T-DM1 is an antibody drug conjugate that combines trastuzumab with emtansine via a stable thioether linker. In two phase III clinical trials, EMILIA and TH3RESA, T-DM1 was shown to be effective in HER2-positive metastatic breast cancer patients who had progressed to taxanes and trastuzumab. We have performed a real-world study to complement the findings of the clinical trials. From 2012 to 2016, 15 patients with HER2-positive breast cancer who had progressed to prior treatment received T-DM1 at our center. We have retrospectively analyzed outcomes in these patients and compared our findings with those of the two clinical trials. Progression-free survival (PFS) was 10 months compared with the 9.6 months of the EMILIA trial and the 6.2 months of the TH3RESA trial, overall survival was 34 months compared with the 29.9 months of the EMILIA trial and the 22.7 months of the TH3RESA trial. PFS was ≥12 months in five patients, three of whom attained a PFS of ≥23 months. Among five patients with metastases of the central nervous system, PFS was six months, OS was not reached, and the objective response rate was 80%. Our findings are in line with those of the EMILIA study and slightly superior to those of the TH3RESA study. In our series of patients, T-DM1 has demonstrated efficacy in the treatment of HER2-positive metastatic breast cancer. Our real-world data thus confirm and support the findings of the two major phase III trials and indicate the usefulness of T-DM1 in routine clinical practice.
Sterile alpha motif and histidine-aspartic acid domain-containing protein 1 (SAMHD1) is a dNTP triphosphohydrolase involved in the regulation of the intracellular dNTP pool, linked to viral restriction, cancer development and autoimmune disorders. SAMHD1 function is regulated by phosphorylation through a mechanism controlled by cyclin-dependent kinases and tightly linked to cell cycle progression. Recently, SAMHD1 has been shown to decrease the efficacy of nucleotide analogs used as chemotherapeutic drugs. Here, we demonstrate that SAMHD1 can enhance or decrease the efficacy of various classes of anticancer drug, including nucleotide analogues, but also anti-folate drugs and CDK inhibitors. Importantly, we show that selective CDK4/6 inhibitors are pharmacological activators of SAMHD1 that act by inhibiting its inactivation by phosphorylation. Combinations of a CDK4/6 inhibitor with nucleoside or folate antimetabolites potently enhanced drug efficacy, resulting in highly synergic drug combinations (CI < 0.04). Mechanistic analyses reveal that cell cycle-controlled modulation of SAMHD1 function is the central process explaining changes in anticancer drug efficacy, therefore providing functional proof of the potential of CDK4/6 inhibitors as a new class of adjuvants to boost chemotherapeutic regimens. The evaluation of SAMHD1 expression in cancer tissues allowed for the identification of cancer types that would benefit from the pharmacological modulation of SAMHD1 function. In conclusion, these results indicate that the modulation of SAMHD1 function may represent a promising strategy for the improvement of current antimetabolite-based treatments.
Background: Approximately 30% to 40% of patients (pts) with HER2[+] advanced breast cancer (ABC) will develop brain metastases (BM) during the course of their disease. Trastuzumab deruxtecan (T-DXd; DS-8201) is an antibody-drug conjugate containing an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a topoisomerase I inhibitor payload. In the phase 2 DESTINY-Breast01 trial, T-DXd showed efficacy in the subgroup of HER2[+] ABC pts with stable BM at baseline. DEBBRAH is assessing the efficacy and safety of T-DXd in HER2[+] and HER2-low-expressing ABC pts with a history of BM and/or leptomeningeal carcinomatosis (LMC). Here, we report primary results from cohorts A and C. Methods: This is an ongoing, multicenter, open-label, 5-cohort, non-comparative, phase 2 study across 18 hospitals in 2 countries. A total of 39 pts aged ≥18 years with pretreated HER2[+] or HER2-low-expressing ABC with stable, progressing, or untreated BM and/or LMC are being enrolled in 5 cohorts: (A) HER2[+] ABC with non-progressing BM after radiotherapy and/or surgery; (B) HER2[+] or HER2-low-expressing ABC with asymptomatic untreated BM; (C) HER2[+] ABC with progressing BM after local treatment; (D) HER2-low-expressing ABC with progressing BM after local treatment; (E) HER2[+] or HER2-low-expressing ABC with LMC. In cohorts A and C, pts must have received prior taxane and ≥1 HER2-targeted therapy for ABC. Pts received 5.4 mg/kg T-DXd intravenously on day 1 of a 21-day cycle until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint for cohort A is 16-week progression-free survival (PFS) per local assessment using RANO-BM for central nervous system (CNS) lesions and RECIST v.1.1 for extracranial lesions (H0: 5%); for cohort C, CNS overall response rate (ORR; H0: 10%). A single-arm binomial design is used for cohorts A and C. A futility interim analysis has been planned in cohort A after accrual of 4 pts. Sample size was planned to attain an 80% power at nominal level of one-sided α of 0.05 in each cohort. Results: Between Jun 29, 2020, and Feb 18, 2021, 26 pts were allocated in the study. Enrollment is complete in cohorts A (n=8 pts) and C (n=9 pts), and ongoing in the remaining cohorts. At data cutoff (May 21, 2021), median follow-up for the cohort A was 5.5 months (IQR 4.4-6.9) and 6.2 months (IQR 5.1-6.4) for the cohort C. In the cohort A, 6 (75.0%) of 8 pts were alive without disease progression at 16 weeks, reaching the primary endpoint (p<0.01). In the cohort C, the CNS ORR was 55.6% (5 pts with partial response), also meeting the primary endpoint (p<0.01). At the time of this analysis, 75.0% of pts of the cohort A and 55.6% of the cohort C remained on therapy. The most frequent adverse events of any grade in 26 pts who received at least 1 dose of T-DXd were fatigue (11 [42.3%]; 3.8% of grade 3), nausea (10 [38.5%]), a decreased neutrophil count (9 [34.6%]; 11.5% of grade 3), and anemia (6 [23.1%]). Treatment-related serious adverse events occurred in 1 (3.8%) of 26 pts due to grade 1 pneumonitis. No treatment-related deaths were reported. Conclusions: T-DXd demonstrated preliminary efficacy with manageable toxicity in pretreated pts with HER2[+] ABC with stable and progressing BM after local treatment. Further investigation is required in larger cohorts to validate these findings. The assessment of the T-DXd antitumor activity in cohorts B, D, and E is currently ongoing. Citation Format: Marta Vaz Batista, Patricia Cortez, Manuel Ruiz, Juan Miguel Cejalvo, Juan de la Haba, Laia Garrigós, Fabricio Racca, Sonia Servitja, Salvador Blanch, Iris Teruel, José Manuel Pérez-García, María Gion, Monica Nave, Antonio Llombart-Cussac, Miguel Sampayo-Cordero, Andrea Malfettone, Javier Cortes, Sofia Braga. Trastuzumab deruxtecan in patients with HER2[+] or HER2-low-expressing advanced breast cancer and central nervous system involvement: Preliminary results from the DEBBRAH phase 2 study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD4-06.
Background: Despite impressive progression-free survival (PFS) results from PARP inhibitors (PARPi) in ovarian cancer, concerns about their effect on post-progression treatment outcomes have recently arisen, particularly when administered in the relapsed setting. Overlapping mechanisms of resistance between PARPi and platinum have been described, and optimal therapies upon progression to PARPi are unknown. We communicate real-world data (RWD) on outcomes of subsequent chemotherapy upon progression to PARPi used as maintenance in ovarian cancer relapses, particularly focusing on platinum rechallenge, according to BRCA status. Methods: Data from high-grade serous or endometrioid ovarian cancer patients who received subsequent chemotherapy after progression to maintenance PARPi in the relapsed setting, in 16 Catalan hospitals between August 2016 and April 2021, and who were followed-up until July 2021, were included. Endpoints were overall response rate (ORR), and PFS and overall survival (OS) measured from the subsequent chemotherapy starting date. Results: 111 patients were included [46 (41.4%) presented pathological BRCA1/2 mutations, 8 (7.5%) in other homologous recombination-related genes]. Sixty-four patients (57.7%) had received two prior chemotherapy lines, including the one immediately prior to PARPi. PARPi were niraparib (n = 60, 54.1%), olaparib (n = 49, 44.1%), and rucaparib (n = 2, 1.8%). A total of 81 patients remained platinum-sensitive (PS population) after progression to PARPi (when progression-free interval [PFI] was >6 months after the last cycle of prior platinum) [median PFI 12.0 months (interquartile range, IQR, 8.8–17.1)]. Of those, 74 were treated with subsequent platinum regimens, with the following results: ORR of 41.9%, median PFS (mPFS) of 6.6 months (95% CI 6–9.2), and median OS (mOS) of 20.6 months (95% CI 13.6–28.9). Analysis of these 74 patients according to BRCA status showed that PFIs for BRCA mutant and non BRCA-mutant patients were 13.6 [IQR11.2–22.2] and 10.3 [IQR 7.4–14.9] months, respectively (p = 0.010); ORR were 40.0% versus 43.6%, respectively; Rates of progression (as best response) to subsequent platinum were 45.7% versus 17.9%, respectively (p = 0.004); mPFS and mOS were 3.5 (95% CI 2.5–8.6) versus 7.5 months (95% CI 6.5–10.1, p = 0.03), and 16.4 (95% CI 9.3–27.5) versus 24.2 months (95% CI 17.2–NR, p = 0.036), respectively. Conclusion: This is the largest series of real-world data on ovarian cancer patients retreated with platinum in the post-PARPi scenario, separately analyzing BRCA mutant and non-mutant patients, to our knowledge. In our platinum-sensitive population, rechallenge with platinum after progression upon PARPi in the 3rd or later lines for ovarian cancer relapses shows relevant ORR and similar PFS outcomes to historical series of the prePARPi era. However, BRCA mutant patients presented significantly higher rates of progression under subsequent platinum and worse survival outcomes associated with subsequent platinum than non-BRCA-mutant patients.
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