Laleh Amiri-Kordestani

In 2020, despite challenges related to the COVID-19 pandemic, the US FDA approved 30 new drugs and biologic agents, 45 supplemental drug and biologic applications and 1 biosimilar application in oncology.

1073 Background: There is significant heterogeneity in the natural history of MBC. Several recent randomized CT have yielded statistically significant advantages for the experimental arm, but neither led to regulatory approval nor practice change. Formal guidance for industry on CT endpoints provided by the US FDA in 2007 was not disease-specific. Patient-focused drug development is mandated by Prescription Drug User Fee Act V. Our WG sought to create specific consensus on endpoints for MBC CT focusing on subtype and line of therapy, with sensitivity to various stakeholders. Methods: A WG composed of medical oncologists, statisticians, advocates, FDA and NCI liaisons performed a systematic literature review of MBC natural history, CT endpoints by subtype (HR+/HER2-, HR+/HER+, HR-/HER2-, HR-/HER2+), and line of therapy (n = 146 papers). External expertise was obtained on industry perspectives, big data and real world evidence (RWE), and patient reported outcomes (PROs). WG members voted anonymously on statements and positions generated from deliberation. Results: The WG reached consensus on definitions relevant to contemporary CT endpoints. WG recommendations on the appropriate choice of OS or PFS are sensitive to expected post progression survival (PPS), and proportional and absolute gains. Currently, for HR-/HER2- MBC, OS is preferred as the optimal primary endpoint regardless of line of therapy; PFS is preferred in settings where expected PPS is longer. Toxicity can outweigh modest gains in PFS; scant data exist to gauge how patients value PFS gain vs toxicity. Where new agents may prolong PFS without impacting OS, exploring/validating graphic approaches that capture grade and timing of toxicity and PROs is warranted. An overview of WG Consensus Statements will be presented in detail. Conclusions: CT design for MBC should be sensitive to natural history (PPS), availability of other effective agents, PROs and toxicity burden. As unique subtypes (e.g. AR+) and novel therapies (e.g. immunotherapy) emerge, reassessment of relevant benchmarks is indicated. Rigorous big data approaches providing insights from RWE may inform CT endpoints in the future.

Purpose Improved therapies and imaging modalities are needed for the treatment of breast cancer brain metastases (BCBM). ANG1005 is a drug conjugate consisting of paclitaxel covalently linked to Angiopep-2, designed to cross the blood–brain barrier. We conducted a biomarker substudy to evaluate ¹⁸F-FLT–PET for response assessment. Methods Ten patients with measurable BCBM received ANG1005 at a dose of 550 mg/m² IV every 21 days. Before and after cycle 1, patients underwent PET imaging with ¹⁸F-FLT, a thymidine analog, retention of which reflects cellular proliferation, for comparison with gadolinium-contrast magnetic resonance imaging (Gd-MRI) in brain metastases detection and response assessment. A 20 % change in uptake after one cycle of ANG1005 was deemed significant. Results Thirty-two target and twenty non-target metastatic brain lesions were analyzed. The median tumor reduction by MRI after cycle 1 was −17.5 % (n = 10 patients, lower, upper quartiles: −25.5, −4.8 %) in target lesion size compared with baseline. Fifteen of twenty-nine target lesions (52 %) and 12/20 nontarget lesions (60 %) showed a ≥20 % decrease post-therapy in FLT–PET SUV change (odds ratio 0.71, 95 % CI: 0.19, 2.61). The median percentage change in SUV_max was −20.9 % (n = 29 lesions; lower, upper quartiles: −42.4, 2.0 %), and the median percentage change in SUV₈₀ was also −20.9 % (n = 29; lower, upper quartiles: −49.0, 0.0 %). Two patients had confirmed partial responses by PET and MRI lasting 6 and 18 cycles, respectively. Seven patients had stable disease, receiving a median of six cycles. Conclusions ANG1005 warrants further study in BCBM. Results demonstrated a moderately strong association between MRI and ¹⁸F-FLT–PET imaging.

E18091 Background: CBR is commonly used as one the secondary endpoints in many cancer clinical trials. There are no comprehensive analyses to demonstrate that CBR adds to the value of the conventional time-to-event efficacy endpoints of progression-free and overall survival (PFS and OS) in clinical trials, and to date, CBR data are not reported in the clinical studies section of the U.S. package inserts for products approved for the treatment of MBC. We conducted a pooled analysis of data from MBC trials submitted to the FDA to understand the association of CBR with PFS and OS. In this analysis, CBR is defined as the percentage of patients with MBC who have achieved complete response, partial response or stable disease ≥ 6 months. Methods: We identified 13 trials of experimental agents with 10,263 patients submitted for treatment of MBC in initial or supplemental New Drug or Biologics License Applications since 2005. Criteria for inclusion of the trials in this analysis were: randomized, active-controlled, multicenter. The estimated PFS hazard ratio (HR) and OS HR versus the estimated odds ratio (OR) of CBR on the log-scale was calculated. Weighted least square regression analyses (weight equal to the number of patients) were performed on log-transformed effects. Responder analysis was performed to compare PFS and OS between patients with and without CBR, irrespective of the treatment assignment. Hazard ratios and 95% confidence intervals of PFS and OS were calculated from stratified Cox regression models with study as a stratification factor. Results: In trial level analysis, there was a moderate association between PFS HR and CBR OR (R² = 0.52) and little to no association between OS HR and CBR OR (R² = 0.01). Based on the responder analysis, in the patient level, the CBR was positively associated with PFS (HR = 0.078, 95% CI: 0.073, 0.084) and OS (HR = 0.32, 95% CI: 0.301, 0.340). Conclusions: There was a moderate association between CBR and PFS. An association between CBR and OS was not established. There is insufficient evidence to add CBR in product labeling if PFS and/or OS are reported.

On September 30, 2013, the FDA granted accelerated approval to pertuzumab (Perjecta; Genentech, Inc.) for use in combination with trastuzumab and docetaxel as neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. The approval was based in part on a randomized multicenter trial in the indicated population that allocated 417 patients to neoadjuvant treatment with trastuzumab–docetaxel (TD), pertuzumab–trastuzumab–docetaxel (PTD), pertuzumab–trastuzumab, or pertuzumab–docetaxel. PTD was administered preoperatively every 3 weeks for four cycles. Following surgery patients received three cycles of 5-fluorouracil, epirubicin, and cyclophosphamide every 3 weeks and trastuzumab every 3 weeks to complete 1 year of therapy. The pathologic complete response rates by the FDA-preferred definition [absence of invasive cancer in the breast and lymph nodes (ypT0/is ypN0)] were 39.3% and 21.5% in the PTD and the TD arms, respectively (P = 0.0063). The most common adverse reactions with PTD were alopecia, diarrhea, nausea, and neutropenia. This approval was based on the totality of evidence, particularly improved survival in the metastatic breast cancer trial, and a fully accrued confirmatory trial. Clin Cancer Res; 20(21); 5359–64. ©2014 AACR.

On February 22, 2013, the FDA licensed ado-trastuzumab emtansine (Kadcyla; Genentech, Inc.) for use as a single agent for the treatment of patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer (MBC) who previously received trastuzumab and a taxane, separately or in combination. The clinical basis for licensure was a phase III trial in 991 patients with HER2-positive MBC that randomly allocated patients to receive ado-trastuzumab emtansine (n = 495) or lapatinib in combination with capecitabine (n = 496). The coprimary endpoints were progression-free survival (PFS) based on tumor assessments by an independent review committee and overall survival (OS). Statistically significant improvements in PFS and OS were observed in patients receiving ado-trastuzumab emtansine compared with patients receiving lapatinib plus capecitabine [difference in PFS medians of 3.2 months, HR, 0.65 (95% confidence interval, CI, 0.55–0.77), P < 0.0001 and difference in OS medians of 5.8 months, HR, 0.68 (95% CI, 0.55–0.85), P = 0.0006]. The most common adverse reactions in patients receiving ado-trastuzumab emtansine were fatigue, nausea, musculoskeletal pain, thrombocytopenia, headache, increased aminotransferase levels, and constipation. Other significant adverse reactions included hepatobiliary disorders and left ventricular dysfunction. Given the PFS and OS results, the benefit–risk profile was considered favorable. Clin Cancer Res; 20(17); 4436–41. ©2014 AACR.