Analyses Adjusting for Selective Crossover Show Improved Overall Survival With Adjuvant Letrozole Compared With Tamoxifen in the BIG 1-98 Study

Overall Survival Update From IMvigor130 on Atezolizumab Versus Chemotherapy for Advanced Urothelial Carcinoma

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Aristotelis Bamias, MD, PhD, of the National and Kapodistrian University of Athens, and colleagues reported on their final overall survival analysis of the phase III IMvigor130 study during the 2023 American Society of Clinical Oncology (ASCO) Genitourinary (GU) Cancers Symposium (Abstract LBA441). “Atezolizumab monotherapy continued to show better tolerability versus chemotherapy with no new safety concerns,” they noted. “These exploratory data support the benefit-risk ratio of atezolizumab monotherapy versus chemotherapy for first-line cisplatin-ineligible PD-L1–high metastatic urothelial carcinoma.”

The investigators focused on patients with previously untreated, PD-L1–high, locally advanced or metastatic urothelial carcinoma. Participants were randomly assigned to receive atezolizumab monotherapy (n = 360) or placebo plus platinum chemotherapy (n = 359).

Data cutoff occurred 49 months after the last patient was randomly assigned. Although there was no apparent overall survival benefit among the intent-to-treat population, the cisplatin-ineligible, PD-L1–high subgroup demonstrated a hazard ratio of 0.56. Similar rates of overall survival at 24 months were reported in both treatment groups (32% vs. 34%). Despite participants on chemotherapy achieving a better objective response rate than those on atezolizumab (44% vs. 24%), the duration of response was short-lived (8.1 vs. 29.6 months).

Among the cisplatin-ineligible population, however, the objective response rate was slightly improved among patients on atezolizumab (40%) compared with those on chemotherapy (33%); the median duration of response was not evaluable and 6.2 months, respectively.

Most patients treated with chemotherapy had grade 3 to 4 treatment-related adverse events (80%), whereas 16% of individuals receiving atezolizumab alone reported similar events. Of note, grade 3 to 4 adverse events of special interest affected 10% and 4% of patients in the atezolizumab and chemotherapy groups, respectively.

Overall Survival With Daratumumab, Lenalidomide, and Dexamethasone in Previously Treated Multiple Myeloma (POLLUX): A Randomized, Open-Label, Phase III Trial.

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PURPOSE: With the initial analysis of POLLUX at a median follow-up of 13.5 months, daratumumab in combination with lenalidomide and dexamethasone (D-Rd) significantly prolonged progression-free survival versus lenalidomide and dexamethasone (Rd) alone in patients with relapsed or refractory multiple myeloma (RRMM). We report updated efficacy and safety results at the time of final analysis for overall survival (OS).

METHODS: POLLUX was a multicenter, randomized, open-label, phase III study during which eligible patients with = 1 line of prior therapy were randomly assigned 1:1 to D-Rd or Rd until disease progression or unacceptable toxicity. After positive primary analysis and protocol amendment, patients receiving Rd were offered daratumumab monotherapy after disease progression.

RESULTS: Significant OS benefit was observed with D-Rd (hazard ratio, 0.73; 95% CI, 0.58 to 0.91; P = .0044) at a median (range) follow-up of 79.7 (0.0-86.5) months. The median OS was 67.6 months for D-Rd compared with 51.8 months for Rd. Prespecified analyses demonstrated an improved OS with D-Rd versus Rd in most subgroups, including patients age = 65 years and patients with one, two, or three prior lines of therapy, International Staging System stage III disease, high-risk cytogenetic abnormalities, and refractoriness to their last prior line of therapy or a proteasome inhibitor. The most common (= 10%) grade 3/4 treatment-emergent adverse events with D-Rd versus Rd were neutropenia (57.6% v 41.6%), anemia (19.8% v 22.4%), pneumonia (17.3% v 11.0%), thrombocytopenia (15.5% v 15.7%), and diarrhea (10.2% v 3.9%).

CONCLUSION: D-Rd significantly extended OS versus Rd alone in patients with RRMM. To our knowledge, for the first time, our findings, together with the OS benefit observed with daratumumab plus bortezomib and dexamethasone in the phase III CASTOR trial, demonstrate OS improvement with daratumumab-containing regimens in RRMM (ClinicalTrials.gov identifier: NCT02076009 [POLLUX]).

Analyses Adjusting for Selective Crossover Show Improved Overall Survival With Adjuvant Letrozole Compared With Tamoxifen in the BIG 1-98 Study

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Among postmenopausal women with endocrine-responsive breast cancer, the aromatase inhibitor letrozole, when compared with tamoxifen, has been shown to significantly improve disease-free survival (DFS) and time to distant recurrence (TDR). We investigated whether letrozole monotherapy prolonged overall survival (OS) compared with tamoxifen monotherapy. PATIENTS AND METHODS Of 8,010 postmenopausal women with hormone receptor-positive, early breast cancer enrolled on the Breast International Group (BIG) 1-98 study, 4,922 were randomly assigned to 5 years of continuous adjuvant therapy with either letrozole or tamoxifen. Of 2,459 patients enrolled in the tamoxifen treatment arm, 619 (25.2%) selectively crossed over to either adjuvant or extended letrozole after initial trial results were presented in January 2005. To gain better estimates of relative treatment effects in the presence of selective crossover, we used inverse probability of censoring weighted (IPCW) modeling. Results Weighted Cox models, by using IPCW, estimated a statistically significant, 18% reduction in the hazard of an OS event with letrozole treatment (hazard ratio [HR], 0.82; 95% CI, 0.70 to 0.95). Estimates of 5-year OS on the basis of IPCW were 91.8% and 90.4% for letrozole and tamoxifen, respectively. The HRs of DFS and TDR events by using IPCW modeling were 0.83 (95% CI, 0.74 to 0.94) and 0.80 (95% CI, 0.67 to 0.94), respectively (P < .05 for DFS, OS, and TDR). Median follow-up was 74 months. CONCLUSION Adjuvant treatment with letrozole, compared with tamoxifen, significantly reduces the risk of death, the risk of recurrent disease, and the risk of recurrence at distant sites in postmenopausal women with hormone receptor-positive breast cancer.

source: JCO