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Targeted Therapies and Immunotherapy Advances in Non-Small Cell Lung Cancer: A Comprehensive Review

Targeted TherapyCAR-TOncologyPrecision Medicine
  • Targeted therapies for NSCLC have revolutionized treatment for patients with specific genetic alterations, with EGFR, ALK, and ROS1 inhibitors showing significant improvements in progression-free survival compared to traditional chemotherapy.
  • Immunotherapy, particularly immune checkpoint inhibitors targeting PD-1/PD-L1 and CTLA-4, has become a cornerstone in NSCLC treatment, with newer targets like LAG-3, TIM-3, and TIGIT showing promise in ongoing clinical trials.
  • Advanced cellular therapies including adoptive cell transfer, CAR-T cells, and cancer vaccines represent the next frontier in NSCLC treatment, particularly for patients with "cold tumors" who don't respond to standard immunotherapies.

Malignant Pleural Disease Treated With Autologous T Cells Genetically Engineered to Target the Cancer-Cell Surface Antigen Mesothelin

NCT02414269Active, Not RecruitingPhase 1
Memorial Sloan Kettering Cancer Center
Posted 5/1/2015

Phase III Study (Tarceva®) vs Chemotherapy to Treat Advanced Non-Small Cell Lung Cancer in Patients With Mutations in the TK Domain of EGFR

NCT00446225CompletedPhase 3
Spanish Lung Cancer Group
Posted 2/15/2007

A Study of RNA Tumor Vaccine in Patients With Advanced Solid Tumors

NCT05202561Unknown StatusPhase 1
First Affiliated Hospital Bengbu Medical College
Posted 3/10/2022

A Study of Atezolizumab in Combination With Carboplatin Plus (+) Paclitaxel With or Without Bevacizumab Compared With Carboplatin+Paclitaxel+Bevacizumab in Participants With Stage IV Non-Squamous Non-Small Cell Lung Cancer (NSCLC)

NCT02366143CompletedPhase 3
Hoffmann-La Roche
Posted 3/31/2015

Pilot Immunotherapy Study With Letetresgene Autoleucel (Lete-cel, GSK3377794)T-cells in New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1)/ LAGE-1a-positive Advanced Non-small Cell Lung Cancer (NSCLC) Either Alone or in Combination With Pembrolizumab

NCT03709706TerminatedPhase 1
GlaxoSmithKline
Posted 12/31/2018

A Trial of AK104 Plus Anlotinib in NSCLC

NCT04646330CompletedPhase 1
Akeso
Posted 11/18/2020

AZD9291 Versus Gefitinib or Erlotinib in Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer

NCT02296125Active, Not RecruitingPhase 3
AstraZeneca
Posted 12/3/2014

Combinations of Cemiplimab (Anti-PD-1 Antibody) and Platinum-based Doublet Chemotherapy in Patients With Lung Cancer

NCT03409614CompletedPhase 3
Regeneron Pharmaceuticals
Posted 3/6/2018

A Global Study to Assess the Effects of MEDI4736 Following Concurrent Chemoradiation in Patients With Stage III Unresectable Non-Small Cell Lung Cancer

NCT02125461CompletedPhase 3
AstraZeneca
Posted 5/7/2014

Phase I/II Study of Anti-Mucin1 (MUC1) CAR T Cells for Patients With MUC1+ Advanced Refractory Solid Tumor

NCT02587689Unknown StatusPhase 1
PersonGen BioTherapeutics (Suzhou) Co., Ltd.
Posted 10/1/2015

A Dose Escalation and Expansion Study of Lomvastomig, a PD-1/TIM-3 Bispecific Antibody, in Participants With Advanced and/or Metastatic Solid Tumors

NCT03708328CompletedPhase 1
Hoffmann-La Roche
Posted 10/15/2018

A Study of XmAb®22841 Monotherapy & in Combination w/ Pembrolizumab in Subjects w/ Selected Advanced Solid Tumors

NCT03849469CompletedPhase 1
Xencor, Inc.
Posted 5/29/2019

A Study Of Oral PF-02341066, A C-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, In Patients With Advanced Cancer

NCT00585195CompletedPhase 1
Pfizer
Posted 4/19/2006

Safety, Immunogenicity and Preliminary Clinical Activity Study of PDC*lung01 Cancer Vaccine in NSCLC

NCT03970746Active, Not RecruitingPhase 1
PDC*line Pharma SAS
Posted 9/10/2019

BIBW 2992 (Afatinib) Versus Chemotherapy as First Line Treatment in NSCLC With EGFR Mutation

NCT00949650CompletedPhase 3
Boehringer Ingelheim
Posted 8/14/2009

CAR T Cell Receptor Immunotherapy Targeting Mesothelin for Patients With Metastatic Cancer

NCT01583686TerminatedPhase 1
National Cancer Institute (NCI)
Posted 5/4/2012

Oncolytic MG1-MAGEA3 With Ad-MAGEA3 Vaccine in Combination With Pembrolizumab for Non-Small Cell Lung Cancer Patients

NCT02879760CompletedPhase 1
Turnstone Biologics, Corp.
Posted 3/8/2017

A Study Of PF-06463922 An ALK/ROS1 Inhibitor In Patients With Advanced Non Small Cell Lung Cancer With Specific Molecular Alterations

NCT01970865CompletedPhase 1
Pfizer
Posted 1/8/2014

Pooled Mutant KRAS-Targeted Long Peptide Vaccine Combined With Nivolumab and Ipilimumab for Patients With Resected Mismatch Repair Protein (MMR-p) Colorectal and Pancreatic Cancer

NCT04117087Active, Not RecruitingPhase 1
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Posted 5/28/2020

A Study of CS1001 in Subjects With Stage IV Non-Small Cell Lung Cancer

NCT03789604Active, Not RecruitingPhase 3
CStone Pharmaceuticals
Posted 12/13/2018

A Study of Relatlimab Plus Nivolumab Versus Nivolumab Alone in Participants With Advanced Melanoma

NCT03470922Active, Not RecruitingPhase 2
Bristol-Myers Squibb
Posted 4/11/2018

A Study of Relatlimab Plus Nivolumab in Combination With Chemotherapy vs. Nivolumab in Combination With Chemotherapy as First Line Treatment for Participants With Stage IV or Recurrent Non-small Cell Lung Cancer (NSCLC)

NCT04623775Active, Not RecruitingPhase 2
Bristol-Myers Squibb
Posted 2/17/2021

A Study of Tiragolumab in Combination With Atezolizumab in Chemotherapy-Naïve Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer

NCT03563716Active, Not RecruitingPhase 2
Genentech, Inc.
Posted 8/10/2018

ALTA-1L Study: A Study of Brigatinib Versus Crizotinib in Anaplastic Lymphoma Kinase Positive (ALK+) Advanced Non-small Cell Lung Cancer (NSCLC) Participants

NCT02737501CompletedPhase 3
Ariad Pharmaceuticals
Posted 5/26/2016

P-MUC1C-ALLO1 Allogeneic CAR-T Cells in the Treatment of Subjects With Advanced or Metastatic Solid Tumors

NCT05239143Active, Not RecruitingPhase 1
Poseida Therapeutics, Inc.
Posted 2/15/2022

Efficacy, Safety, Tolerability of Gefitinib as 1st Line in Caucasian Patients With EGFR Mutation Positive Advanced NSCLC

NCT01203917CompletedPhase 4
AstraZeneca
Posted 9/1/2010

An Investigational Immuno-therapy Trial of Nivolumab, or Nivolumab Plus Ipilimumab, or Nivolumab Plus Platinum-doublet Chemotherapy, Compared to Platinum Doublet Chemotherapy in Patients With Stage IV Non-Small Cell Lung Cancer (NSCLC)

NCT02477826CompletedPhase 3
Bristol-Myers Squibb
Posted 8/5/2015

Biological Therapy in Treating Patients With Metastatic Cancer

NCT00004604CompletedPhase 1
Duke University
Posted 2/1/1997

A Study to Assess the Safety and Efficacy of AZD7789 in Participants With Advanced or Metastatic Solid Cancer

NCT04931654Active, Not RecruitingPhase 1
AstraZeneca
Posted 9/28/2021

CTLA-4 and PD-1 Antibodies Expressing EGFR-CAR-T Cells for EGFR Positive Advanced Solid Tumor

NCT03182816Unknown StatusPhase 1
Shanghai Cell Therapy Research Institute
Posted 6/7/2017

Study of BMS-936558 (Nivolumab) Compared to Docetaxel in Previously Treated Advanced or Metastatic Squamous Cell Non-small Cell Lung Cancer (NSCLC) (CheckMate 017)

NCT01642004CompletedPhase 3
Bristol-Myers Squibb
Posted 10/16/2012

A Trial of ChAdOx1 and MVA Vaccines Against MAGE-A3 and NY-ESO-1

NCT04908111SuspendedPhase 1
Cancer Research UK
Posted 10/15/2021

Trial of RNActive®-Derived Cancer Vaccine and Local Radiation in in Stage IV Non Small Cell Lung Cancer (NSCLC)

NCT01915524TerminatedPhase 1
CureVac
Posted 4/1/2013

Phase I-Ib/II Study of MBG453 as Single Agent and in Combination With PDR001 in Patients With Advanced Malignancies

NCT02608268TerminatedPhase 1
Novartis Pharmaceuticals
Posted 11/23/2015

Study of Selective BRAF Kinase Inhibitor Dabrafenib Monotherapy Twice Daily and in Combination With Dabrafenib Twice Daily and Trametinib Once Daily in Combination Therapy in Subjects With BRAF V600E Mutation Positive Metastatic (Stage IV) Non-small Cell Lung Cancer.

NCT01336634CompletedPhase 2
Novartis Pharmaceuticals
Posted 8/5/2011

Efficacy Study of Vx001 Vaccine in NSCLC Patients

NCT01935154CompletedPhase 2
Vaxon Biotech
Posted 8/1/2012

Safety Study of Enoblituzumab (MGA271) in Combination With Ipilimumab in Refractory Cancer

NCT02381314CompletedPhase 1
MacroGenics
Posted 3/26/2015

Arginase-1 Peptide Vaccine in Patients With Metastatic Solid Tumors

NCT03689192CompletedPhase 1
Herlev Hospital
Posted 12/17/2018

Evaluation of SAR408701 in Patients With Advanced Solid Tumors

NCT02187848TerminatedPhase 1
Sanofi
Posted 7/23/2014

A Study to Learn About the Effectiveness of Cancer Medicines in Patients With Metastatic Non-small Cell Lung Cancer in Norway.

NCT05834348Completed
Pfizer
Posted 6/23/2023

ARCHER1050: A Study of Dacomitinib vs. Gefitinib in 1st-Line Treatment Of Advanced NSCLC.

NCT01774721CompletedPhase 3
Pfizer
Posted 5/9/2013

A Clinical Research of CAR T Cells Targeting CEA Positive Cancer

NCT02349724Unknown StatusPhase 1
Southwest Hospital, China
Posted 12/1/2014

Safety and Efficacy of CEA-Targeted CAR-T Therapy for Relapsed/Refractory CEA+ Cancer

NCT04348643Unknown StatusPhase 1
Chongqing Precision Biotech Co., Ltd
Posted 2/20/2020

A Study Comparing Alectinib With Crizotinib in Treatment-Naive Anaplastic Lymphoma Kinase-Positive Advanced Non-Small Cell Lung Cancer Participants

NCT02075840CompletedPhase 3
Hoffmann-La Roche
Posted 8/19/2014

BIBW 2992 (Afatinib) vs Gemcitabine-cisplatin in 1st Line Non-small Cell Lung Cancer (NSCLC)

NCT01121393CompletedPhase 3
Boehringer Ingelheim
Posted 4/19/2010

PD-L1 Antibody (TQB2450) Plus Chemotherapy for Previously Untreated Limited- Stage Small-cell Lung Cancer

NCT04539977RecruitingPhase 2
Shanghai Pulmonary Hospital, Shanghai, China
Posted 9/1/2020

A Study of Vemurafenib in Participants With BRAF V600 Mutation-Positive Cancers

NCT01524978CompletedPhase 2
Hoffmann-La Roche
Posted 4/12/2012

A Randomized Phase 2 Study of Atezolizumab (an Engineered Anti-PDL1 Antibody) Compared With Docetaxel in Participants With Locally Advanced or Metastatic Non-Small Cell Lung Cancer Who Have Failed Platinum Therapy - "POPLAR"

NCT01903993CompletedPhase 2
Hoffmann-La Roche
Posted 8/6/2013

Study of Durvalumab + Tremelimumab, Durvalumab, and Placebo in Limited Stage Small-Cell Lung Cancer in Patients Who Have Not Progressed Following Concurrent Chemoradiation Therapy

NCT03703297Active, Not RecruitingPhase 3
AstraZeneca
Posted 9/27/2018

A Safety and Tolerability Study of INCAGN02390 in Select Advanced Malignancies

NCT03652077CompletedPhase 1
Incyte Corporation
Posted 9/24/2018

Combination Study With Soluble LAG-3 Fusion Protein Eftilagimod Alpha (IMP321) and Pembrolizumab in Patients With Previously Untreated Unresectable or Metastatic NSCLC, or Recurrent PD-X Refractory NSCLC or With Recurrent or Metastatic HNSCC

NCT03625323CompletedPhase 2
Immutep S.A.S.
Posted 2/18/2019

Safety Study of Enoblituzumab (MGA271) in Combination With Pembrolizumab or MGA012 in Refractory Cancer

NCT02475213CompletedPhase 1
MacroGenics
Posted 7/1/2015

MGC018 With or Without MGA012 in Advanced Solid Tumors

NCT03729596TerminatedPhase 1
MacroGenics
Posted 11/21/2018

Study of Pembrolizumab (MK-3475) in Participants With Progressive Locally Advanced or Metastatic Carcinoma, Melanoma, or Non-small Cell Lung Carcinoma (P07990/MK-3475-001/KEYNOTE-001)

NCT01295827CompletedPhase 1
Merck Sharp & Dohme LLC
Posted 3/4/2011

A Study of MGD013 in Patients With Unresectable or Metastatic Neoplasms

NCT03219268CompletedPhase 1
MacroGenics
Posted 8/18/2017

Trial of an RNActive®-Derived Cancer Vaccine in Stage IIIB/IV Non Small Cell Lung Cancer (NSCLC)

NCT00923312CompletedPhase 1
CureVac
Posted 5/1/2009

IO102 With Pembrolizumab, With or Without Chemotherapy, as First-line Treatment of Metastatic NSCLC

NCT03562871CompletedPhase 1
IO Biotech
Posted 8/22/2018

Study of CXCR5 Modified EGFR Targeted CAR-T Cells for Advanced NSCLC

NCT05060796RecruitingEarly Phase 1
Second Affiliated Hospital of Guangzhou Medical University
Posted 9/1/2019

Dose Escalation Study of a PD1-LAG3 Bispecific Antibody in Patients With Advanced and/or Metastatic Solid Tumors

NCT04140500Active, Not RecruitingPhase 1
Hoffmann-La Roche
Posted 11/11/2019

Genetically Modified T-Cell Therapy in Treating Patients With Advanced ROR1+ Malignancies

NCT02706392TerminatedPhase 1
Fred Hutchinson Cancer Center
Posted 3/16/2016

Avelumab in First-line NSCLC (JAVELIN Lung 100)

NCT02576574CompletedPhase 3
EMD Serono Research & Development Institute, Inc.
Posted 10/29/2015

An Investigational Drug, PF-02341066 Is Being Studied Versus Standard Of Care In Patients With Advanced Non-Small Cell Lung Cancer With A Specific Gene Profile Involving The Anaplastic Lymphoma Kinase (ALK) Gene

NCT00932893CompletedPhase 3
Pfizer
Posted 9/1/2009

Study of Vibostolimab Alone and in Combination With Pembrolizumab in Advanced Solid Tumors (MK-7684-001) ( KEYVIBE-001)

NCT02964013CompletedPhase 1
Merck Sharp & Dohme LLC
Posted 12/13/2016

PDR001 Plus LAG525 for Patients With Advanced Solid and Hematologic Malignancies

NCT03365791CompletedPhase 2
Novartis Pharmaceuticals
Posted 1/24/2018

Anti-MUC1 CAR T Cells and PD-1 Knockout Engineered T Cells for NSCLC

NCT03525782Unknown StatusPhase 1
The First Affiliated Hospital of Guangdong Pharmaceutical University
Posted 2/1/2018

Non-Histone Lactylation Emerges as Key Regulator in Cancer Progression and Therapeutic Target

Targeted Therapy
  • Non-histone lactylation, a novel post-translational modification, plays critical roles in cancer progression by modulating protein stability, enzyme activity, and cellular signaling pathways beyond traditional histone modifications.
  • Research reveals that lactylation affects diverse biological processes including cardiovascular diseases, neurological disorders, immune responses, and particularly cancer development through mechanisms like DNA damage repair and tumor microenvironment modulation.
  • Multiple enzymes including P300, KAT8, AARS1, and AARS2 function as lactylation "writers," while HDACs and sirtuins serve as "erasers," creating a dynamic regulatory system that influences disease pathogenesis.
  • Therapeutic strategies targeting lactylation pathways show promise, with small molecule inhibitors and specific blockers demonstrating potential to overcome drug resistance and enhance cancer treatment efficacy.

Yuhan's Lung Cancer Drug Leclaza Secures European Approval in Combination Therapy

Precision MedicineOncologyDrug ApprovalTargeted Therapy
  • Yuhan Corporation's third-generation EGFR-TKI lazertinib (Leclaza) has received European Commission approval in combination with J&J's Rybrevant for first-line treatment of EGFR-mutated non-small cell lung cancer.
  • The Phase 3 MARIPOSA study demonstrated the combination therapy reduced disease progression risk by 30% compared to osimertinib, with median progression-free survival of 23.7 months versus 16.6 months.
  • This milestone marks the first Korean anticancer drug approved in both the U.S. and Europe, triggering a $30 million payment to Yuhan as part of their $1.255 billion licensing deal with Johnson & Johnson.

Aktis Oncology's First-in-Class Nectin-4 Radiopharmaceutical AKY-1189 Shows Promising Tumor Uptake Across Multiple Cancer Types

Targeted TherapyOncology
  • Aktis Oncology's AKY-1189, the industry's only Nectin-4-directed radioligand therapy, demonstrated significant tumor uptake across multiple solid tumor types in first human data from 15 evaluable patients.
  • The novel miniprotein radiopharmaceutical showed excellent uptake in ER-positive breast cancer and bladder cancer, with potential applications beyond current Nectin-4 therapy Padcev.
  • Dosimetry analysis in eight patients revealed a wide therapeutic index with transient kidney uptake and no treatment-emergent adverse events, supporting progression to formal clinical trials.
  • The company is preparing to initiate phase 1 studies in South Africa and the US in 2025, following a recent $60 million deal with Lilly and $175 million Series B financing.

Global Breast Cancer Therapeutics Market Expected to Reach $78.61 Billion by 2033

OncologyTargeted TherapyMonoclonal AntibodyAIPrecision MedicineDrug Approval
• The global breast cancer therapeutics market, valued at $32.93 billion in 2023, is projected to reach $78.61 billion by 2033, growing at a CAGR of 9.09% over the next decade.
• North America dominates the market with a 38.61% revenue share, driven by high breast cancer prevalence and presence of key pharmaceutical companies including Pfizer, Roche, and Novartis.
• Targeted therapies hold the largest market segment at 64.85%, with hormone receptor-positive treatments accounting for 66.97% of the market as precision medicine approaches gain traction.

NIH's Novel Five-Drug Combination Shows Promise for Relapsed Aggressive B-Cell Lymphoma

Targeted TherapyOncologyMonoclonal Antibody
  • NIH researchers have developed ViPOR, a non-chemotherapy five-drug regimen that achieved complete remission in 38% of patients with relapsed or refractory diffuse large B-cell lymphoma.
  • The treatment was particularly effective in two specific subtypes: non-GCB DLBCL (62% complete response) and double-hit GCB DLBCL (53% complete response), offering new hope for patients with limited options.
  • At the two-year mark, 36% of all treated patients were still alive and 34% remained disease-free, with some maintaining remission beyond four years despite previously facing poor prognoses.

New Trial Data Shows Enhertu Reduces Breast Cancer Progression Risk by 38% as Access Remains Denied in England

Targeted TherapyOncology
  • New trial results from the Destiny-Breast06 study show Enhertu reduced the risk of HER2-low breast cancer progression by 38% compared to standard chemotherapy, with patients living without disease progression for 13.2 months versus 8.1 months.
  • The drug demonstrated superior efficacy with 60% of patients responding to treatment compared to 30% with chemotherapy, building on previous studies showing overall survival improvements of over six months.
  • Despite compelling clinical evidence, approximately 1,000 women annually in England and Wales are denied access to Enhertu due to NICE's cost-effectiveness concerns, while the drug remains available in Scotland and 13 other European countries.
  • Patient advocates and charities describe the access disparity as "utterly unacceptable," with ongoing negotiations between NICE, NHS England, and manufacturers Daiichi Sankyo and AstraZeneca to resolve pricing issues.

Tagrisso Demonstrates 84% Reduction in Disease Progression Risk for EGFR-Mutated Stage 3 NSCLC

Targeted Therapy
  • The phase 3 LAURA trial showed Tagrisso (osimertinib) reduced the risk of disease progression or death by 84% compared to placebo in patients with locally advanced, unresectable stage 3 EGFR-mutated NSCLC following chemoradiotherapy.
  • Patients treated with Tagrisso achieved a median progression-free survival of 39.1 months versus 5.6 months for placebo recipients, representing a seven-fold improvement in disease control.
  • Based on these results, Tagrisso is expected to become the new standard of care for EGFR-mutated, locally advanced NSCLC patients, marking the first targeted therapy approved for this patient population.
  • The FLAURA2 trial demonstrated that Tagrisso combined with chemotherapy showed a favorable trend toward overall survival improvement and consistent benefits in post-progression outcomes for advanced EGFR-mutated NSCLC patients.

FDA Grants Accelerated Approval to Krazati Plus Cetuximab for KRAS G12C-Mutated Colorectal Cancer

Drug ApprovalPrecision MedicineTargeted Therapy
  • The FDA granted accelerated approval to Krazati (adagrasib) plus cetuximab for adults with KRAS G12C-mutated locally advanced or metastatic colorectal cancer who have received prior standard chemotherapy treatments.
  • The combination therapy targets a specific genetic mutation and is approved for patients whose tumors are determined to have the KRAS G12C mutation by an FDA-approved test.
  • The most common adverse reactions include rash, nausea, diarrhea, vomiting, fatigue, and musculoskeletal pain, occurring in at least 20% of patients.
  • This approval represents a significant advancement in precision medicine for colorectal cancer patients with this specific genetic alteration.

Combination Immunotherapy Strategies Show Promise in Overcoming NSCLC Treatment Resistance

Targeted Therapy
  • Combination immunotherapies demonstrate superior efficacy compared to monotherapy approaches in NSCLC, with dual checkpoint inhibition and chemo-immunotherapy combinations showing improved overall survival and progression-free survival rates.
  • Multiple resistance mechanisms to targeted therapies and immunotherapy have been identified in NSCLC, including target-dependent mutations, bypass pathway activation, and tumor microenvironment changes that limit treatment effectiveness.
  • Novel therapeutic strategies including fourth-generation EGFR-TKIs, antibody-drug conjugates, and combination approaches targeting multiple pathways are being developed to overcome resistance mechanisms.
  • Biomarker-driven patient selection and personalized treatment approaches are emerging as critical factors for optimizing combination therapy outcomes in NSCLC patients.

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