US Food and Drug Administration Approval Summary: Fam-Trastuzumab Deruxtecan-nxki for Human Epidermal Growth Factor Receptor 2-Low Unresectable or Metastatic Breast Cancer.

PURPOSE: The US Food and Drug Administration approved fam-trastuzumab deruxtecan-nxki (DS-8201a, T-DXd) for the treatment of adult patients with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-low (immunohistochemistry 1 + or immunohistochemistry 2+/in situ hybridization-) breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. PATIENTS AND METHODS: Approval was based on DESTINY-Breast04, a phase III, randomized, open-label, multicenter trial in patients with unresectable or metastatic HER2-low breast cancer, determined at a central laboratory. A total of 557 patients were randomly assigned (2:1) to receive either T-DXd 5.4 mg/kg intravenously once every 3 weeks (n = 373) or physicians' choice of chemotherapy (n = 184). RESULTS: The study met its primary efficacy end point of progression-free survival (PFS) by blinded independent central review assessment in the hormone receptor-positive (HR+) cohort (N = 494) with an estimated hazard ratio (HR) of 0.51(95% CI, 0.40 to 0.64; P < .0001). Key secondary end points were also met, including PFS in the intent-to-treat population with an HR of 0.50 (95% CI, 0.40 to 0.63; P < .0001), overall survival (OS) in the HR+ cohort with an HR of 0.64 (95% CI, 0.48 to 0.86; P = .0028) and OS in the intent-to-treat with an HR of 0.64 (95% CI, 0.49 to 0.84; P = .0010). The safety profile of T-DXd was consistent with previously approved indications, and no new safety signals were observed in this study population. CONCLUSION: The approval of T-DXd in HER2-low metastatic breast cancer was based on statistically significant and clinically meaningful PFS and OS improvements observed in the DESTINY-Breast04 trial and represents the first approved therapy specifically for the treatment of HER2-low metastatic breast cancer.

U.S. FDA Drug Approvals for Gynecological Malignancies: A Decade in Review.

Over the last decade, there has been tremendous progress in the treatment of patients with gynecologic cancers with a changing therapy landscape. This summary provides an overview of U.S. Food and Drug Administration (FDA) approvals for gynecologic cancers from 2010 to 2020, totaling 17 new indications. For each of the approved indications, endpoints, trial design, results, and regulatory considerations are outlined. Among these 17 indications, six received accelerated approval (AA) and 11 received regular approval (RA). As of September 2021, of the six AA, three have subsequently demonstrated clinical benefit resulting in conversion to RA and the remaining three have ongoing clinical trials that have not yet reported results. Approval decisions for these 17 indications were supported by primary efficacy endpoints of progression-free survival (n = 10), objective response rate (n = 6), and overall survival (n = 1) and showed a favorable benefit-risk profile. Among the 17 indications, 15 received priority review and three applications participated in one or more novel Oncology Center of Excellence initiatives, including Real Time Oncology Review, Assessment Aid, and Project Orbis. Current FDA thinking on drug development opportunities and regulatory initiatives currently under way will be discussed.

U.S. FDA Drug Approvals for Breast Cancer: A Decade in Review.

Over the last decade, the treatment of patients with breast cancer has been greatly impacted by the approval of multiple drugs and indications. This summary describes 30 FDA approvals of treatments for breast cancer from 2010 to 2020. The trial design endpoints, results, and regulatory considerations are described for each approved indication. Of the 30 indications, 23 (76.6%) received regular and 7 (23.3%) received accelerated approval. Twenty-six approvals were granted in metastatic breast cancer (MBC) and four in early breast cancer. Approval decisions for the 26 MBC indications were initially supported by progression-free survival (PFS) in 21 (80.8%), overall survival (OS) or a combination of OS and PFS in two (7.7%), and objective response rate (ORR) in three (11.5%). The four approvals in early breast cancer utilized pathologic complete response (pCR) in one (25%) and invasive disease-free survival (iDFS) in three (75%) trials. Among the 30 indications, 22 received priority review, seven were granted Breakthrough Therapy Designation, and 10 applications participated in one or more pilot Oncology Center of Excellence regulatory review initiatives, including Real Time Oncology Review, Assessment Aid, and Project Orbis. FDA initiatives to advance breast cancer drug development are also described.

FDA Approval Summary: Fam-Trastuzumab Deruxtecan-Nxki for the Treatment of Unresectable or Metastatic HER2-Positive Breast Cancer.

On December 20, 2019, the FDA granted accelerated approval to fam-trastuzumab deruxtecan-nxki [DS-8201a; T-DXd; tradename ENHERTU (Daiichi Sankyo)] for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. Approval was based on data from study DS8201-A-U201 (DESTINY-Breast01) with supportive safety data from study DS8201-A-J101. The primary efficacy endpoint in DESTINY-Breast01 was overall response rate (ORR) based on confirmed responses by blinded independent central review (ICR) using RECIST v1.1 in all participants who were assigned to receive the recommended dose of 5.4 mg/kg while secondary endpoints included duration of response (DoR). The confirmed ORR based on ICR in these 184 patients was 60.3% [95% confidence interval (CI): 52.9-67.4] and the median DoR was 14.8 months (95% CI: 13.8-16.9). Interstitial lung disease, including pneumonitis, was experienced in patients treated with T-DXd and can be severe, life threatening, or fatal. In addition, neutropenia and left ventricular dysfunction were included as Warnings and Precautions in labeling. Other important common adverse reactions were nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anemia, diarrhea, and thrombocytopenia. Overall, the totality of efficacy and safety data supported the accelerated approval of T-DXd for the intended indication.

FDA Approval Summary: Alpelisib Plus Fulvestrant for Patients with HR-positive, HER2-negative, PIK3CA-mutated, Advanced or Metastatic Breast Cancer.

On May 24, 2019, the FDA granted regular approval to alpelisib in combination with fulvestrant for postmenopausal women, and men, with hormone receptor (HR)-positive, HER2-negative, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutated, advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or after an endocrine-based regimen. Approval was based on the SOLAR-1 study, a randomized, double-blind, placebo-controlled trial of alpelisib plus fulvestrant versus placebo plus fulvestrant. The primary endpoint was investigator-assessed progression-free survival (PFS) per RECIST v1.1 in the cohort of trial participants whose tumors had a PIK3CA mutation. The estimated median PFS by investigator assessment in the alpelisib plus fulvestrant arm was 11 months [95% confidence interval (CI), 7.5-14.5] compared with 5.7 months (95% CI, 3.7-7.4) in the placebo plus fulvestrant arm (HR, 0.65; 95% CI, 0.50-0.85; two-sided P = 0.001). The median overall survival was not yet reached for the alpelisib plus fulvestrant arm (95% CI, 28.1-NE) and was 26.9 months (95% CI, 21.9-NE) for the fulvestrant control arm. No PFS benefit was observed in trial participants whose tumors did not have a PIK3CA mutation (HR, 0.85; 95% CI, 0.58-1.25). The most common adverse reactions, including laboratory abnormalities, on the alpelisib plus fulvestrant arm were increased glucose, increased creatinine, diarrhea, rash, decreased lymphocyte count, increased gamma glutamyl transferase, nausea, increased alanine aminotransferase, fatigue, decreased hemoglobin, increased lipase, decreased appetite, stomatitis, vomiting, decreased weight, decreased calcium, decreased glucose, prolonged activated partial thromboplastin time, and alopecia.

FDA Approval Summary: Olaparib Monotherapy or in Combination with Bevacizumab for the Maintenance Treatment of Patients with Advanced Ovarian Cancer.

On December 19, 2018, the U.S. Food and Drug Administration (FDA) granted approval to olaparib monotherapy for first-line maintenance treatment of BRCA-mutated (BRCAm) advanced ovarian cancer and, on May 8, 2020, expanded the indication of olaparib to include its use in combination with bevacizumab for first-line maintenance treatment of homologous recombination deficient (HRD)-positive advanced ovarian cancer. Both these approvals were based on randomized, double-blind, placebo-controlled trials. Approval for olaparib monotherapy was based on the SOLO-1 trial, comparing the efficacy of olaparib versus placebo in patients with BRCAm advanced ovarian, fallopian tube, or primary peritoneal cancer after surgical cytoreduction and first-line platinum-based chemotherapy. Two companion diagnostic (CDx) tests were approved with this indication: BRACAnalysis CDx, for germline BRCA1/2 alterations, and FoundationOne CDx, for BRCA1/2 alterations in tissue specimens. Approval for olaparib in combination with bevacizumab was based on the results of the PAOLA-1 trial that compared olaparib with bevacizumab versus placebo plus bevacizumab in patients with advanced high-grade epithelial ovarian cancer, fallopian tube, or primary peritoneal cancer after first-line platinum-based chemotherapy and bevacizumab. Myriad myChoice CDx was designated as a companion diagnostic device for use of olaparib plus bevacizumab combination for ovarian cancer associated with HRD-positive status. Both trials demonstrated clinically meaningful improvements in progression-free survival and favorable benefit-risk profiles for the indicated populations. This article summarizes the FDA thought process and data supporting the approval of olaparib as monotherapy and in combination with bevacizumab for maintenance therapy in this setting. IMPLICATIONS FOR PRACTICE: These approvals represent the first poly (ADP-ribose) polymerase inhibitor, alone or in combination with bevacizumab, approved in first-line maintenance treatment of women with advanced ovarian cancer after cytoreductive surgery and chemotherapy. In patients with BRCA-mutated tumors, olaparib monotherapy demonstrated a 70% reduction in the risk of disease progression or death compared with placebo, and olaparib in combination with bevacizumab demonstrated a 67% reduction in the risk of disease progression or death compared with bevacizumab alone in homologous recombination deficient-positive tumors. These approvals represent a major advance for the treatment of women with advanced ovarian cancer who are in complete or partial response after their initial platinum-based chemotherapy.

FDA Approval Summary: Atezolizumab Plus Paclitaxel Protein-bound for the Treatment of Patients with Advanced or Metastatic TNBC Whose Tumors Express PD-L1.

On March 8, 2019, the FDA granted accelerated approval to atezolizumab in combination with paclitaxel protein-bound for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 [PD-L1 stained tumor-infiltrating immune cells (IC) of any intensity covering ≥1% of the tumor area], as determined by an FDA-approved test. Approval was based on data from IMpassion130, which randomized patients to receive atezolizumab or placebo in combination with paclitaxel protein-bound. Investigator-assessed progression-free survival (PFS) in the intent-to-treat (ITT) and PD-L1-positive populations were coprimary endpoints. After 13-month median follow-up, the estimated median PFS in the PD-L1-positive population was 7.4 months in the atezolizumab arm and 4.8 months in the placebo arm [HR = 0.60; 95% confidence interval (CI), 0.48-0.77]. Overall survival (OS) results were immature with 43% deaths in the ITT population, representing 59% of the OS events required to perform the final OS analysis. Adverse reactions occurring in ≥20% of patients receiving atezolizumab with paclitaxel protein-bound were alopecia, peripheral neuropathies, fatigue, nausea, diarrhea, anemia, constipation, cough, headache, neutropenia, vomiting, and decreased appetite. Accelerated approval was appropriate taking into account the unmet medical need along with the immaturity of the OS results and potential for PFS in the PD-L1-expressing population to predict clinical benefit.

The risk of hypertension after preoperative discontinuation of angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists in ambulatory and same-day admission patients.

BACKGROUND: The continued use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II subtype I receptor antagonists (ARBs) medications in the preoperative period has been reported to be associated with intraoperative hypotension that can be unresponsive to pressor drugs. As a result, several investigators suggested discontinuation of these medications before scheduled surgery but did not report on unintended consequences that might result from discontinuation. We conducted a prospective, single-blind, randomized trial to observe the effect of the medications on preoperative arterial blood pressure recordings in patients presenting for ambulatory and same-day surgery. METHODS: Six hundred forty-four patients presenting for ambulatory and same-day surgery were enrolled prospectively between 2006 and 2011 and randomly assigned to 2 groups based on continuation or discontinuation of ACEIs and ARBs. An intention-to-treat analysis was performed. The primary outcome was presence of hypertension (HTN) immediately before surgery. Secondary outcomes included surgical cancellations due to HTN, prolongation of hospitalization, adverse clinical events, and HTN in the postoperative period. RESULTS: Data for 526 patients were analyzed. There were 262 patients in the discontinuation group and 264 patients in the continuation group. Discontinuation of ACEIs and ARBs on the day of surgery was not associated with increased prevalence of preoperative HTN (P = 0.775). The upper bound of a 95% confidence interval for the difference in prevalence of Stage 1 and 2 HTN between study arms indicates that discontinuation of study medication is unlikely to be associated with an increase in Stage 1 HTN of >4.8 percentage points and in Stage 2 HTN of no >5.8 percentage points. Discontinuation was not associated with an increase in postoperative HTN, with prolongation of hospitalization or with adverse clinical events. CONCLUSIONS: Discontinuing ACEIs and ARBs in patients on the day of surgery did not result in a substantively increased incidence of pre- or postoperative HTN compared with patients who continued these medications on the day of surgery. The results provide an evidentiary basis for the safety of discontinuing ACEIs and ARBs on the day of surgery without increasing adverse hemodynamic outcomes.

Primary myeloid sarcoma masquerading as an obstructing duodenal carcinoma.

Myeloid Sarcoma (MS), a rare extra hematopoietic carcinoma composed of blast cells, is located primarily in extramedullary sites such as skin, soft tissue, lymph nodes, and bone. MS usually presents in the setting of coexisting acute myeloid leukemia (AML) and myeloproliferative disorders. Gastrointestinal involvement (GI) is extremely rare from nonspecific abdominal symptoms to obstruction. Eight cases of myeloid sarcoma involving the duodenum including the current case have been reported, overall mean age being 40 years (range 17-71) and M : F ratio 7 : 1. The prognosis of patients with de novo MS cases has been reported to be better than those who have a coexisting leukemia. MS is a rare extramedullary tumor, which should be considered in the differential diagnosis of a soft tissue mass involving the duodenum, especially if there is a coexisting hematological disorder. De novo cases often progress to AML, and current therapy involves Daunorubicin- and Cytarabine-based chemotherapy. The wide cytogenetic and molecular heterogeneity of MS implies a potential role for more targeted MS therapies, which may offer a curative strategy.

Cutting edge: inhibition of T cell activation by TIM-2.

T cell Ig and mucin domain protein 2 (TIM-2) has been shown to regulate T cell activation in vitro and T cell-mediated disease in vivo. However, it is still not clear whether TIM-2 acts mainly to augment T cell function or to inhibit it. We have directly examined the function of TIM-2 in murine and human T cell lines. Our results indicate that expression of TIM-2 significantly impairs the induction of NFAT and AP-1 transcriptional reporters by not only TCR ligation but also by the pharmacological stimuli PMA and ionomycin. This does not appear to be due to a general effect on cell viability, and the block in NFAT activation can be bypassed by expression of activated alleles of Ras or calcineurin, or MEK kinase, in the case of AP-1. Thus, our data are consistent with a model whereby TIM-2 inhibits T cell activation.

CARMA1 is required for Akt-mediated NF-kappaB activation in T cells.

Many details of the generic pathway for induction of NF-kappaB have been delineated, but it is still not clear how multiple, diverse receptor systems are able to converge on this evolutionarily conserved family of transcription factors. Recent studies have shown that the CARMA1, Bcl10, and MALT1 proteins are critical for coupling the common elements of the NF-kappaB pathway to the T-cell receptor (TCR) and CD28. We previously demonstrated a role for the serine/threonine kinase Akt in CD28-mediated NF-kappaB induction. Using a CARMA1-deficient T-cell line, we have now found that the CARMA complex is required for induction of NF-kappaB by Akt, in cooperation with protein kinase C activation. Furthermore, using a novel selective inhibitor of Akt, we confirm that Akt plays a modulatory role in NF-kappaB induction by the TCR and CD28. Finally, we provide evidence for a physical and functional interaction between Akt and CARMA and for Akt-dependent phosphorylation of Bcl10. Therefore, in T cells, Akt impinges upon NF-kappaB signaling through at least two separate mechanisms.