leptomeningeal disease or carcinomatous meningitis are excluded

A Randomized, Double-Blind, Phase 3 Trial of Adagrasib plus Pembrolizumab plus Chemotherapy vs. Placebo plus Pembrolizumab plus Chemotherapy in Participants with Previously Untreated, Locally Advanced or Metastatic Non-squamous Non small Cell Lung Cancer with KRAS G12C Mutation (KRYSTAL-4)

MOA: Adagrasib is an oral, selective inhibitor of KRASG12C mutant

Key Eligibility:

• Histologically or cytologically confirmed diagnosis of Nsq NSCLC
• Measurable disease per RECIST v1.1
• Evidence of KRASG12Cmutation via tumor sample and/or ctDNA by
  approved testing
• Any PD-L1 expression (0-100%) as determined by Ventana or pharmDx IHC
• Tumor tissue (archival or fresh) should be submitted
• Prior systemic anti-cancer tx given for advanced NSCLC is not allowed
  • Prior systemic neoadjuvant, adjuvant, or peri-operative systemic tx is
    allowed if completed at least 6 months prior to first dose
• Pts with brain metastases are eligible if pts are asymptomatic and not in
  need of immediate local therapy
• Pts with leptomeningeal metastases or brainstem lesions are excluded
• Pts with documented additional targetable oncogenic driver mutation or
  alteration genes such as EGFR, ALK, BRAF V600E, HER2, MET exon 14,
  ROS1, RET, or NTRK1/2/3 for which there is a SoC treatment available are
  excluded
• Pts who received previous treatment targeting KRASG12C mutation in any
  setting are excluded

A Phase 3 Study of the Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor NVL-655 Compared to Alectinib in First-Line Treatment of Patients With ALK-Positive Advanced Non-Small Cell Lung Cancer (ALKAZAR) (NVL-655-04)

MOA: NVL-655 is an ALK TKI, designed for broader coverage of ALK resistance mutations, activity in the CNS, and selectivity over TRKB.

Key Eligibility Criteria:

• Histologically or cytologically confirmed LA (not amenable for multimodality treatment) or metastatic NSCLC
• Documented ALK rearrangement in tissue or blood (circulating tumor DNA [ctDNA]) – Local testing
  • Pre-treatment tumor tissue must be submitted for central analysis during screening
• No prior systemic anticancer tx for NSCLC, including but not limited to molecularly targeted agents, angiogenesis inhibitors, immunotherapy, or chemotherapy
  • Adj/neoadjuvant chemotherapy is allowed if completed ≥12 months prior to randomization.
  • Prior ALK TKI as adj/neoadj tx is not permitted
• No other known oncogenic driver alterations other than ALK
• Measurable disease by RECIST 1.1

A Phase III, Randomised, Open-Label, Multicentre Study of Datopotamab Deruxtecan or Docetaxel in Previously Treated TROP2-positive Advanced or Metastatic Non-squamous Non-Small Cell Lung Cancer Without Actionable Genomic Alterations (TROPION-Lung17, D763QC00001)

MOA: Datopotamab Deruxtecan (Dato-DXd) is an ADC targeting TROP2 containing a topoisomerase I inhibitor payload

Key Eligibility Criteria:

• Documented Stage IIIB, IIIC, or Stage IV non-squamous NSCLC without AGA at the time of randomization
  • Must have negative test results for EGFR, ALK, ROS1 genomic alterations
  • No known tumor genomic alterations in NTRK, BRAF, RET, MET exon 14 skipping, KRAS G12C, HER2 or any AGA with approved targeted tx
  • KRAS mutations, with exception of G12C, are eligible
• Radiographic PD on/after most recent tx for adv/met NSCLC
• 1-2 prior lines of tx with plt-based chemo + anti-PD-(L)1 combined or sequentially (in any order)
  • Prior tx with docetaxel excluded
  • Prior tx with any anti-TROP2 agent excluded
• Must provide FFPE tumor sample for assessment of TROP2
• Spinal cord compression or brain metastases excluded
  • If asymptomatic, stable, and without corticosteroids or anticonvulsants for at least 7 days prior to randomization are eligible
• At least 1 measurable lesion per RECIST v1.1

A Randomized, Open-Label, Phase 3 Study of ZL-1310, a DLL3 Antibody-Drug Conjugate (ADC), Compared to Investigator’s Choice Therapy in Participants with Relapsed Small Cell Lung Cancer

MOA: ZL-1310 is an ADC that targets DLL3 and contains a topoisomerase I inhibitor payload

Key Eligibility Criteria:

• Confirmed diagnosis of SCLC
• Archival tumor tissue or fresh tumor tissue must be submitted at screening. DLL3 expression will be assessed retrospectively (fine needle aspiration biopsies are not sufficient)
  • NOTE: if archived tissue is not available/insufficient and a biopsy is not feasible, the patient may still be enrolled with Sponsor's approval
• Must have received only 1L plt-based chemo and had documented disease progression during/after most recent systemic tx
  • Prior 1L systemic tx should be plt-base chemo with an anti-PD(L)1 agent
    • Maintenance tx with anti-PD-(L1)/lurbinectedin/tarlatamab does not count as a separate line of tx
    • Plt-based chemo for limited-stage SCLC is considered one line of tx if disease progression occurs within 6 months of completion of plt-based chemo
  • 2L systemic tx is not allowed, except for tarlatamab
• Measurable disease according to RECIST v1.1
• Prior tx with ADC containing any topoisomerase I inhibitor payload are excluded
• Treated and stable CNS metastases are eligible (parenchimal).
  • Metastasis to leptomeninges are excluded
• Untreated and asymptomatic CNS metastases are eligible but must not require steroids and/or anti-convulsants, nor local tx

An Interventional Phase 3, Double-Blind, Randomized Study to Evaluate Efficacy and Safety of PF-08634404 in Combination With Chemotherapy Versus Pembrolizumab in Combination With Chemotherapy in Adult Participants With Locally Advanced or Metastatic Non-Small Cell Lung Cancer

MOA: PF-08634404 is a PD-1xVEGF bispecific antibody.

Key Eligibility Criteria:

• LA (Stage IIIB/C) or met (Stage IV) squamous or non-squamous NSCLC not eligible for curative surgery and/or chemoradiotherapy
• PD-L1 status available based on local SoC testing results
• Archival tissue (blocks or slides) should be submitted
  • If archival tissue is not available, a new baseline tumor biopsy with adequate tissue can be obtained, unless medically infeasible.
• Measurable disease by RECIST v1.1
• Participants with known AGAs with available front-line tx are excluded
  • Pts with non-squamous NSCLC must have documented negative results for EGFR, ALK, and ROS1 AGAs
• Known active CNS or leptomeningeal metastases are excluded
• Pts with clinically significant risk of hemorrhage or fistula are excluded
• Prior systemic anti-tumor therapy, including anti-PD-(L)1 tx for LA/met NSCLC are excluded
  • (Neo)adjuvant anti-PD-(L)1 allowed if PD occurred ≥9 months after the last dose
  • Other (neo)adjuvant or definitive therapy is allowed if PD occurred ≥6 months after the last dose.

A randomized, Phase 3, open-label study to evaluate PF-08046054/SGN-PDL1V vs Docetaxel in adult participants with previously-treated programmed cell death ligand (PD-L1) positive non-small cell lung cancer (NSCLC)

MOA: PF-08046054/SGN-PDL1V is an anti-PD-L1 ADC with a MMAE payload

Key Eligibility Criteria:

• Histologically or cytologically documented unresectable Stage IIIB, IIIC, IV NSCLC not eligible for definitive chemoradiotherapy.
  • Tumors with small cell and neuroendocrine histology components are excluded
• PD-L1 expression on ≥50% of tumor cells based on local IHC testing
• Participants who have NSCLC with known AGAs are permitted
• Archival or fresh tissue required for biomarker analysis.
• Pts must have received the following therapies and progressed during or relapsed after receiving their most recent prior therapy:
  • Pts with no known AGA: must have received chemo + anti-PD-L1 mAb
  • Pts with known AGAs: must have received at least 1 approved targeted therapy, chemotherapy, and an anti-PD-L1 mAb.
• Brain metastases are excluded unless asymptomatic, stable, and not requiring steroids or anticonvulsants for at least 4 weeks prior to start of study intervention
• Prior tx with an anti-PD-L1 agent within 5 half-lives are excluded
• Prior receipt of an MMAE-containing agent or docetaxel are excluded

A Phase 3 Randomized Double-blind Study of Adjuvant Pembrolizumab With or Without V940 in Participants With Resectable Stage II to IIIB (N2) NSCLC not Achieving pCR After Receiving Neoadjuvant Pembrolizumab With Platinum-based Doublet Chemotherapy (INTerpath-009) (V940-009)

MOA: V940 is a lipid encapsulated mRNA based Individualized Neoantigen Therapy (INT) encoding neoantigens to induce specific T cells and associated anti-tumor responses (both CD8 and CD4)

Key Eligibility Criteria:

• Histologically/cytologically confirmed diagnosis of resectable Stage II, IIIA, or IIIB (N2) NSCLC
• No prior therapy (except pts enrolled after the neoadjuvant treatment and surgery)
  • Pt who received up to 4 cycles of pembrolizumab and platinum-doublet chemotherapy, followed by R0 or R1 lobectomy or pneumonectomy, may enroll if all eligibility criteria are met
  • No prior anti-PD(L)1 or with another stimulatory/coinhibitory TCR or cancer vaccine, including another INT
  • Chemotherapy and pembrolizumab followed by surgery will be eligible
• Able to undergo protocol therapy, including necessary surgery
• Documentation of absence of tumor-activating EGFR mutations and ALK gene rearrangements
  • Pt with predominantly squamous histology does not require molecular testing for EGFR

Molecularly Informed Lung Cancer Treatment in a Community Cancer Network: A Pragmatic Consortium and Longitudinal Prospective Study (MYLUNG Program: Part 3) Order-Set-Go: Increasing Biomarker Testing Rates in Patients with Non-small-cell Lung Cancer Through Use of Clinical Decision Support Tools (MYLUNG/23329/LUN 576)

Brief Summary: This longitudinal study looks to quantify the testing timeline, operational barriers, and outcomes of biomarker-guided therapy in a large, community-based, and largely unselected patient population with early stage and advanced stage, treatment-naive non-small cell lung cancer, whether squamous or non-squamous.

Key Eligibility Criteria:

• Adult subjects (18 years and older) with newly diagnosed early stage, locally advanced or metastatic non-small cell lung cancer
• Must be eligible for systemic therapy based on the treating provider's assessment. If systemic therapy was recommended and documented by the treating provider but the patient declined, they can still be eligible for the study
• Subjects who developed locally advanced or metastatic disease after receiving adjuvant or neoadjuvant therapy are eligible if the adjuvant/neoadjuvant therapy was completed at least 12 months prior to the development of locally advanced or metastatic disease
• Stage IA at the time of enrollment excluded
• Subjects with small cell lung cancer excluded
• Subjects with Unknown primary tumor origin excluded

SUNRAY-01, A Global Pivotal Study in Participants with KRAS G12C-Mutant, Locally Advanced or Metastatic Non-Small Cell Lung Cancer Comparing First-Line Treatment of LY3537982 and Pembrolizumab vs Placebo and Pembrolizumab in those with PD-L1 expression >= 50% or LY3537982 and Pembrolizumab, Pemetrexed, Platinum vs Placebo and Pembrolizumab, Pemetrexed, Platinum regardless of PD-L1 Expression (J3M-MC-JZQB)

MOA: LY3537982 is an orally bioavailable small molecule inhibitor of the KRASG12C protein

Key Eligibility Criteria:

• Locally advanced or metastatic (Stage IIIB-IIIC or Stage IV) NSCLC
• Previously untreated, not suitable for curative intent surgery
  • Prior neoadj/adjuvant or consolidation therapy will be allowed provided treatment was completed 6 months prior to study entry
  • 1 cycle of SOC prior to study enrollment will be allowed for cases where immediate therapy is clinically indicated, as follows:
    • Part A and C: single cycle of pembrolizumab
    • Study treatment should start approximately 21 days after Day 1 of the prior treatment
• KRASG12C mutation and PD-L1 expression determined in tumor tissue or blood (local testing) are required
• No known targetable mutation or alteration in genes such as EGFR, ALK, BRAF (V600E), HER2, MET (exon 14), ROS1, RET, or NTRK1/2/3 (testing is not required).
• No active CNS metastases and/or carcinomatous meningitis

A Phase 1/2 Open-Label, Dose-Escalation and Clinical Response Study of Quaratusugene Ozeplasmid in Combination with Osimertinib in Patients with Advanced, EGFR-Mutant, Metastatic Non-Small Cell Lung Cancer who have Progressed after Treatment with Osimertinib (ONC-003)

MOA: Quaratusugene ozeplasmid is a nanoparticle encapsulating an optimized TUSC2 expression plasmid. Decreased expression of TUSC2 is associated with worse OS.

Key Eligibility Criteria:

• Unresectable stage III or IV NSCLC
• EGFR mutation-positive
• Phase 2: measurable disease per RECIST 1.1.
  • Phase 2a:
    • Cohort 1 must have progression on osimertinib alone
    • Cohort 2 must have progression after treatment with osimertinib, pemetrexed and a platin or single agent osimertinib followed by combination pemetrexed and a platin with or without osimertinib
  • Phase 2b: osimertinib treatment must be the only prior systemic treatment.