ASCO 2024 highlights blog

Friday 31st May

• Neoantigens, which result from changes in tumor DNA sequences, can be initially identified using predictive algorithms after whole-genome or whole-exome transcriptome sequencing. These neoantigens are then synthesized to create a neoantigen mRNA vaccine, which is packaged in lipid nanoparticles for delivery in vivo.
• Promising clinical data from metastatic melanoma (phase II KEYNOTE-942) suggests that the addition of a personalized neoantigen mRNA vaccine to standard adjuvant pembrolizumab may provide clinical benefit compared with pembrolizumab alone. It is critical for pharma to partner with a proficient testing/diagnostic provider, to effectively harness the potential of neoantigen mRNA vaccines, ensuring accurate neoantigen identification and reliable clinical outcomes.
• Additional phase III adjuvant trials in resected stage IIB/IIC/III/IV melanoma, non–small cell lung cancer (NSCLC), squamous cancer of the skin, renal cell cancer, and bladder cancer are planned.
• In addition to combinatorial treatments, incorporation of the latest technological advancements in sequencing and cellular analysis to understand tumor microenvironment, may generate new prognostic or therapeutic insights
• The effective use of advanced data science in healthcare can revolutionize the way medical data is managed and utilized, leading to more efficient, timely, and high-quality patient care via stimulated cross-functional communication among HCPs, reduced time from testing to diagnosis and improved patient outcome.
• The 5-year analysis of the CROWN trial shows that Lorlatinib treatment produces the longest progression-free survival observed in ALK-positive NSCLC, further establishing Lorlatinib as the preferred first-line treatment for patients with metastatic ALK-positive NSCLC.
• Amivantamab combined with Lazertinib represents a promising new standard of care for the first-line treatment of EGFR mutant NSCLC, particularly for high-risk subgroups. However, defining an optimal panel of biomarkers for treatment stratification is essential to help identify molecular subsets of NSCLC that can be matched with targeted therapies, thereby improving outcomes across all subsets.
• Subcutaneous (SC) dosing of amivantamab should is favored over intravenous (IV) dosing in treating refractory EGFR-mutated, advanced non-small cell lung cancer (NSCLC) as it can reduce treatment time and clinical toxicity, thereby improving patient outcomes and care efficiency.

Indications for Industry

• It is critical for pharma to partnering with a proficient testing/diagnostic provider, to effectively harness the potential of neoantigen mRNA vaccines, ensuring accurate neoantigen identification and reliable clinical outcomes.
• Accessibility to such a personalized medicine (neoantigen mRNA vaccine) will need to be addressed: NHS cancer vaccine launch pad (CVLP) is the first initiative world-wide to address this challenge.
• As more clinical trial data becomes available for various targeted therapies, it's essential to balance optimal efficacy and improved tolerability when selecting treatment options. Defining an optimal panel of biomarkers for treatment stratification is essential to help identify molecular subsets of NSCLC that can be matched with targeted therapies, thereby improving outcomes across all subsets.
• SC over IV dosing of amivantamab should be favored as it should alleviate time and clinical toxicity and improve outcomes for patients and care efficiency.
  

Saturday 1st June

• Key features, such as linker cleavage enhancing ADC selectivity and new antibody conjugation sites improving stability, have contributed to decreased off-target toxicity and on-target off-tumor toxicity in new ADCs. However, biomarkers that can evaluate ADC toxicity and guide adjustments during early-phase trials to maximize therapeutic benefits and minimize toxicity are still missing.
• Two large population-based studies (one global and one UK biobank study) further solidify the understanding that identifying pathogenic variants early can significantly inform cancer risk reduction and improve clinical outcomes. However, the actual genetic testing rate in practice falls significantly short of guideline recommendations. It is imperative to address this issue to ensure better healthcare outcomes for cancer patients.
• Genomic alterations in ctDNA enhance prognostic accuracy compared to clinical features alone. While evidence supports the prognostic value of ctDNA burden, its predictive value regarding the benefit of LuPSMA treatment requires further clinical validation.
  
  

Indications for Industry

• Genetic testing can provide overwhelming information to recipients, especially patients, and not all of this information is clinically actionable yet. Clearer guidance is needed on reporting genetic test results, specifying which results should be included, so patients can make more informed decisions without confusion.
• Dynamic biomarker testing should be implemented to monitor the efficacy of ADC treatment due to the development of acquired resistance. LBx-based real-time biomarker testing, spatial genomics, and molecular imaging can all contribute to the potential success in ADC treatment.
• Combination drug therapies, including ADC+ TKIs, ADC+ICIs, ADC + statin and ADC + DNA-damaging agents, may also be a future approach to overcome this complexed highly personalized acquired ADC resistance
  
  

Sunday 2nd June

• ADC target expression matters but it is not always clinically relevant: selecting patients based on target expression is critical for Teliso-V in NSQ EGFR wtNSCLC, but not strictly necessary for Sac-TMT in TNBC.
• Tissue-based and "liquid biopsy" prognostic molecular biomarkers have been identified through independent studies. However, it is crucial to conduct larger clinical trials to confirm the clinical utility of these emerging prognostic biomarkers and incorporate them into clinical practice, thereby facilitating risk-stratified therapy decisions and biomarker-driven clinical trials.
• Osimertinib will become the new standard of care for patients with unresectable stage III EGFRm NSCLC who have not progressed after definitive chemoradiotherapy, while consolidation durvalumab will become the new standard of care for patients with LS-SCLC who have not progressed after cCRT. The next step is to implement a personalized, biomarker-driven approach utilizing genomic patient stratification, which can further ensure better results in PFS for patients with SCLC.
• Although biomarker expression is common in gastrointestinal and hepatobiliary tumors, accessing molecular profiling in the community setting has proven to be challenging.
  
  

Indications for Industry

• Evaluating the expression levels of ADC targets is challenging due to analytical and interpretative issues associated with IHC and the temporal and spatial heterogeneity of tumors. Improvements are urgently needed to fully realize the potential of target expression evaluation for the rapidly expanding range of ADC options.
• Ensuring the practice of EGFR mutation testing in stage III disease is critical to identify patients who might be eligible for or benefit from Osimertinib treatment.
• Strategic biomarker testing, including ensuring the accessibility of both immunohistochemistry and NGS in standard of care treatment paradigms, is crucial to optimizing the selection of targeted therapies for patients with upper gastrointestinal and hepatobiliary cancers.

Monday 3rd June

• BRAF V600E mCRC continues to be a disease with a poor prognosis in need of novel therapeutic approaches.
• Highly sensitive techniques is needed to detect small fragments of tumor-specific alterations in the background of cell-free DNA from non-cancerous cells, and prospective validation is required before such assays can be used to guide therapy outside of the clinical trial setting.
• Tucatinib (TUC), a highly selective HER2-directed TKI and Trastuzumab (Tras) is a humanized monoclonal antibody target to HER2.
• Phase II MOUNTAINEER trial have shown the statistically significant and clinically meaningful improvement in OS from TUC+Tras treatment in HER2+ and RAS WT mCRC with progression on or intolerance to last systemic therapy (medium OS is 23.9 month for TUC+Tras treatment compared to 21.1 month for TUC treatment alone).
• CodeBreaK support trial trial have shown a trending improved OS in soto960+pani compared to control (medium OS is 11.9 month for soto+pani vs. 10.3 month for investigator’s choice) for patients with chemo refractory KRAS G12C-mutated mCRC.
• ADC target expression matter: selecting patients based on target (c-Met) expression is clinically relevant and critical to aid patient selection for ABBV-400 in CRC patients.
  

Indications for Industry

• Biomarker-driven patient stratification may be needed to further identify potential patients among the BRAF V600E mCRC cohort who might benefit from ERAS-007 treatment.
• TUC+Trasis is an important chemotherapy-free treatment option in HER2+ mCRC. Results from the upcoming phase III MOUNTAINEER trial will support its use as a 1L treatment (dual HER2 targeted therapy) for patients with HER2+ mCRC.
• Results from CodeBreaK support trial support the use of soto960+pani as a potential SOC for patients with chemo refractory KRAS G12C-mutated mCRC.
• Not all targeted therapies will show superior therapeutic activity. Treatment choices should be carefully evaluated in combination with an individual's biomarker testing results and treatment history.

References:

Educational session “State-of-the-Art Advancements in Adjuvant Cancer Vaccines and Biomarkers”; abstract LBA9512“Individualized neoantigen therapy mRNA-4157 (V940) plus pembrolizumab in resected melanoma: 3-year update from the mRNA-4157-P201 (KEYNOTE-942) trial”.

Abstract 1100 “Shareable artificial intelligence to extract cancer outcomes from electronic health records”; abstract 11001 “Efficacy of eSyM: Acute care utilization among patients with cancer who do versus do not report ePROs”; abstract 11002 “An AI-assisted navigation approach for patients with radiographic suspicion of new pancreas cancer”

Abstract LBA8503 “Lorlatinib vscrizotinib in treatment-naïve patients with advanced ALK+ non-small cell lung cancer: 5-year progression-free survival and safety from the CROWN study”

Abstract 8504 “Amivantamabplus lazertinib vsosimertinib in first-line EGFR-mutant advanced non-small cell lung cancer (NSCLC) with biomarkers of high-risk disease: A secondary analysis from the phase 3 MARIPOSA study”

Abstract LBA8505 “Subcutaneousamivantamabvs intravenous amivantamab, both in combination with lazertinib, in refractory EGFR-mutated, advanced non-small cell lung cancer (NSCLC): Primary results, including overall survival (OS), from the global, phase 3, randomized controlled PALOMA-3 trial”

Abstract 10512 “Real-world cancer care utilization among patients with breast cancer with germline variants of uncertain significance”; abstract 10513 “Tracking uncertainty in germline genetic testing for hereditary cancer syndromes: Sources, attributes, and resolution of variants of uncertain significance in over 1 million individuals”; abstract 10514 “Gene-environment interactions between clonal hematopoiesis of indeterminate potential and air pollution in non-small cell lung cancer among non-smokers”.

Abstract 3000 “First-in-human trial of M9140, an anti-CEACAM5 antibody drug conjugate (ADC) with exatecan payload, in patients (pts) with metastatic colorectal cancer (mCRC)”; abstract 3001 “First-in-human study of ABBV-706, a seizure-related homolog protein 6 (SEZ6)–targeting antibody-drug conjugate (ADC), in patients (pts) with advanced solid tumors”; abstract 3002 “Phase I/II first-in-human study to evaluate the safety and efficacy of tissue factor-ADC MRG004A in patients with solid tumors”.

Abstract educational session “Unlocking the Potential: Biomarkers of Response to Antibody–Drug Conjugates”

Abstract 10503 “Clinical behavior of breast cancer in young BRCA carriers and prognostic impact of the timing of genetic testing: Results from an international cohort study”; abstract 10505 “Association between rare pathogenic variants in established cancer risk genes and the diagnosis of single and multiple common cancers: A UK Biobank study”

Abstract 5007 “A clinical-genetic (CG) circulating tumor DNA (ctDNA)-based prognostic model for predicting overall survival (OS) in men with metastatic castrate-resistant prostate cancer (mCRPC) treated with potent androgen receptor inhibition (Alliance)”; abstract 5008 “Baseline ctDNAanalyses and associations with outcomes in taxane-naive patients with mCRPCtreated with 177Lu-PSMA-617 versus change of ARPI in PSMAfore”.

Abstract 103 “Telisotuzumab vedotin monotherapy in patients with previously treated c-Met–overexpressing non-squamous EGFR wildtype advanced NSCLC: Primary analysis of the LUMINOSITY trial.”; 104 “Sacituzumab tirumotecan (SKB264/MK-2870) in patients (pts) with previously treated locally recurrent or metastatic triple-negative breast cancer (TNBC): Results from the phase III OptiTROP-Breast01 study”.

Abstract 11509 “Molecular characterization of patients with localized Ewing sarcoma targeting discrete prognostic groups: A report from the Children’s Oncology Group”; 11510 “Prospective evaluation of pre-treatment ctDNA burden in localized osteosarcoma to identify patients with inferior outcomes: A report from the LEOPARD study”, 11511 “Impact of ATRX loss on survival and immune microenvironment in multiple sarcoma subtypes”.

Abstract LBA4 “Osimertinib (osi) after definitive chemoradiotherapy (CRT) in patients (pts) with unresectable stage (stg) III epidermal growth factor receptor-mutated (EGFRm) NSCLC: Primary results of the phase 3 LAURA study.”

Abstract LBA5 “ADRIATIC: Durvalumab (D) as consolidation treatment (tx) for patients (pts) with limited-stage small-cell lung cancer (LS-SCLC).”

Abstract 3517 “Updated results from ERAS-007 plus encorafenib and cetuximab (EC) in patients (pts) with EC-naïve metastatic BRAF V600E colorectal cancer (CRC) in the phase 1b/2 HERKULES-3 study.”

Abstract 3009 “Performance characteristics of a tissue-agnostic genome-wide methylome enrichment MRD assay for head and neck malignancies.”; abstract 3010 “Personalized cell-free tumor DNA analysis for patients with HNSCC: Liquid biopsy for minimal residual disease detection in head and neck squamous cell carcinoma (LIONESS).”; abstract 3011 “Circulating tumor cells and tumor DNA in patients with resectable colorectal liver metastases: The MIRACLE.”

Abstract LBA3510 “Overall survival (OS) of phase 3 CodeBreaK 300 study of sotorasib plus panitumumab (soto+pani) versus investigator’s choice of therapy for KRAS G12C-mutated metastatic colorectal cancer (mCRC).”

Abstract 3509 “Final results of a phase 2 study of tucatinib and trastuzumab for HER2-positive mCRC (MOUNTAINEER).”

Abstract 3515 “First-in-human study of ABBV-400, a novel c-Met–targeting antibody-drug conjugate, in advanced solid tumors: Results in colorectal cancer.”