Paul Richards

Phase III Study of Iniparib Plus Gemcitabine and Carboplatin Versus Gemcitabine and Carboplatin in Patients With Metastatic Triple-Negative Breast Cancer

PURPOSE There is a lack of treatments providing survival benefit for patients with metastatic triple-negative breast cancer (mTNBC), with no standard of care. A randomized phase II trial showed significant benefit for gemcitabine, carboplatin, and iniparib (GCI) over gemcitabine and carboplatin (GC) in clinical benefit rate, response rate, progression-free survival (PFS), and overall survival (OS). Here, we formally compare the efficacy of these regimens in a phase III trial. PATIENTS AND METHODS Patients with stage IV/locally recurrent TNBC who had received no more than two previous chemotherapy regimens for mTNBC were randomly allocated to gemcitabine 1,000 mg/m(2) and carboplatin area under the curve 2 (days 1 and 8) alone or GC plus iniparib 5.6 mg/kg (days 1, 4, 8, and 11) every 3 weeks. Random assignment was stratified by the number of prior chemotherapies. The coprimary end points were OS and PFS. Patients receiving GC could cross over to iniparib on progression. RESULTS Five hundred nineteen patients were randomly assigned (261 GCI; 258 GC). In the primary analysis, no statistically significant difference was observed for OS (hazard ratio [HR] = 0.88; 95% CI, 0.69 to 1.12; P = .28) nor PFS (HR = 0.79; 95% CI, 0.65 to 0.98; P = .027). An exploratory analysis showed that patients in the second-/third-line had improved OS (HR = 0.65; 95% CI, 0.46 to 0.91) and PFS (HR = 0.68; 95% CI, 0.50 to 0.92) with GCI. The safety profile for GCI was similar to GC. CONCLUSION The trial did not meet the prespecified criteria for the coprimary end points of PFS and OS in the ITT population. The potential benefit with iniparib observed in second-/third-line subgroup warrants further evaluation.

Gemcitabine, Carboplatin, and Paclitaxel for Patients With Carcinoma of Unknown Primary Site: A Minnie Pearl Cancer Research Network Study

PURPOSE To evaluate the efficacy and toxicity of the novel chemotherapy combination that includes gemcitabine, carboplatin, and paclitaxel in the treatment of patients with carcinoma of unknown primary site. PATIENTS AND METHODS One hundred twenty patients were treated with the following regimen, administered every 21 days for a planned four courses: gemcitabine 1,000 mg/m(2) intravenously (i.v.) on days 1 and 8, carboplatin at an estimated area under the concentration-time curve of 5 mg min/mL i.v. on day 1, and paclitaxel 200 mg/m(2) i.v. on day 1. After four courses, stable and responding patients were given weekly paclitaxel 70 mg/m(2) i.v. for 6 weeks for three 8-week courses. All patients had relatively poor prognostic features. Sixty-three patients had well-differentiated adenocarcinoma, 56 patients had poorly differentiated carcinoma, and 104 patients had performance status of 0 or 1. RESULTS Twenty-eight (25%) of 113 assessable patients (95% confidence interval, 22% to 30%) had major objective responses to treatment. Response rates were similar in the two major histologic types. Response rate did not seem to be improved by continued therapy with weekly paclitaxel. The median progression-free survival time was 6 months. Median survival for the entire group was 9 months, and the actuarial survival at 1 and 2 years was 42% and 23%, respectively. CONCLUSION Combination chemotherapy with gemcitabine, carboplatin, and paclitaxel followed by weekly paclitaxel is an active and tolerable treatment for patients with carcinoma of unknown primary site. The survival seen in this poor-prognosis group of patients in this multicenter community-based trial is notable and similar to other taxane-based regimens for these patients. Study of additional combinations or sequences of newer drugs, as well as the exploration of targeted biologic agents for patients with an identified target in their tumors, is warranted.

Sunitinib Plus Paclitaxel Versus Bevacizumab Plus Paclitaxel for First-Line Treatment of Patients With Advanced Breast Cancer: A Phase III, Randomized, Open-Label Trial

INTRODUCTION A multicenter, open-label phase III study was conducted to test whether sunitinib plus paclitaxel prolongs progression-free survival (PFS) compared with bevacizumab plus paclitaxel as first-line treatment for patients with HER2(-) advanced breast cancer. PATIENTS AND METHODS Patients with HER2(-) advanced breast cancer who were disease free for ≥ 12 months after adjuvant taxane treatment were randomized (1:1; planned enrollment 740 patients) to receive intravenous (I.V.) paclitaxel 90 mg/m(2) every week for 3 weeks in 4-week cycles plus either sunitinib 25 to 37.5 mg every day or bevacizumab 10 mg/kg I.V. every 2 weeks. [corrected] RESULTS The trial was terminated early because of futility in reaching the primary endpoint as determined by the independent data monitoring committee during an interim futility analysis. At data cutoff, 242 patients had been randomized to sunitinib-paclitaxel and 243 patients to bevacizumab-paclitaxel. Median PFS was shorter with sunitinib-paclitaxel (7.4 vs. 9.2 months; hazard ratio [HR] 1.63 [95% confidence interval (CI), 1.18-2.25]; 1-sided P = .999). At a median follow-up of 8.1 months, with 79% of sunitinib-paclitaxel and 87% of bevacizumab-paclitaxel patients alive, overall survival analysis favored bevacizumab-paclitaxel (HR 1.82 [95% CI, 1.16-2.86]; 1-sided P = .996). The objective response rate was 32% in both arms, but median duration of response was shorter with sunitinib-paclitaxel (6.3 vs. 14.8 months). Bevacizumab-paclitaxel was better tolerated than sunitinib-paclitaxel. This was primarily due to a high frequency of grade 3/4, treatment-related neutropenia with sunitinib-paclitaxel (52%) precluding delivery of the prescribed doses of both drugs. CONCLUSION The sunitinib-paclitaxel regimen evaluated in this study was clinically inferior to the bevacizumab-paclitaxel regimen and is not a recommended treatment option for patients with advanced breast cancer.

Interim safety results of eribulin (E) combined with ramucirumab (RAM) in patients (pts) with advanced metastatic breast cancer (MBC).

110 Background: VEGF-mediated angiogenesis contributes to breast cancer (BC) pathogenesis. RAM (IMC-1121B), a fully human IgG1 monoclonal antibody (MAb), targets VEGFR-2, blocking the interaction of VEGF ligands and VEGFR‑2. DC101 (murine anti-VEGFR-2 MAb) impairs vascular function and increases tumor hypoxia in xenograft BC models and inhibits tumor growth in cytotoxic-resistant models. E is a novel non-taxane microtubule inhibitor indicated in MBC pts who have received ≥2 prior chemotherapy regimens, including an anthracycline and a taxane. It is hypothesized that addition of RAM to E as 3rd-5th line therapy in MBC will result in an improvement of median PFS in this ongoing, multicenter, US study. A planned safety analysis of an initial cohort is reported. METHODS Pts with locally recurrent or MBC (HER2+ or HER2-) and 2-4 prior chemotherapy regimens are randomized 1:1 to receive RAM+E or E (E 1.4 mg/m2 Days 1, 8; RAM 10 mg/kg Day 1; q21 days). Pts are stratified by TNBC and prior antiangiogenic therapy status and must have ECOG PS 0-1 and normal LVEF. Planned accrual: 134 pts. RESULTS Evaluable pts (n=13, 8 RAM+E) received ≥1 dose of RAM+E or E and completed 2 cycles of therapy (or discontinued prior to completing the initial 2 cycles). Median age is 55 yrs. Assessment of adverse events (all cause) revealed nausea, fatigue, headache, and neutropenia were more frequent for RAM+E; anemia was more frequent for E. G1 sensory neuropathy was reported for 1 pt in each arm. One RAM+E pt experienced G3 febrile neutropenia and odynophagia, recovered within a week, and subsequently received reduced dosage (E = 1.1 mg/m2; RAM = 8 mg/kg). No deaths are reported. The safety assessment committee recommended to continue the trial unmodified. CONCLUSIONS Based on preliminary data, the combination of RAM+E demonstrates an acceptable toxicity profile. Accrual continues, with planned updated safety and dose intensity data to be presented at the meeting. [Table: see text].

Functional subtyping with BluePrint 80-gene profile to identify distinct triple-positive subtypes with and without trastuzumab/chemosensitivity.

114 Background: Classification by molecular subtype can aid in the selection of therapy for patients with breast cancer. However at present, the methodology for molecular subtyping is not standardized. The aim of the prospective NBRST study is to compare chemosensitivity as defined by pathological Complete Response (pCR) using the 80-gene BluePrint (BP) functional subtype profile vs. conventional IHC/FISH subtyping. METHODS The study includes women aged 18-90 with histologically proven breast cancer, written informed consent, no excision biopsy or axillary dissection, and no prior therapy for breast cancer. Neo-adjuvant Chemotherapy (NCT) was at the discretion of the physician adhering to NCCN approved or other peer-reviewed regimens. BP in combination with MammaPrint classifies patients into 4 molecular subgroups: Luminal A, Luminal B, HER2 and Basal. RESULTS 721 patients had definitive surgery. 58/335 (17%) IHC/FISH HR+/HER2- patients were re-classified by BP as Basal (57) or HER2 (1). 92/222 (41%) IHC/FISH HER2+ patients were re-classified as BP Luminal (67) or BP Basal (25). 7/164 (4%) IHC/FISH triple negative (TN) patients were re-classified as BP Luminal (5) or BP HER2 (2). NCT pCR rates were 3% in Luminal A and 9% in Luminal B patients versus 10% pCR in IHC/FISH luminal patients. The NCT pCR rate was 54% in BP HER2 patients. This is significantly superior (p = 0.02) to the pCR rate in IHC/FISH HER2+ patients (40%). BP Basal and IHC/FISH TN had a pCR rate of 35%. Functional BP subtyping divided the 137 IHC/FISH triple positive patients into two major subgroups: BP Luminal (n = 66, pCR = 11%) and BP HER2 (n = 60, pCR = 45%).11 patients were re-classified as BP Basal with pCR = 45%. CONCLUSIONS Molecular subtyping using BP leads to a reclassification of 23% of tumors. The re-classification is most prominent in classically assessed triple positive patients where 48% of patients are re-assigned to the less responsive BP Luminal-type group vs. 44% of patients assigned to the responsive BP HER2-type group. These findings confirm the more accurate identification of molecular subgroups for treatment decision by BluePrint functional subtype classifier. CLINICAL TRIAL INFORMATION NCT01479101.

Abstract P4-14-10: Pertuzumab overcomes chemotherapy/trastuzumab resistance in ER+/Her2+ tumors classified as luminal functional subtype by the 80-gene BluePrint assay in the prospective neo-adjuvant breast registry symphony trial (NBRST)

Background The prospective Neo-adjuvant Breast Registry Symphony Trial (NBRST) enrolled over 1000 US patients between June 2011 and December 2014. The aim of NBRST study is to compare chemosensitivity as defined by pathological Complete Response (pCR) using the 80-gene BluePrint functional subtype profile vs. conventional IHC/FISH subtyping. Treatment was at the discretion of the physician utilizing standard NCCN regimens. Pertuzumab, a monoclonal antibody, inhibits the dimerization of HER2 with other HER receptors. Pertuzumab received US FDA approval for the neo-adjuvant treatment of HER2-positive breast cancer in September 2013. Essentially all patients with HER2 positive cancers were treated with chemotherapy + trastuzumab and after this date pertuzumab was added, creating 2 distinct groups of Her2 treated patients. The aim of the current analysis is to compare the pCR rate of trastuzumab (H) vs trastuzumab and pertuzumab (H + P) by conventional and BluePrint functional subtype. Methods The current analysis includes women from the NBRST study, with histologically proven breast cancer, who received neo-adjuvant chemotherapy plus H or H + P and who provided written informed consent. Pathological assessment of Her2 was done according to ASCO CAP guidelines at the time of diagnosis. BluePrint (BP) classifies patients into Luminal, HER2 or Basal-type. pCR is defined as T0/isN0. All pCRs were verified with a de-identified copy of the surgical pathology report. Fisher9s exact test was used to compare pCR rates within different subgroups. Results 252 IHC/FISH Her2+ patients received H (166) or H + P (86). The median age was 53 (range 23-81). 8% was stage I, 68% stage II and 24% stage III. 65% were ER positive. BP classified 55% of patients as HER2, 32% as Luminal, and 14% as Basal-type. The pCR rates and p-values within different subgroups of clinical Her2+ patients are provided in the table below. Conclusions Addition of pertuzumab to trastuzumab significantly increased response rate in ER+/Her2+, BP HER2 and BP Luminal patients but not in ER-negative and BP Basal patients. Pertuzumab overcame resistance to NCT/trastuzumab in a substantial proportion of the IHC/FISH Her2+/BP Luminal subgroup; indicated by a significantly increased pCR rate. Citation Format: Peter B, Pat W, Paul B, Jennifer B, Pellicane JV, Murray MK, Dul CL, Mislowsky AM, Nash CH, Richards PD, Lee LL, Stork-Sloots L, de Snoo F, Untch S, Gittleman M, Akbari S, Rotkis MC. Pertuzumab overcomes chemotherapy/trastuzumab resistance in ER+/Her2+ tumors classified as luminal functional subtype by the 80-gene BluePrint assay in the prospective neo-adjuvant breast registry symphony trial (NBRST). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-10.

P1-12-10: Phase II Study Evaluating Lapatinib (L) in Combination with Albumin Bound Paclitaxel (ab-Pac) in Women Who Have Received 0–1 Chemotherapy Regimen for HER2 Overexpressing (HER2+) Metastatic Breast Cancer (MBC).

Background: L, a dual kinase inhibitor of epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor-2 (HER2), approved for the treatment of HER2+ MBC in combination with capecitabine following progression after trastuzumab, anthracycline, and taxane. L in combination with chemotherapy has significantly improved progression free survival in patients (pts) with HER2+ MBC. Ab-Pac is a cremophor free, albumin-bound paclitaxel approved for use in pts with MBC demonstrating superior efficacy and safety when compared to other taxanes. Methods: Phase II study (LPT111111) evaluated the efficacy and safety of L in combination with ab -Pac in 60 pts with histologically confirmed stage IV HER2+ (IHC 3+/FISH+) invasive MBC. Pts received 0–1 prior chemotherapeutic regimen in the metastatic setting and no prior treatment with L. Prior taxane therapy permitted provided this was > 12 months prior to study entry, LVEF>50%, peripheral neuropathy ab -Pac (125 mg/m 2 IV on Days 1, 8, 15, q28 days) plus L (1250 mg daily). Planned safety analysis of the first 5 pts prompted a protocol amendment with a 20% dose reduction for both agents due to Grade (G) 3 neutropenia and diarrhea. Subsequent pts received ab -Pac (100 mg/m 2 IV on Day 1, 8, 15, q28 days) in combination with L (1000 mg daily). Pts with SD or a response continued L alone until progression. Response assessments performed every 2 cycles. The primary endpoint was overall response rate (ORR) and secondary endpoints were progression-free survival (PFS), time to response, duration of response and overall survival (OS). Results: Here we present the final analysis of all subjects receiving at least 6 months of protocol therapy. Median age is 56 years; 45 pts (75%) received treatment as 1 st line therapy and 15 (25%) as 2 nd line; 57% hormone receptor positive and 43% negative; 42% received trastuzumab and 40% received a taxane in either (neo) adjuvant or metastatic setting. After a median of 5.6 months, 7% pts had a complete response, 47% a partial response and 17% had stable disease, the ORR was 53% [95% CI: 41% to 66%]. The median time to response was 7.8 wks [95% CI: 7.4 to 8.1] with a median duration of response of 48.7 wks [95% CI: 31.7 to 57.1]. The median PFS was 39.7 wks [95% CI: 34.1 to 63.9]. Duration of exposure to ab-Pac; 48% received less than 6 cycles, 30% received 6 cycles and 22% received greater than 6 cycles. Table 1 shows the most common G ≥2 treatment-related toxicities. Two fatal adverse events; one pt with a h/o arrhythmia experienced sudden death of presumed cardiac origin and the other subject with h/o COPD, hypertension and uncontrolled diabetes experienced acute renal failure. No G 3/4 elevation in LFTs observed. Conclusions: L 1000 mg with ab -Pac 100 mg/m 2 IV on Day 1, 8, 15, q28 day is feasible with manageable and predictable toxicity. The ORR of 53% compares favorably with other HER2 based combinations in this setting and warrants further exploration. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-10.