On May 28, 2021, the FDA granted accelerated approval to sotorasib (Lumakras, Amgen) for the treatment of adults with advanced non-small cell lung cancer (NSCLC) with a Kirsten rat sarcoma ...proto-oncogene (KRAS) G12C mutation who have received at least one prior systemic therapy. The approval was based on CodeBreaK 100 (Study 20170543), a dose-escalation and dose-expansion trial in patients with an advanced, KRAS G12C-mutated, solid tumor. The overall response rate (ORR) observed in patients with KRAS G12C-mutated NSCLC treated with sotorasib (n = 124) was 36% 95% confidence interval (CI), 28-45. The median duration of response was 10.0 months (95% CI, 6.9-not estimable). The most common adverse reactions (≥20%) were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough. This is the first approval of a targeted therapy for KRAS G12C-mutated NSCLC. Because of pharmacokinetic data and ORRs of patient cohorts who took sotorasib at lower doses in the dose-escalation portion of CodeBreaK 100, a dose comparison study is being conducted as a post-marketing requirement.
The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management ...challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.
On October 2, 2020, FDA approved nivolumab with ipilimumab as first-line treatment for adult patients with unresectable malignant pleural mesothelioma (MPM). The approval was based on results from ...Study CA209743 (CHECKMATE-743), an open-label trial of patients with MPM randomized to receive nivolumab and ipilimumab for up to 2 years (
= 303) or six cycles of chemotherapy with cisplatin or carboplatin plus pemetrexed (
= 302). Overall survival (OS) was improved for patients who received nivolumab and ipilimumab, with a median OS of 18.1 months 95% confidence interval (CI), 16.8-21.5 compared with 14.1 months (95% CI: 12.5-16.2; HR, 0.74; 95% CI, 0.61-0.89;
= 0.002), for patients who received chemotherapy. The magnitude of benefit was larger for patients with non-epithelioid versus epithelioid histology. Additional clinical pharmacology data support an alternative dosing regimen of nivolumab than evaluated in the trial, which will reduce the number of required treatment visits. This application was reviewed under FDA's Project Orbis, in collaboration with Australia's Therapeutic Goods Administration, Switzerland's Swissmedic, Health Canada, and Brazil's National Health Surveillance Agency or ANVISA (Agência Nacional de Vigilância Sanitária). Nivolumab and ipilimumab is the first drug regimen approved by FDA for MPM since 2004.
Lung adenocarcinoma (ADC), the most common lung cancer type, is recognized increasingly as a disease spectrum. To guide individualized patient care, a non-invasive means of distinguishing indolent ...from aggressive ADC subtypes is needed urgently. Computer-Aided Nodule Assessment and Risk Yield (CANARY) is a novel computed tomography (CT) tool that characterizes early ADCs by detecting nine distinct CT voxel classes, representing a spectrum of lepidic to invasive growth, within an ADC. CANARY characterization has been shown to correlate with ADC histology and patient outcomes. This study evaluated the inter-observer variability of CANARY analysis. Three novice observers segmented and analyzed independently 95 biopsy-confirmed lung ADCs from Vanderbilt University Medical Center/Nashville Veterans Administration Tennessee Valley Healthcare system (VUMC/TVHS) and the Mayo Clinic (Mayo). Inter-observer variability was measured using intra-class correlation coefficient (ICC). The average ICC for all CANARY classes was 0.828 (95% CI 0.76, 0.895) for the VUMC/TVHS cohort, and 0.852 (95% CI 0.804, 0.901) for the Mayo cohort. The most invasive voxel classes had the highest ICC values. To determine whether nodule size influenced inter-observer variability, an additional cohort of 49 sub-centimeter nodules from Mayo were also segmented by three observers, with similar ICC results. Our study demonstrates that CANARY ADC classification between novice CANARY users has an acceptably low degree of variability, and supports the further development of CANARY for clinical application.
Radiomics, the science of extracting quantifiable data from routine medical images, is a powerful tool that has many potential applications in oncology. The Response Evaluation Criteria in Solid ...Tumors Working Group (RWG) held a workshop in May 2022, which brought together various stakeholders to discuss the potential role of radiomics in oncology drug development and clinical trials, particularly with respect to response assessment. This article summarizes the results of that workshop, reviewing radiomics for the practicing oncologist and highlighting the work that needs to be done to move forward the incorporation of radiomics into clinical trials.
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Background: Alongside persistent disparities in healthcare outcomes in HO, there is an inability to adequately recruit, maintain and promote a diverse and inclusive work force nationwide. To our ...knowledge, a structured approach to DEI education/recruitment in HO training is lacking. We sought to establish a longitudinal curriculum aimed at educating HO trainees in structural barriers impacting cancer equity and developing tools to enhance Underrepresented in Medicine (URiM) recruitment. Methods: Trainee-led DEI framework was presented to program leadership and officially adopted into the curriculum for the 2021-22 academic year. This consisted of initiatives across 4 domains: 1. Curricular Development (emphasis on disparities during trainee orientation, didactic lectures on cancer disparities, financial toxicity, workforce diversity, pandemic impact on cancer inequities) ; 2. Recruitment & Retention (implicit bias training, targeted recruitment from HBCUs, trainee-led discussions on enhancing recruitment); 3. Engagement & Mentorship (local community mentorship within institution, external mentorship through ASCO URM MSR program); 4. Disparities Research (career guidance sessions with invited faculty, development of registry-based studies to evaluate disparities). Impact of new curriculum was measured through anonymous surveys, at 1, 7, and 12 months during the academic year. A 5-point Likert scale (strongly disagree to strongly agree) was utilized. Results: At baseline, surveyed trainees were predominantly PGY5 (33%), ages 31-40 (66%), and self-identified as White or Caucasian (47%). Over the academic year, trainee recognition of structural barriers that prevented oncologic care delivery increased. More trainees felt departmental/fellowship-wide DEI efforts were transparent and impactful leading to quantifiable changes, and creation of new mentorship opportunities. Trainees rated the following as most helpful to address biases in the workplace: opportunities to mentor minority high school/college-level students, implicit bias training, and formal lectures. Anonymous qualitative feedback from fellows favored small group discussions and encouraged a top-down approach to promoting diversity in leadership. One trainee-mentored URiM medical student presented work at the ASCO annual conference on cancer disparities, while program leadership efforts led to incoming trainee class comprised of 25% URiM. Conclusions: We demonstrate feasibility of a longitudinal DEI curriculum in HO trainee education and recruitment that raises awareness and creates opportunity for URiM. Future efforts will build on this curriculum utilizing trainee feedback and departmental buy-in with the goal of building an oncologic workforce that better reflects the patients we care for.
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Background: While the American Council on Graduate Medical Education (ACGME) set up a Planning Committee for Diversity in GME in 2018, no formalized milestones or training ...mandates have been announced. The nation-wide protests for racial justice following the senseless killings of Breonna Taylor, Ahmaud Arbery and George Floyd further brought to the forefront the need for immediate action to address widespread inequities across graduate medical education, our healthcare system and society as a whole. Therefore, the Johns Hopkins Hematology/Medical Oncology Fellowship Program focused on creating an anti-racism curriculum to foster dialogue on systemic racism and discrimination, grounded in the institutional and geographic context of our training program. Methods: Using the Kern six step curriculum development method, we created a comprehensive anti-racism initiative, which included virtual townhalls with Black alumni of the fellowship, book clubs, readings, and lectures. We sought to deepen the fellowship’s awareness of the impact of racism and inequity upon trainees, underrepresented minority oncologists and hematologists, and patients in order to develop initiatives to confront them productively. Trainees received a survey 6 months after the start of the curriculum to assess the impact of the initiatives upon trainees, and inform iterative changes to the curriculum. Results: 25 of 34 fellows across all post-graduate years (PGY) completed the survey. Fellows agreed that the curriculum was helpful (68%) and encouraging (60%). Collectively, fellows reported that the curriculum increased their awareness of instances of racism in medicine, caused them to think about next steps that the fellowship could take to address racism, and enabled them to identify available resources for support and further education. Respondents selected community engagement and recruitment of diverse fellowship classes as the most pressing priorities for the program. Conclusions: Social justice and anti-racism education belong in the formalized training of our hematology/medical oncology fellows. To this end, our ongoing curricular expansion is focusing on anti-racism training, diverse recruitment and youth mentorship. Collectively, a comprehensive yet program-specific approach facilitates opportunities for learning, engagement and development of the skills necessary to engage in this life-long work for ourselves, our communities and our patients.
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Background: While existing data suggest a detriment of immune checkpoint inhibitors (ICI) in other targetable mutations in non-small cell lung cancer (NSCLC), limited retrospective analyses ...suggest patients with Kirsten rat sarcoma oncogene ( KRAS)-mutated NSCLC benefit from ICI in the front-line (1L). To better define this benefit, pooled data from 12 registrational clinical trials investigating 1L ICI with or without chemotherapy (chemo) in patients with documented KRAS status (mutant or wildtype) was evaluated for efficacy of ICI+chemo, ICI alone, and chemo alone. Methods: Pooled data was evaluated for objective response rate (ORR) and overall survival (OS) by KRAS status (mutant, G12C, or wildtype). ORR and 95% confidence intervals (CI) were estimated using Clopper-Pearson method; median OS was estimated using Kaplan-Meier methods. Subgroup analyses were performed using Cox model stratified by KRAS status and PD-L1 status (Positive (combined positive score (CPS) ≥1), Negative (CPS<1), High (CPS≥50), Low (CPS<50)). Results: KRAS mutational status was reported in 1430 patients (61% wildtype, 39% mutated). KRAS G12C was reported in 11% of patients with a KRAS mutation (157/555). Demographics were similar between KRAS mutated, G12C, and wildtype patients. Amongst all patients, 60% were male, 89% white, 60% positive PD-L1, 67% former or current smokers. Table 1 shows outcomes of chemo+ICI, ICI alone, and chemo alone in each population. Conclusions: This retrospective, pooled analysis suggests that patients with KRAS-mutated NSCLC benefit from 1L chemo-ICI similarly to those with KRAS wild-type NSCLC, and should receive combination therapy upfront. Patients with KRAS-mutated NSCLC derived the greatest benefit from the combination of chemo-ICI as compared to ICI or chemo alone. The small number of patients with documented KRAS G12C mutation limits interpretation of the data for this subgroup. Clinical trials investigating targeted therapies for KRAS-mutated NSCLC in the 1L should include a chemo-ICI comparator arm. Table: see text
9000
Background: FDA-approved 1L treatment options for patients with PD-L1-high advanced NSCLC (PD-L1 score ≥50%) include IO ± chemo (± anti-angiogenics) but it is unclear if chemo substantially ...improves efficacy outcomes when added to IO in this patient population. Methods: Data was pooled from 12 randomized controlled trials that investigated anti-PD-(L)1 regimens ± chemo for the 1L treatment of patients with advanced NSCLC. PD-L1 score was defined as the proportion of tumor cells stained by the assay and analysis was conducted for patients with tumor PD-L1 score ≥50%. OS, PFS, and ORR were compared between chemo-IO and IO alone via a pooled analysis. Median survival times were estimated using Kaplan-Meier methods. Hazard ratios were estimated using Cox proportional hazards models stratified by trial; odds ratios were estimated using a logistic regression model with trial as a covariate. All analyses were adjusted for age, sex, race, ECOG, histology and smoking status. Results: A total of 3,189 patients with NSCLC and PD-L1 score ≥50% were identified for this analysis. Baseline characteristics were: 38% ages 65-74 years and 11% ages ≥75 years; 69% male; 80% White; 66% ECOG ≥1; and 89% former/current smokers. Median OS in the pooled chemo-IO ( N=455) and IO-only ( N=1,298) arms was 25.0 vs 20.9 months (HR 0.82; 95% CI: 0.62, 1.08); median PFS was 9.6 vs 7.1 months, respectively (HR 0.69; 95% CI: 0.55, 0.87). ORR was higher with chemo-IO than with IO alone (61% vs 43%; Odds ratio 1.2, 95% CI: 1.1, 1.3). Conclusions: This exploratory, hypothesis-generating pooled analysis suggests that most subgroups of patients with advanced NSCLC with PD-L1 score ≥50% receiving FDA-approved chemo-IO regimens may have OS and PFS outcomes that are comparable with or better than IO-only regimens. Patients ≥75 years of age receiving chemo-IO may not have improved outcomes over IO. These results support shared decision-making that balances potential benefits and risks of adding chemo to IO regimens based on patient factors that may impact tolerability. Table: see text
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