TBCRC 018: phase II study of iniparib in combination with irinotecan to treat progressive triple negative breast cancer brain metastases

Nearly half of patients with advanced triple negative breast cancer (TNBC) develop brain metastases (BM) and most will also have uncontrolled extracranial disease. This study evaluated the safety and efficacy of iniparib, a small molecule anti-cancer agent that alters reactive oxygen species tumor metabolism and penetrates the blood brain barrier, with the topoisomerase I inhibitor irinotecan in patients with TNBC-BM. Eligible patients had TNBC with new or progressive BM and received irinotecan and iniparib every 3weeks. Time to progression (TTP) was the primary end point; secondary endpoints were response rate (RR), clinical benefit rate (CBR), overall survival (OS), toxicity, and health-related quality of life. Correlative endpoints included molecular subtyping and gene expression studies on pre-treatment archival tissues, and determination of germline BRCA1/2 status. Thirty-seven patients began treatment; 34 were evaluable for efficacy. Five of 24 patients were known to carry a BRCA germline mutation (4 BRCA1, 1 BRCA2). Median TTP was 2.14months and median OS was 7.8months. Intracranial RR was 12%, while intracranial CBR was 27%. Treatment was well-tolerated; the most common grade 3/4 adverse events were neutropenia and fatigue. Grade 3/4 diarrhea was rare (3%). Intrinsic subtyping revealed 19 of 21 tumors (79%) were basal-like, and intracranial response was associated with high expression of proliferation-related genes. This study suggests a modest benefit of irinotecan plus iniparib in progressive TNBC-BM. More importantly, this trial design is feasible and lays the foundation for additional studies for this treatment-refractory disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-014-3039-y) contains supplementary material, which is available to authorized users

TBCRC 018: phase II study of iniparib in combination with irinotecan to treat progressive triple negative breast cancer brain metastases

Nearly half of patients with advanced triple negative breast cancer (TNBC) develop brain metastases (BM) and most will also have uncontrolled extracranial disease. This study evaluated the safety and efficacy of iniparib, a small molecule anti-cancer agent that alters reactive oxygen species tumor metabolism and penetrates the blood brain barrier, with the topoisomerase I inhibitor irinotecan in patients with TNBC-BM. Eligible patients had TNBC with new or progressive BM and received irinotecan and iniparib every 3 weeks. Time to progression (TTP) was the primary end point; secondary endpoints were response rate (RR), clinical benefit rate (CBR), overall survival (OS), toxicity, and health-related quality of life. Correlative endpoints included molecular subtyping and gene expression studies on pre-treatment archival tissues, and determination of germline BRCA1/2 status. Thirty-seven patients began treatment; 34 were evaluable for efficacy. Five of 24 patients were known to carry a BRCA germline mutation (4 BRCA1, 1 BRCA2). Median TTP was 2.14 months and median OS was 7.8 months. Intracranial RR was 12 %, while intracranial CBR was 27 %. Treatment was well-tolerated; the most common grade 3/4 adverse events were neutropenia and fatigue. Grade 3/4 diarrhea was rare (3 %). Intrinsic subtyping revealed 19 of 21 tumors (79 %) were basal-like, and intracranial response was associated with high expression of proliferation-related genes. This study suggests a modest benefit of irinotecan plus iniparib in progressive TNBC-BM. More importantly, this trial design is feasible and lays the foundation for additional studies for this treatment-refractory disease. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10549-014-3039-y) contains supplementary material, which is available to authorized users

EV-101: A Phase I Study of Single-Agent Enfortumab Vedotin in Patients With Nectin-4-Positive Solid Tumors, Including Metastatic Urothelial Carcinoma

To assess the safety/tolerability and antitumor activity of enfortumab vedotin (EV), a novel investigational antibody-drug conjugate that delivers the microtubule-disrupting agent, monomethyl auristatin E, to cells that express Nectin-4. EV-101 is a phase I dose escalation/expansion study that enrolled patients with Nectin-4-expressing solid tumors (eg, metastatic urothelial carcinoma [mUC]) who progressed on ≥ 1 prior chemotherapy regimen and/or programmed death-1 receptor/programmed death ligand-1 [PD-(L)1] inhibitor, including a cohort of patients with mUC who received prior anti-PD-(L)1 therapy. Patients received escalating doses of EV up to 1.25 mg/kg on days 1, 8, and 15 of every 28-day cycle. Primary objectives were evaluation of safety/tolerability and pharmacokinetics; antitumor activity was a secondary objective. Enrolled patients with mUC (n = 155) were heavily pretreated, with 96% having prior platinum-based chemotherapy and 29% receiving ≥ 3 lines of prior treatment. Maximum tolerated dose of EV was not established; however, the recommended phase II dose was identified as 1.25 mg/kg. Rash, peripheral neuropathy, fatigue, alopecia, and nausea were the most common treatment-related adverse events (TRAEs); the most common TRAEs were grade 1-2 in severity. Among the 112 patients with mUC treated with single-agent EV 1.25 mg/kg, the investigator-assessed confirmed objective response rate (ORR) was 43%, and duration of response was 7.4 months. Median overall survival (OS) was 12.3 months, and the OS rate at 1 year was 51.8%. Similar ORR and estimated median OS were observed in patients ≥ 75 years of age with and without prior anti-PD-(L)1 treatment, liver metastases, or upper-tract disease. Single-agent EV was generally well tolerated and provided clinically meaningful and durable responses in patients with mUC; survival data are encouraging. A pivotal phase II and a confirmatory phase III study are ongoing

A phase I study of enfortumab vedotin (ASG-22CE; ASG-22ME): Updated analysis of patients with metastatic urothelial cancer

106 Background: Enfortumab vedotin, an antibody–drug conjugate, delivers monomethyl auristatin E to tumors expressing Nectin-4, which is overexpressed in metastatic urothelial cancer (mUC). Methods: This Phase I study (NCT02091999) enrolled patients (pts) with solid tumors, including pts with mUC, treated with ≥1 prior chemotherapy regimen. All pts received different dose levels of IV enfortumab vedotin (0.5, 0.75, 1, 1.25 mg/kg) once weekly for 3 out of 4 wks. Nectin-4 expression was determined by IHC on archival tumor specimens and quantified by histochemical scoring (H-score). Primary endpoint was tolerability; secondary endpoint was antitumor activity assessed every 8 wks per RECIST v1.1. Results: As of 3 Jan 2017, 68 pts with mUC (46 M/22 F; median age, 67 yr [range: 41–84]) had been treated. Of these, 62% received ≥2 prior therapies in the metastatic setting and 40% had prior immune checkpoint inhibitor (CPI) therapy. In these pts, Nectin-4 expression was high and prevalent (median H-score, 280 [range: 32–300]). Treatment-related adverse events (TRAEs) were reported in 58 pts (85%); diarrhea, fatigue, nausea, and pruritus were TRAEs reported in ≥25% of pts. Most TRAEs were grade ≤2 in severity; 19 pts (28%) experienced a TRAE of grade ≥3. The most common grade ≥3 AEs (occurring in ≥5 pts), regardless of attribution to treatment, were urinary tract infection (10%) and hypophosphatemia (9%). No treatment-related deaths have occurred. Sixty pts had ≥1 post-baseline assessment. Antitumor activity was observed across the dose range; overall response rate (ORR) was 40% (95% CI: 27.6–53.5) for all evaluable pts (n = 60), 46% (95% CI: 25.6–67.2) in pts with prior CPI exposure (n = 24), and 44% (95% CI: 19.8–70.1) in pts with metastasis to the liver (n = 16). Complete responses were noted in 3 pts at doses ≥1 mg/kg. Median treatment duration was 26 wks (range: 5.1–64.6), median duration of response was 18 wks (95% CI: 8.4–40.1), and median progression-free survival was 17 wks (95% CI: 15.1–23.3). Study enrollment is ongoing. Conclusions: Enfortumab vedotin demonstrated a favorable tolerability profile with encouraging antitumor activity in heavily pretreated mUC, including pts for whom CPIs have failed. Clinical trial information: NCT02091999

Mature results from EV-101: A phase I study of enfortumab vedotin in patients with metastatic urothelial cancer (mUC)

377 Background: Enfortumab vedotin (EV) is an antibody\u96drug conjugate that delivers MMAE, a microtubule disrupting agent, to tumors expressing Nectin-4, a protein found on most urothelial cancers. Preliminary results of the EV-101 study (NCT02091999) suggest EV is active and tolerable. Methods: Patients with mUC treated with ≥1 prior chemotherapy, or those ineligible for cisplatin, received EV 1.25 mg/kg on Day 1, 8, and 15 every 28 day cycle. The primary objective was tolerability; antitumor activity (ORR per RECIST v1.1), assessed every 8 wk, was a secondary objective. Results: As of14 Sept 2018,112 pts with mUC received EV with a median follow up of 13.4 mo. Bladder was the primary tumor site in 86 pts (77%) and 33 (29.5%) had liver metastases (LM). Nearly all pts received prior platinum chemotherapy; 89 (79.5%) received prior anti-PD(L)1. EV was well tolerated; fatigue (53%), alopecia (46%), and decreased appetite (42%) were the most commonly reported treatment-related AEs (TRAEs). Anemia (8%), hyponatremia (7%), UTI (7%), and hyperglycemia (6%) were the grade ≥3 AEs reported in ≥5% of pts regardless of attribution; 4 fatal TRAEs were reported (respiratory failure, urinary tract obstruction, diabetic ketoacidosis, multi-organ failure). Confirmed ORR was 42% (CR, n = 5; PR, n = 42). Among responders, median duration of response was 7.7 mo (95% CI 5.6, 9.6) and 23.4% of responses were ongoing with a median follow up of 11.3 mo. Estimated median PFS and OS were 5.4 mo (95% CI 5.1, 6.3) and 12.5 mo (95% CI 9.3, 16.1), respectively; OS at 1 yr was 51.8%. Similar results were seen in pts with prior anti-PD(L)1 and with LM (Table). Conclusions: Single-agent EV was generally well tolerated and provided encouraging response and survival data in a population with an unmet medical need including pts with LM, which is associated with poor prognosis. Phase 2 and 3 monotherapy studies as well as evaluation of combination therapies are ongoing. Clinical trial information: NCT02091999. [Table: see text

Enfortumab vedotin (EV) in patients (Pts) with metastatic urothelial carcinoma (mUC) with prior checkpoint inhibitor (CPI) failure: A prospective cohort of an ongoing phase 1 study

431 Background: EV is an ADC that selectively targets and kills cells expressing Nectin-4 by delivering a potent microtubule-disrupting agent, monomethyl auristatin E. As mUC tumors express Nectin-4 in almost all pts, the EV clinical profile was assessed in an ongoing Phase 1 study (NCT02091999) at the recommended phase 2 dose (RP2D; 1.25 mg/kg) in mUC pts with CPI failure, a population with a high unmet medical need. Methods: Pts with mUC, treated with ≥1 prior chemotherapy or who were ineligible for platinum chemotherapy, and who had disease progression after CPI therapy received an IV infusion of EV at RP2D on Days 1, 8, and 15 of each 28-day cycle. Primary endpoint was tolerability; a secondary endpoint was investigator-assessed antitumor activity per RECIST v1.1. Results: As of 2 Oct 2017, 62 pts with mUC and prior CPI failure received EV at RP2D (48 M/14 F; median age, 68 yr [range: 41–83]; ECOG 0/1 29%/71%). Primary tumor site was bladder in 73% pts; 63% pts had visceral and 27% had liver metastasis (LM). Most pts (71%) had ≥2 prior therapies in the metastatic setting, including platinum (87%) or taxanes (26%). CPI was the most recent therapy in 76% pts; time from last CPI to first EV dose was < 12 wk for 58% pts. Median treatment duration was 14.8 wk (range: 1.6–40.4); 39 pts continue treatment. Treatment-related AEs occurring in ≥30% pts were fatigue, rash, nausea, alopecia, decreased appetite and diarrhea; most grade ≤2. Grade ≥3 AE reported in ≥5% pts, regardless of attribution, was hyponatremia (6.5%). One fatal AE (respiratory failure) was possibly treatment related. Response evaluable pts (n = 54) had ≥1 post baseline scan or discontinued prior to scan. ORR (confirmed + unconfirmed) was 54% (95% CI: 39.6–67.4); 15 pts had a confirmed PR, 5 had unconfirmed PR, and 9 are pending subsequent assessment. This ORR is similar to CPI-naïve pts (59%; 95% CI: 36.4–79.3). ORR from 17 evaluable pts with LM was 41% (95% CI: 18.4–67.1). Conclusions: EV is tolerable and exhibits antitumor activity in a cohort of pts with mUC and disease progression after CPI. A phase 2 study assessing EV in this population with high unmet need has been initiated (NCT03219333; EV-201 study). Clinical trial information: NCT02091999