Dan James

ABSTRACT: The efficacy and safety of acalabrutinib plus obinutuzumab and acalabrutinib monotherapy vs zanubrutinib in patients with treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma without del(17p) were compared using an unanchored matching-adjusted indirect comparison. Individual patient-level data from ELEVATE-TN (acalabrutinib plus obinutuzumab, n = 162; acalabrutinib monotherapy, n = 163) were weighted to match published aggregate baseline data from SEQUOIA cohort 1, which excluded patients with del(17p) (zanubrutinib, n = 241), using variables that were prognostic/predictive of investigator-assessed progression-free survival (INV-PFS) in an exploratory Cox regression analysis of ELEVATE-TN. After matching, INV-PFS was longer with acalabrutinib plus obinutuzumab (hazard ratio [HR], 0.41; 95% confidence interval [CI], 0.23-0.74) and comparable with acalabrutinib monotherapy (HR, 0.91; 95% CI, 0.53-1.56) vs zanubrutinib. Acalabrutinib monotherapy had significantly lower odds of any grade hypertension vs zanubrutinib (odds ratio [OR], 0.44; 95% CI, 0.20-0.99), whereas acalabrutinib plus obinutuzumab had significantly higher odds of neutropenia (OR, 2.19; 95% CI, 1.33-3.60) and arthralgia (OR, 2.33; 95% CI, 1.37-3.96) vs zanubrutinib. No other significant differences in safety were observed. In summary, acalabrutinib plus obinutuzumab had longer INV-PFS with increased odds of neutropenia and arthralgia than zanubrutinib, whereas acalabrutinib monotherapy had similar INV-PFS with lower odds of any grade hypertension. These trials were registered at www.ClinicalTrials.gov as #NCT02475681 and #NCT03336333.

Introduction The second-generation Bruton tyrosine kinase inhibitors acalabrutinib (acala) and zanubrutinib (zanu) have not been compared with each other in a head-to-head randomized controlled trial (RCT). Acala with and without obinutuzumab (obin) was evaluated in the ELEVATE-TN RCT in treatment-naïve patients with chronic lymphocytic leukemia (CLL). Zanu was evaluated in treatment-naïve patients with CLL/small lymphocytic leukemia (SLL) in cohorts 1 and 2 of the SEQUOIA RCT. We used an unanchored matching-adjusted indirect comparison (MAIC) to compare the efficacy and safety of acala ± obin versus zanu in patients with treatment-naïve CLL/SLL without del(17p). Datasets were derived from comprehensive individual patient data (IPD) from ELEVATE-TN and published aggregate data from cohort 1 in SEQUOIA. Methods In this unanchored MAIC, we weighted IPD for the acala + obin and acala monotherapy arms from ELEVATE-TN to match zanu baseline data from SEQUOIA. We excluded patients with del(17p) in ELEVATE-TN to match cohort 1 in SEQUOIA, which excluded patients with del(17p). Patients were matched based on variables considered prognostic and/or predictive of investigator-assessed progression-free survival (INV-PFS) in an exploratory multivariate Cox-regression analysis of ELEVATE-TN. These were age, ECOG status, Binet stage, bulky disease, B2 microglobulin, cytopenia, del(11q), trisomy 12, IGHV status,and TP53 mutation. The efficacy analysis assessed INV-PFS in randomized patients (acala + obin, n = 162; acala monotherapy, n = 163; zanu, n = 241) using the Oct 2021 data cut-off (DCO) for ELEVATE-TN and the Oct 2022 DCO for SEQUOIA (median follow-up 58 versus 44 months). Pseudo-IPD for INV-PFS for zanu were obtained from Kaplan-Meier curves. The safety analysis assessed the incidence of adverse events (AEs) and reported the odds ratios (ORs) of AEs in treated patients (acala + obin, n = 162; acala monotherapy, n = 162; zanu, n = 240). To compare the incidence of AEs, the ELEVATE-TN Sep 2020 DCO was used to match the median follow-up from the SEQUOIA Oct 2022 DCO (47 versus 44 months). Results In the efficacy analysis, the acala + obin and acala monotherapy effective sample sizes (ESSs) post-matching were 124 (76%) and 105 (64%), respectively. Matching had little impact on acala + obin and acala monotherapy INV-PFS (Figure 1). Post-matching, 36-month INV-PFS was higher with acala + obin (95%; 95% CI: 90-97) than with zanu (84%; 95% CI: 79-88). The MAIC-weighted Cox hazard ratio (HR) found INV-PFS to be superior with acala + obin versus zanu (HR: 0.41; 95% CI: 0.23-0.74; Figure 1). No evidence of a difference between acala monotherapy post-matching and zanu was found when looking at 36-month INV-PFS (86%; 95% CI: 78-91 versus 84%; 95% CI: 79-88; HR: 0.91; 95% CI: 0.53-1.56). In the safety analysis, the acala + obin and acala monotherapy ESSs post-matching were 123 (76%) and 103 (64%), respectively. There were no significant differences in the odds of having most types of AE with acala + obin versus zanu, except for higher odds of having any grade neutropenia (OR: 2.19; 95% CI: 1.33-3.60) and arthralgia (OR: 2.33; 95% CI: 1.37-3.96). Acala monotherapy showed lower odds of having any grade hypertension (OR: 0.44, 95% CI: 0.20-0.99; Figure 2) and no significant differences in the odds of having other types of AEs versus zanu. Conclusions In this MAIC of ELEVATE-TN and SEQUOIA evaluating patients with treatment-naïve CLL/SLL without del(17p), acala + obin had a longer INV-PFS versus zanu, while there was no evidence of a difference between acala monotherapy and zanu. Acala + obin and acala monotherapy generally had similar safety profiles to zanu. However, acala monotherapy was associated with lower odds of any grade hypertension versus zanu, while acala + obin was associated with higher odds of any grade neutropenia and arthralgia versus zanu. Although the results of MAIC analyses can only be hypothesis-generating, these results address an important data gap by systematically comparing these two commonly used regimens where randomized, prospective data are not available.

Among patients with unresectable stage III non-small cell lung cancer (NSCLC), those whose tumors harbor epidermal growth factor receptor mutations (EGFRm) are associated with comparatively fewer treatment options and worse prognosis. With the recent approval of targeted treatment, characterizing the economic burden and EGFRm testing and provider referral patterns is crucial to understanding the unmet needs of these patients. This was a retrospective analysis of Optum’s Market Clarity Dataset from January 1, 2018 to June 30, 2023. Eligibility criteria included diagnosis with unresectable stage III EGFRm NSCLC and chemoradiotherapy (CRT) initiation (index date) within 90 days. Primary outcomes were per patient per month (PPPM) all-cause and NSCLC-related health care resource utilization (HCRU) and costs, and EGFRm testing and provider referral patterns. A total of 144 patients were followed for a median of 15.5 months; 56.3% of patients underwent EGFRm testing before CRT initiation. All-cause and NSCLC-related costs during follow-up were $28,020 and $22,816 PPPM, respectively. Ambulatory utilization was the major driver of this economic burden. Pharmacy costs accounted for $4244 (15.1%) and $3736 (16.4%) of the total all-cause and NSCLC-related costs, respectively. Between diagnosis and CRT initiation, the most common specialties visited were oncology/hematology (seen by 67.4% of patients), radiology (26.4%), pulmonology (22.2%), and cardiology (21.5%). Patients who visited three or more specialties on separate days before CRT initiation had a median time to CRT initiation of 33.0 days versus 22.0 days when patients visited multiple specialties on the same day (suggestive of a multidisciplinary care team, MDT). Patients with unresectable stage III EGFRm NSCLC incur substantial economic burden, especially in ambulatory HCRU and costs. With the recent approval of targeted treatment for these patients, reflex EGFRm testing in all early-stage NSCLC at diagnosis is encouraged. Our results also suggest MDT involvement may improve completeness in diagnosis and staging, resulting in acceleration of treatment planning and management. Chemotherapy followed by radiotherapy, known as chemoradiotherapy (CRT), is recommended as the most appropriate treatment for patients with unresectable (inoperable) stage III non-small cell lung cancer (NSCLC). In the USA, 10–15% of patients with unresectable stage III NSCLC have tumors that contain a mutation in the epidermal growth factor receptor gene (known as EGFRm NSCLC). EGFR is a protein that controls cell growth and division. Osimertinib has emerged as a promising new treatment for patients with EGFRm, but little is known about their needs and course of treatment. Our study assessed the economic burden, provider referral patterns, and mutation testing patterns associated with treatment in the era prior to osimertinib’s approval. We used insurance claims and electronic health records to identify 144 patients with EGFRm and unresectable stage III NSCLC. After initiating CRT, costs averaged $28,020 per patient per month, mostly attributable to ambulatory (office/outpatient) visits (49.0% of total costs) and medications (15.1%). Between NSCLC diagnosis and CRT initiation, patients most frequently visited oncology/hematology specialists (seen by 67.4% of patients). Suggestive of a multidisciplinary team of providers, 13 patients (9.0%) had same-day consultations with multiple specialties before CRT initiation. The median time to CRT initiation from diagnosis was 11 days earlier than patients who saw three or more specialists in sequential order. Although all patients had EGFRm, only 76.4% of testing claims occurred before CRT initiation. To improve patient care and treatment access, multidisciplinary provider consultations and EGFR testing prior to CRT initiation are encouraged.