Impact of PROphet Test in Changing Physicians' Therapeutic Decision-Making for Checkpoint Immunotherapy in Non-Small-Cell Lung Cancer.

PURPOSE: Immune Checkpoint Inhibitor (ICI) regimens are approved for first-line treatment of metastatic nononcogene-driven NSCLC. Guidelines do not differentiate which patients with PD-L1 ≥ 50% should receive ICI monotherapy. The clinically validated PROphet NSCLC plasma proteomic-based test is designed to inform this therapeutic decision. METHODS: One hundred oncologists were presented with 3 "virtual" metastatic NSCLC cases with PD-L1 scores and asked to recommend an approved first-line regimen. They then watched an online educational webinar on the PROphetNSCLC test. Postwebinar, the same cases were represented with the addition of a PROphet result, and oncologists again recommended a first-line regimen. Responses were compared to assess the impact on first-line treatment selection. RESULTS: Treatment recommendation changed in 39.6% of PROphet-tested cases, with 93% of physicians changing at least 1 case. In the PD-L1 ≥ 50% group, 89% of physicians changed their recommendation, followed by 77%, in PD-L1 < 1%, and 36% in PD-L1 1% to 49%. ​In the PD-L1 ≥ 50%, PROphet POSITIVE group, the recommendation for ICI monotherapy increased from 60% to 89%. ​For the PD-L1 ≥ 50%, PROphet NEGATIVE group, the recommendation for monotherapy dropped from 60% to 9%. In the PD-L1 < 1%, PROphet NEGATIVE group, 35% of patients were spared toxicity from ICI compared to 11% in PROphet untested cases. CONCLUSION: Adding PROphet to PD-L1 expression impacted therapeutic decision making in first-line NSCLC. PROphet identifies those predicted to have an overall survival benefit from ICI monotherapy versus combination versus chemotherapy, improving the probability of efficacy and reducing toxicity for some patients.

Top 20 EGFR+ NSCLC Clinical and Translational Science Papers That Shaped the 20 Years Since the Discovery of Activating EGFR Mutations in NSCLC. An Editor-in-Chief Expert Panel Consensus Survey.

The year 2024 is the 20th anniversary of the discovery of activating epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC). Since then, tremendous advances have been made in the treatment of NSCLC based on this discovery. Some of these studies have led to seismic changes in the concept of oncology research and spurred treatment advances beyond NSCLC, leading to a current true era of precision oncology for all solid tumors. We now routinely molecularly profile all tumor types and even plasma samples of patients with NSCLC for multiple actionable driver mutations, independent of patient clinical characteristics nor is profiling limited to the advanced incurable stage. We are increasingly monitoring treatment responses and detecting resistance to targeted therapy by using plasma genotyping. Furthermore, we are now profiling early-stage NSCLC for appropriate adjuvant targeted treatment leading to an eventual potential "cure" in early-stage EGFR+ NSCLC which have societal implication on implementing lung cancer screening in never-smokers as most EGFR+ NSCLC patients are never-smokers. All these advances were unfathomable in 2004 when the five papers that described "discoveries" of activating EGFR mutations (del19, L858R, exon 20 insertions, and "uncommon" mutations) were published. To commemorate this 20th anniversary, we assembled a global panel of thoracic medical oncology experts to select the top 20 papers (publications or congress presentation) from the 20 years since this seminal discovery with December 31, 2023 as the cutoff date for inclusion of papers to be voted on. Papers ranked 21 to 30 were considered "honorable mention" and also annotated. Our objective is that these 30 papers with their annotations about their impact and even all the ranked papers will serve as "syllabus" for the education of future thoracic oncology trainees. Finally, we mentioned potential practice-changing clinical trials to be reported. One of them, LAURA was published online on June 2, 2024 was not included in the list of papers to be voted on but will surely be highly ranked if this consensus survery is performed again on the 25th anniversay of the discovery EGFR mutations (i.e. top 25 papers on the 25 years since the discovery of activating EGFR mutations).

Characterization of Incidental Pathogenic Germline Findings Detected via ctDNA among Patients with Non-Small Cell Lung Cancer in a Predominantly Hispanic/Latinx Population.

Pathogenic germline variants (PGVs) may be under-detected as causative etiologies in patients with non-small cell lung cancer (NSCLC). The prevalence of PGVs has been reported between 1 and 15% of patients, depending on the patient population. The rate within Hispanic/Latinx populations remains unknown. We retrospectively analyzed the genomic results (Guardant360, Redwood City, CA, USA) of 878 patients with advanced or metastatic NSCLC at five centers in South Florida, USA, from 2019 to 2022 to analyze the rate of incidental PGVs (iPGVs) identified via circulating cell-free tumor DNA (ctDNA). We then stratified the results by tumor histology, age, gender, race, ethnicity, genetic pathway, and co-mutations. Twenty-one iPGVs were identified (21/878 = 2.4%). Among the 21 iPGVs identified, 14 patients were female (66.7%) and 7 were male (33.3%), with a median age of 67 years and tobacco history of 2.5 pack-years. In total, 52.4% of patients identified as Hispanic/Latinx (n = 11) of any race; 19.0% as Ashkenazi Jewish (n = 4), 9.5% as non-Hispanic/Latinx black (n = 2), and 19.0% as non-Hispanic/Latinx white (n = 4). iPGVs in the homologous recombination repair pathway were solely expressed in this cohort (10 ATM, 8 BRCA2, and 3 BRCA1). In total, 76% (16/21) of patients with iPGVs co-expressed somatic alterations, with 56% (9/16) demonstrating alterations in targetable genes. Overall, our real-world findings offer a point prevalence of iPGVs in patients with NSCLC of diverse populations, such as patients who report Hispanic/Latinx ethnicity.

Drug Shortages in Oncology: ASCO Clinical Guidance for Alternative Treatments.

PURPOSE: To increase awareness, outline strategies, and offer clinical guidance on navigating the complexities of treatment planning amid antineoplastic drug shortages. METHODS: A multidisciplinary panel of oncologists, ethicists, and patient advocates was assembled to provide rapid clinical guidance to help providers navigate appropriate patient care in cases where rationing or alternative therapies must be considered. The groups of content experts developed general principles for resource allocation during shortages and clinical guidance on alternative therapies for specific disease sites. The recommendations are supported by evidence when available. RESULTS: A total of 44 volunteers with content expertise formed the Advisory Group that developed general guidance on the prioritization of antineoplastic agents in limited supply. Disease site-specific clinical guidance was then produced by subgroups on the basis of members' specialties and expertise. The majority of alternative treatment options were developed in consideration of cisplatin and carboplatin shortages. All guidance is posted on ASCO's website. RECOMMENDATIONS: The prioritization of antineoplastic agents in limited supply should be based on specific goals of the therapy where evidence-based medicine has shown survival outcome and life-extending benefit in both early and advanced stages. Recommendations for specific disease sites are presented. While management options vary according to the disease site, alternatives are presented. For settings in which there are no alternatives with comparable efficacy and safety, it is recommended that patients are referred to an area where the necessary drug is available or can be obtained.Additional information is available at asco.org/drug-shortages.

Liquid Biopsy Versus Tissue Biopsy to Determine Front Line Therapy in Metastatic Non-Small Cell Lung Cancer (NSCLC).

In the last decade, non-small-cell lung cancer (NSCLC) treatment has improved with the approval of multiple therapies to target specific genetic alterations. Though, next generation sequencing (NGS) has traditionally been conducted from tissue biopsy samples, developing data supports the use of plasma-based circulating tumor DNA (ctDNA), also known as "liquid biopsy," to complement tissue biopsy approaches in guiding front-line therapy. This study is a retrospective analysis of 170 new NSCLC patients treated at 2 cancer centers within a 5-year period who received both tissue and liquid biopsy NGS as standard of care. Based on a treatment schema defined by testing sufficiency, biomarker detection, and turnaround time (TAT), physicians based the majority of their treatments on liquid biopsy results (73.5%) versus tissue biopsy (25.9%). Liquid biopsy NGS returned results on average 26.8 days faster than tissue and reported higher testing success. For guideline-recommended biomarkers, liquid biopsy was 94.8% to 100% concordant with tissue. In comparing testing modalities, a liquid-first approach identified guideline-recommended biomarkers in 76.5% of patients versus 54.9% in a tissue-first approach. There was no significant difference in time-to-treatment, or survival outcomes (overall survival and progression free survival) based on liquid versus tissue biopsy findings. This research demonstrates that liquid biopsy NGS is an effective tool to capture actionable genetic alterations in NSCLC. Due to its high concordance to tissue, faster TAT, and similarity in outcomes and time-to-treatment, liquid biopsy can be used either as a first-line test or concordantly with tissue biopsy to guide treatment decisions in NSCLC.

Treatment Considerations for Patients With Advanced Squamous Cell Carcinoma of the Lung.

Squamous cell carcinoma (SCC) of the lung has a markedly different molecular profile to adenocarcinoma of the lung and remains difficult to treat because of the lack of targeted therapies for this type of non-small cell lung cancer (NSCLC). With immune checkpoint inhibitors moving from second-line treatment to first-line in NSCLC, effective second-line options following immunotherapy is an urgent unmet need. Appropriate treatment decisions are currently hindered by a lack of prospective clinical data. However, available real-world data suggest that ramucirumab plus docetaxel warrants prospective evaluation in this setting. Also, afatinib is approved in the second line in patients with SCC progressing on first-line platinum-based chemotherapy and may also be an option following immunochemotherapy combinations. Afatinib has the advantage of oral administration with a well-defined tolerability profile. Docetaxel, gemcitabine and platinum-based chemotherapy may be options for some patients, but overall, there are very few options for patients requiring second-line treatment after immunotherapy. This lack of options has prompted efforts to further define the molecular profile of lung SCC to match patients with relevant targeted therapies and to elucidate additional genomic targets. In order to ensure patients with SCC of the lung receive optimal treatment, genomic testing is essential to identify those patients who might benefit from existing targeted agents or clinical trials, and further prospective data are urgently required to assess potential second-line regimens following immunotherapy.

STARBOARD: encorafenib + binimetinib + pembrolizumab for first-line metastatic/unresectable BRAF V600-mutant melanoma.

Despite the significant progress in the treatment of unresectable or metastatic BRAF V600-mutant melanoma, there remains two primary treatment options: targeted therapy and immunotherapy. Targeted therapy or immunotherapy alone is associated with efficacy limitations including efficacy limited to select patient subsets. With separate mechanisms of action and different response patterns, the combination of targeted agents and immunotherapy to treat patients with BRAF V600-mutant melanoma may further improve patient outcomes. Current treatment guidelines recommend treatment with targeted agents alone, immunotherapy, or the combination of targeted agents and immunotherapy. The randomized, double-blind STARBOARD trial aims to evaluate efficacy and safety of encorafenib, binimetinib and pembrolizumab in treatment-naive patients with metastatic or unresectable locally advanced BRAF V600-mutant melanoma in comparison to pembrolizumab.

Targeted therapy, including BRAF- and MEK-inhibitors, and immunotherapies have greatly contributed to advances in the treatment of BRAF-mutant melanoma. Additionally, immunotherapy in combination with targeted therapy has been shown to improve patient outcomes. In this study, the authors assess the efficacy and safety of a combination of a BRAF-inhibitor (encorafenib), an MEK-inhibitor (binimetinib) and an anti-PD-1 (pembrolizumab) in patients with metastatic BRAF-mutant melanoma. Clinical Trial Registration: NCT04657991 (ClinicalTrials.gov).

Treatment considerations for patients with advanced squamous cell carcinoma of the lung: a plain language summary.

What is this article about?: This plain language summary reports the key points of a recent review article that discussed current treatment options for a type of cancer called squamous cell carcinoma (SCC) of the lung. What is SCC of the lung?: SCC of the lung is a type of non-small-cell lung cancer (NSCLC for short) that is usually linked with smoking. It can be difficult to treat because it is often diagnosed after it has spread to other parts of the body. What first-line treatment options are available for people with SCC of the lung?: Most patients receive a combination of chemotherapy and immunotherapy as their first-line treatment (the first treatment they receive after their diagnosis). Immunotherapy drugs have improved how long people with SCC of the lung can live for. However, for most patients, they eventually stop working. At this point, other second-line treatments are considered, meaning treatments patients receive after their first-line treatment is stopped due to side effects or because it no longer works. What second-line treatment options are available to people with SCC of the lung?: Immunotherapy drugs were originally developed as second-line options after chemotherapy. However, immunotherapy drugs are now used with chemotherapies as first-line treatments. This has left a gap for second-line treatment options. There are some drugs available for second-line treatment, such as afatinib, which comes as a tablet, and docetaxel with or without ramucirumab, which is given as an infusion. Other potential treatments are being developed. What emerging treatment options are being developed?: Some early clinical trials of potential treatments have shown promise, but more results are needed. Research into the genetic mutations linked with the development of SCC of the lung is also ongoing. It is hoped that this will help identify patients who might benefit from specific treatments. Who should read this article?: People with SCC of the lung and their caregivers, patient advocates, and healthcare professionals, including those who are helping people learn about scientific discoveries and potential new therapeutic strategies.

Real-world performance of blood-based proteomic profiling in first-line immunotherapy treatment in advanced stage non-small cell lung cancer.

PURPOSE: Immune checkpoint inhibition (ICI) therapy has improved patient outcomes in advanced non-small cell lung cancer (NSCLC), but better biomarkers are needed. A clinically validated, blood-based proteomic test, or host immune classifier (HIC), was assessed for its ability to predict ICI therapy outcomes in this real-world, prospectively designed, observational study. MATERIALS AND METHODS: The prospectively designed, observational registry study INSIGHT (Clinical Effectiveness Assessment of VeriStrat® Testing and Validation of Immunotherapy Tests in NSCLC Subjects) (NCT03289780) includes 35 US sites having enrolled over 3570 NSCLC patients at any stage and line of therapy. After enrolment and prior to therapy initiation, all patients are tested and designated HIC-Hot (HIC-H) or HIC-Cold (HIC-C). A prespecified interim analysis was performed after 1-year follow-up with the first 2000 enrolled patients. We report the overall survival (OS) of patients with advanced stage (IIIB and IV) NSCLC treated in the first-line (ICI-containing therapies n=284; all first-line therapies n=877), by treatment type and in HIC-defined subgroups. RESULTS: OS for HIC-H patients was longer than OS for HIC-C patients across treatment regimens, including ICI. For patients treated with all ICI regimens, median OS was not reached (95% CI 15.4 to undefined months) for HIC-H (n=196) vs 5.0 months (95% CI 2.9 to 6.4) for HIC-C patients (n=88); HR=0.38 (95% CI 0.27 to 0.53), p<0.0001. For ICI monotherapy, OS was 16.8 vs 2.8 months (HR=0.36 (95% CI 0.22 to 0.58), p<0.0001) and for ICI with chemotherapy OS was unreached vs 6.4 months (HR=0.41 (95% CI 0.26 to 0.67), p=0.0003). HIC results were independent of programmed death ligand 1 (PD-L1). In a subgroup with PD-L1 ≥50% and performance status 0-1, HIC stratified survival significantly for ICI monotherapy but not ICI with chemotherapy. CONCLUSION: Blood-based HIC proteomic testing provides clinically meaningful information for immunotherapy treatment decision in NSCLC independent of PD-L1. The data suggest that HIC-C patients should not be treated with ICI alone regardless of their PD-L1 expression.

Advanced Squamous Cell Carcinoma of the Lung: Current Treatment Approaches and the Role of Afatinib.

Options for the treatment of squamous cell lung carcinoma expanded in recent years with the introduction of the immune checkpoint inhibitors into routine clinical practice in both the first- and second-line settings but are still limited. As a result, pembrolizumab, given either alone or in combination with platinum-based chemotherapy, is now a standard first-line treatment for squamous cell lung cancer. However, few options exist once patients have progressed on immune checkpoint inhibitors and chemotherapy. In this setting, the irreversible ErbB family blocker, afatinib, has a potential role as second or subsequent therapy for some patients. The Phase III LUX-Lung 8 study demonstrated that afatinib significantly prolonged progression-free and overall survival compared with erlotinib in patients with squamous cell lung carcinoma. Notably, retrospective, ad-hoc biomarker analyses of a subset of patients from LUX-Lung 8 suggested that patients with ErbB family mutations derived particular benefit from afatinib, especially those with ErbB2 (HER2) mutations. Afatinib has a manageable and predictable safety profile, and adverse events can be managed with the use of a tolerability-guided dose modification protocol. Until more data are available, afatinib could be considered as a potential second-line treatment option for patients who have progressed on combined pembrolizumab and platinum-based chemotherapy and are ineligible for more established second-line options, or as a third-line option in patients who have received first-line immunotherapy, and second-line chemotherapy or chemotherapy and antiangiogenesis therapy. However, further data are required to support the use of afatinib following immunotherapy. Given that treatment options are limited in both of these settings, investigating an agent with an entirely new mechanism of action is warranted. If available, molecular analysis to identify ErbB family mutations or the use of proteomic profiling could help to further isolate patients who are likely to derive the most benefit from afatinib.