Molecular Tumor Board Case Series: Targeted Treatments For Cancer And Their Toxicities: Amivantamab-Induced Linear IgA Bullous Dermatosis.

In the era of targeted treatments based on next generation sequencing (NGS) analysis, clinicians must be diligent in aligning patients with treatments giving them the best chance of survival while weighing the risk of toxicity caused by agents targeting specific gene mutations. In this case, we describe a patient with Epidermal Growth Factor Receptor (EGFR) exon 20 insertion mutation positive recurrent lung adenocarcinoma who received amivantamab and experienced severe dermatologic toxicity.

Bridging the Gap: Innovative 'Center for Precision Oncology' in Missouri.

Background: Next generation sequencing (NGS) has become standard practice for identification and treatment of targetable driver mutations in advanced cancer. However, NGS interpretation of clinical applicability can be challenging to clinician, with potential impact on patient's outcome. Specialized precision medicine services are poised to bridge this gap by creating collaborative frameworks to formulate and deliver genomic patient care plans. Methods: Saint Luke's Cancer Institute in Kansas City, Missouri, (SLCI) instituted the Center for Precision Oncology (CPO) in 2017. The program accepts patient referrals for a multidisciplinary molecular tumor board and offers CPO clinic visits. An Institutional Review Board-approved molecular registry was initiated. It catalogues genomic files along with patient demographics, treatment and outcomes. CPO patient volumes, recommendation acceptance, clinical trial matriculation and funding for drug procurement were closely tracked. Results: In 2020 there were 93 referrals to the CPO with 29 patient clinic visits. 20 patients matriculated to CPO-recommended therapies. Two patients were successfully enrolled in Expanded Access Programs (EAPs). CPO successfully procured eight off-label treatments. Treatments initiated per CPO recommendations totaled over $1 million in drug costs. Conclusion: Precision medicine services are essential tool for oncology clinicians. In addition to expert NGS analysis interpretation, precision medicine programs provide crucial multidisciplinary support for patients to understand the implications of their genomic report and pursue targeted treatment as indicated. Molecular registries associated with these services offer valuable opportunities for research.

Molecular Tumor Board Case Series: Targeting KRAS G12C in Lung Cancer.

Next-generation sequencing (NGS) identifies biomarkers with prognostic and predictive importance in patients with cancer. The enormous amounts of data generated by comprehensive NGS adds complexity to the identification of valid drug therapy targets. Rapid progress made in targeted drug development creates the need for novel methods to access these treatments for patients. Molecular tumor boards (MTB) not only aid in identifying targetable gene mutations by carefully reviewing NGS data, they can also take lead in creating patient access to the appropriate targeted therapy. Here we describe two patients with Kirsten Rat Sarcoma (KRAS) G12C mutation positive lung adenocarcinoma for whom MTB was able to procure AMG510 or sotorasib, a covalent KRAS G12C inhibitor, by expanded access program ahead of FDA approval.

Response to osimertinib in a colorectal cancer patient with an EGFR T790M mutation: A case report.

BACKGROUND: Although common in lung cancer, somatic epidermal growth factor receptor (EGFR) mutations are rarely found in colorectal cancer, occurring in approximately 3% of cases. Treatment with anti-EGFR antibodies is commonplace, but EGFR tyrosine kinase inhibitors are not standard treatments in colorectal cancer. Here we report a case of sustained response to osimertinib in a colorectal cancer patient with an EGFR T790M mutation on cell-free DNA analysis. CASE SUMMARY: A 72-year old woman with a past medical history of post-polio syndrome confined to a wheelchair, scoliosis and hypothyroidism presented with metastatic sigmoid colon adenocarcinoma with hepatic metastases. Next generation sequencing revealed a RAS/RAF wild-type, microsatellite stable, PD-L1 negative malignancy. Mutations in TP3 and APC were also identified, as well as EGFR amplification. Cell-free DNA analysis revealed an EGFR T790M mutation. She was unable to tolerate first-line treatment with panitumumab, 5-fluorouracil and leucovorin, progressed on second-line treatment with trifluridine/tipiracil plus bevacizumab, and was unable to tolerate third-line treatment with regorafenib. She was started on fourth-line treatment with off-label osimertinib, with clinical response - decrease in size of hepatic metastases and a pericardial effusion. She remained on treatment with osimertinib for seven months. CONCLUSION: This case shows the benefit of multi-gene sequencing assays to identify potential therapeutic options in patients with refractory disease.

Squamous cell carcinoma of the lung: improving the detection and management of immune-related adverse events.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have revolutionized treatment for patients with non-small lung cancer (NSCLC). Currently approved ICIs are monoclonal antibodies that target programmed death receptor 1 (PD-1), its ligand PD-L1, or CTLA-4. With ICIs comes a novel collection of toxicities: immune-related adverse events (IRAEs). Management of IRAEs requires multidisciplinary expertise. We review the biology of IRAEs and their management in patients with squamous NSCLC. AREAS COVERED: We review the pathophysiology of ICIs and IRAEs. For IRAEs related to squamous NSCLC, Cochrane Central, EMBASE, and PubMed were queried for trials with patients with squamous cell carcinoma or adenocarcinoma histology, who were assessed for incidence rates of IRAEs. Thirteen trials met inclusion criteria. National guidelines are reviewed to outline management strategies for IRAEs. EXPERT OPINION: IRAEs are unique compared to standard chemotherapy. As the role of ICIs expand across all stages of squamous cell NSCLC and with different combinations of antineoplastics, management of IRAEs will become crucial. Optimal management of IRAEs requires multidisciplinary teamwork. Further investigation into the pathophysiology of IRAEs can enhance current management strategies.

Real-world survival analysis by tumor mutational burden in non-small cell lung cancer: a multisite U.S. study.

BACKGROUND: Tumor mutational burden (TMB) is a potential biomarker to predict tumor response to immuno-oncology agents in patients with metastatic non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: A multi-site cohort study evaluated patients diagnosed with stage IV NSCLC between 2012 and 2019 who had received comprehensive genomic profiling (CGP) and any NSCLC-related treatment at 9 U.S. cancer centers. Baseline characteristics and clinical outcomes were compared between patients with TMB <10 and TMB ≥10. RESULTS: Among the 667 patients with CGP results, most patients received CGP from Foundation Medicine (64%) or Caris (20%). Patients with TMB ≥10 (vs. TMB <10) were associated with a positive smoking history. TMB was associated with ALK (p = 0.01), EGFR (p < 0.01), and TP53 (p < 0.05) alterations. TMB >10 showed a significant association towards longer overall survival (OS) (HR: 0.43, 95% CI: 0.21-0.88, p = 0.02) and progression-free survival (PFS) (HR: 0.43, 95% CI: 0.21-0.85, p = 0.02) in patients treated with first-line immunotherapy and tested by Foundation Medicine or Caris at treatment initiation. CONCLUSIONS: TMB levels greater than or equal to 10 mut/Mb, when tested by Foundation Medicine or Caris at treatment initiation, were significantly associated with improved OS and PFS among patients treated with first-line immunotherapy-containing regimens. Additional prospective research is warranted to validate this biomarker along with PD-L1 expression.

Non-secretory multiple myeloma with unusual TFG-ALK fusion showed dramatic response to ALK inhibition.

Non-secretory multiple myeloma (NSMM) constitutes a distinct entity of multiple myeloma characterized by the absence of detectable monoclonal protein and rarely an absence of free light chains in the serum and urine. Given its rarity, the genomic landscape, clinical course, and prognosis of NSSM are not well characterized. Here, we report a case of a patient with relapsed and refractory NSMM with brain metastasis harboring a TFG-ALK fusion showing a dramatic and durable (over two years) response to commercially available anaplastic lymphoma kinase (ALK) inhibitors. The case emphasizes the beneficial role of molecular profiling in this target-poor disease.