Research matters

When you’re focusing on the future of cancer care, it helps to start with a clear and accurate picture of the present.

Breast Cancer
Andrew L. Pecora MD, Andrew Ip MD MS, Ching-Kun Wang MD, Stuart L. Goldberg MD, Andre H. Goy MD, Lili Brillstein, MPH, CEO, Glenn Pomerantz MD JD, Michael B. Atkins MD, and Donald M. Berwick MD
We have previously described a digital classification schema (Cota Nodal Address [CNA]) which incorporates validated prognostic elements. We propose to demonstrate that reducing variation in cancer care among similar patients might lead to decreased costs without affecting clinical benefit. Identifying variation is difficult under claims-based coding systems (i.e. ICD-10) that group cancer subtypes. We aim to use the CNA model to investigate variations in care.
Sai-Hong Ignatius Ou, Jin-Liern Hong, Petros Christopoulos, Huamao M Lin, Sylvie Vincent, Eric N Churchill, Junpei Soeda, Daniel Kazdal, Albrecht Stenzinger, Michael Thomas
EGFR exon 20 insertion (ex20ins) mutations represent 5% to 10% of EGFR mutations in NSCLC. Identifying patients with EGFR ex20ins is challenging owing to the limited coverage of polymerase chain reaction (PCR) assays and the relatively recent use of next-generation sequencing (NGS). This study analyzes the spectrum of EGFR ex20ins variants in a large patient population from a global clinical trial and several real-world cohorts and the ability of PCR kits to identify these alterations.
Mehdi Hamadani, Laura Liao, Tony Yang, Lei Chen, Craig Moskowitz
The treatment landscape for diffuse large B-cell lymphoma (DLBCL) has recently changed. We examined characteristics and clinical outcomes of DLBCL patients who initiated a third (3L) and fourth (4L) line of therapy during a contemporary time frame.
Anna Minchom, Santiago Viteri, Lyudmila Bazhenova, Shirish M. Gadgeel, Sai-Hong Ignatius Ou, José Trigo, Joshua M. Bauml, Daniel Backenroth, Archan Bhattacharya, Tracy Li, Parthiv Mahadevia, Nicolas Girard
In the single-arm CHRYSALIS study, amivantamab showed durable responses and manageable safety in patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertion mutations (ex20ins) who progressed on prior platinum-based chemotherapy. External controls can provide context for interpreting amivantamab efficacy.
Peter Feng Wanga, Christopher W. Yee, Boris Gorsh, Miriam L. Zichlin, Prani Paka, Rachel H. Bhak, Natalie Boytsov, Anamika Khanal, Ahmed Noman, Maral DerSarkissian, Shannon Ferrante, Mei Sheng Duh
Patients with relapsed/refractory multiple myeloma (RRMM) resistant to multiple drug classes remain a high unmet need population. This longitudinal retrospective cohort study assessed real-world treatment patterns and outcomes in adults with RRMM. Patients who had three or more prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (double-exposed) were further categorized as refractory to a PI and an immunomodulatory agent (double-class refractory, n = 381) or additionally to an anti-CD38 monoclonal antibody (triple-class refractory, n = 173). Treatment options are limited for patients with double-class or triple-class refractory disease. Retreatment is a part of standard of care. Bortezomib and lenalidomide had the highest retreatment rates among double-class and triple-class refractory patients. Survival outcomes remain poor among RRMM patients with median overall survival (OS) of 22.3 and 11.6 months for double-class refractory and triple-class refractory patients, respectively. This study highlights the need for novel efficacious therapies in this heavily pretreated RRMM population.
Dina Oksen, Patricia Prince, Emmanuelle Boutmy, Elizabeth M. Garry, Barbara Ellers-Lenz, Adina Estrin, Andreas Johne, Patrice Verpillat, Nicolle M. Gatto
Real-world data (RWD) reflecting patient treatment in routine clinical practice can be used to develop external control groups for single-arm trials. External controls can provide valuable benchmark results on potential comparator drug effectiveness, particularly in rare indications when randomized controlled trials are either infeasible or unethical. This paper describes lessons learned from a descriptive real-world external control cohort study conducted to provide benchmark data for a single-arm clinical trial in a rare oncology biomarker driven disease. Conducting external control cohort studies to evaluate treatment effectiveness in rare indications likely will present data and analysis challenges as seen in the example study. However, there are mitigating measures that can be applied in the study design, identification of RWD sources, and data analysis. The lessons learned and reported here with a proposal of an external control study framework can provide guidance for future research in this area, and may be applicable as well in other rare indications. Taking these learnings into consideration, the use of real-world external controls to contextualize treatment effectiveness in rare indications is a valuable approach and warrants further application in the future.
Benjamin A.Derman, Andrew J.Bellib, Minoo Battiwalla, Mehdi Hamadani, Ankit Kansagra, Hillard M.Lazarus, Ching-KunWang
The landscape for evidence generation in hematologic malignancies is rapidly evolving. While randomized controlled trials (RCTs) remain the gold standard in support of drug efficacy, approval and use, the supplemental use of real-world data (RWD), generated as part of routine healthcare delivery, and real-world evidence (RWE), the insights derived from RWD, in this setting has become increasingly common. There is a wide variety of sources of RWD, each with its own strengths and weaknesses that need to be considered when determining its appropriate use in RWE generation. RWD and RWE have historically been utilized in the post-approval setting to assess real-world application, efficacy, and safety of approved therapies. However, due to increasing awareness of the advantages of additional sources of information, RWE sourced from clinical data are being increasingly used to provide context for regulatory decision-making across several diseases including hematologic malignancies. Today, many commercial vendors offer fully aggregated, de-identified and standardized real-world clinical data. To maximize the potential of RWD and RWE, important considerations are needed to ensure patient privacy and to reduce the potential for biases and residual confounding. Continued collaboration among researchers, regulators and industry partners are needed to optimize evidence generation to ensure that new therapies reach patients as quickly and safely as possible.
Donna R. Rivera, Henry J. Henk, Elizabeth Garrett-Mayer, Jennifer B. Christian, Andrew J. Belli, Suanna S. Bruinooge, Janet L. Espirito, Connor Sweetnam, Monika A. Izano, Yanina Natanzon, Nicholas J. Robert, Mark S. Walker, Aaron B. Cohen, Marley Boyd, Lindsey Enewold, Eric Hansen, Rebecca Honnold, Lawrence Kushi, Pallavi S. Mishra Kalyani, Ruth Pe Benito, Lori C. Sakoda, Elad Sharon, Olga Tymejczyk, Emily Valice, Joseph Wagner, Laura Lasiter, Jeff D. Allen
The purpose of this study was to evaluate the potential collective opportunities and challenges of transforming real-world data (RWD) to real-world evidence for clinical effectiveness by focusing on aligning analytic definitions of oncology end points. Patients treated with a qualifying therapy for advanced non-small cell lung cancer in the frontline setting meeting broad eligibility criteria were included to reflect the real-world population. Although a trend toward improved outcomes in patients receiving PD-(L)1 therapy over standard chemotherapy was observed in RWD analyses, the magnitude and consistency of treatment effect was more heterogeneous than previously observed in controlled clinical trials. The study design and analysis process highlighted the identification of pertinent methodological issues and potential innovative approaches that could inform the development of high-quality RWD studies.
Laura Lasiter, Olga Tymejczyk, Elizabeth Garrett-Mayer, Shrujal Baxi, Andrew J. Belli, Marley Boyd, Jennifer B. Christian, Aaron B. Cohen, Janet L. Espirito, Eric Hansen, Connor Sweetnam, Nicholas J. Robert, Mackenzie Small, Mark D. Stewart, Monika A. Izano, Joseph Wagner, Yanina Natanzon, Donna R. Rivera, Jeff Allen
In prior work, Friends of Cancer Research convened multiple data partners to establish standardized definitions for oncology real-world end points derived from electronic health records (EHRs) and claims data. Here, we assessed the performance of real-world overall survival (rwOS) from data sets sourced from EHRs by evaluating the ability of the end point to reflect expected differences from a previous randomized controlled trial across five data sources, after applying inclusion/exclusion criteria. The KEYNOTE-189 clinical trial protocol of platinum doublet chemotherapy (chemotherapy) vs. programmed cell death protein 1 (PD-1) in combination with platinum doublet chemotherapy (PD-1 combination) in first-line nonsquamous metastatic non-small cell lung cancer guided retrospective cohort selection. The Kaplan-Meier product limit estimator was used to calculate 12-month rwOS with 95% confidence intervals (CIs) in each data source. Cox proportional hazards models estimated hazard ratios (HRs) and associated 95% CIs, controlled for prognostic factors. Once the inclusion/exclusion criteria were applied, the five resulting data sets included 155 to 1,501 patients in the chemotherapy cohort and 36 to 405 patients in the PD-1 combination cohort. Twelve-month rwOS ranged from 45% to 58% in the chemotherapy cohort and 44% to 68% in the PD-1 combination cohort. The adjusted HR for death ranged from 0.80 (95% CI: 0.69, 0.93) to 1.15 (95% CI: 0.71, 1.85), controlling for age, gender, performance status, and smoking status. This study yielded insights regarding data capture, including ability of real-world data to precisely identify patient populations and the impact of criteria on end points. Sensitivity analyses could elucidate data set–specific factors that drive results.
Sundar Jagannath, Yi Lin, Hartmut Goldschmidt, Donna Reece, Ajay Nooka, Alicia Senin, Paula Rodriguez-Otero, Ray Powles, Kosei Matsue, Nina Shah, Larry D. Anderson Jr, Matthew Streetly, Kimberly Wilson, Hoa Van Le, Arlene S. Swern, Amit Agarwal, David S. Siegel
Patients with relapsed and refractory multiple myeloma (RRMM) who are triple-class exposed (to an immunomodulatory agent, proteasome inhibitor, and anti-CD38 antibody) have limited treatment options and there is no standard of care. Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T-cell therapy, demonstrated efficacy in triple-class exposed RRMM patients in the KarMMa trial (NCT03361748). In this retrospective study (KarMMa-RW), patient-level data from triple-class exposed RRMM patients were merged into a single data model and compared with KarMMa using trimmed stabilized inverse probability of treatment weighting. Endpoints included overall response rate (ORR; primary), rate of very good partial response or better (≥VGPR), progression-free survival (PFS), and overall survival (OS). Of 1949 real-world triple-class exposed RRMM patients, 190 received subsequent (index) line of therapy and met KarMMa eligibility criteria (Eligible RRMM cohort). With a median follow-up of 13.3 months in KarMMa and 10.2 months in Eligible RRMM, ORR, and ≥VGPR were significantly improved in KarMMa versus Eligible RRMM (ORR, 76.4% vs 32.2%; ≥VGPR, 57.9% vs 13.7%; both P < 0.0001) as were PFS (11.6 vs 3.5 months; P = 0.0004) and OS (20.2 vs 14.7 months; P = 0.0006). This study demonstrated that ide-cel significantly improved responses and survival compared with currently available therapies in triple-class exposed RRMM.

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