SG is a Trop-2–directed antibody-drug conjugate (ADC) approved in multiple countries for the treatment of relapsed or refractory mTNBC. In the phase III ASCENT study (n = 529), significantly longer PFS (hazard ratio [HR], 0.43; 95% CI, 0.35-0.54), and OS (HR, 0.51; 95% CI, 0.41-0.62) were observed with SG vs chemotherapy treatment of physician's choice (TPC), as of the data cutoff date of Mar 11, 2020 (median follow-up of 17.7 months). The incidence of obesity has grown to epidemic proportions in recent decades, and it is unclear what impact this may have on treatment outcomes especially for ADCs like SG which have weight-based dosing. Here, we look at the safety and efficacy of SG vs TPC among BMI subgroups. This ad hoc subgroup analysis included pts from the full intent-to-treat population of ASCENT who received SG at 10 mg/kg of body weight or TPC. BMI was assessed at baseline and was classified as follows: underweight/normal (< 25 kg/m2), overweight (25 - < 30 kg/m2), and obese (≥ 30 kg/m2). As of Feb 25, 2021, longer PFS and OS, and higher ORR were observed with SG compared with TPC in pts from all BMI subgroups (Table). Grade ≥ 3 treatment-emergent adverse events (TEAEs) were observed in 68%, 78%, and 77% of pts treated with SG in the underweight/normal, overweight, and obese subgroups, respectively. TEAEs leading to dose reductions were observed in 11%, 24%, and 41% of pts, respectively, and TEAEs leading to treatment discontinuation were observed in 4%, 3%, and 8%, respectively.Table: 189PUnderweight/Normal(< 25 kg/m2)46%Overweight(25 - < 30 kg/m2)29%Obese(≥ 30 kg/m2)25%SG n = 127TPC n = 114SG n = 71TPC n = 84SG n = 68TPC n = 64Median PFS,a mo4.21.94.61.55.92.6(95% CI)(2.9-5.6)(1.5-2.8)(3.3-6.3)(1.4-1.6)(4.1-8.3)(1.6-3.0)HR0.50.310.34(95% CI)(0.37-0.69)(0.20-0.47)(0.21-0.53)Median OS, mo10.96.210.86.714.98.7(95% CI)(9.4-13.0)(4.8-7.1)(9.0-14.2)(5.2-8.9)(11.2-16.8)(6.7-9.8)HR0.550.510.45(95% CI)(0.42-0.74)(0.35-0.74)(0.30-0.67)ORR,a %25.27.933.81.239.71.6(95% CI)(17.9-33.7)(3.7-14.5)(23.0-46.0)(0.0-6.5)(28.0-52.3)(0.0-8.4)aIndependent review.ORR, objective response rate; OS, overall survival; PFS, progression-free survival. Open table in a new tab aIndependent review. ORR, objective response rate; OS, overall survival; PFS, progression-free survival. To our knowledge, this is the first study evaluating the impact of BMI on treatment with ADCs. SG demonstrated improved efficacy vs TPC and a manageable safety profile in all evaluated BMI subgroups from ASCENT. Although a larger proportion of pts with high BMI (especially obese pts) had SG dose reduction, this did not translate into a decrease in efficacy.

SG is a novel antibody-drug conjugate (ADC) composed of an anti–Trop-2 antibody coupled to SN-38 via a proprietary, hydrolyzable linker. SG is approved for pts with mTNBC who received ≥2 prior chemotherapies (>1 in the metastatic setting) and has accelerated approval for pts with metastatic urothelial cancer who received prior platinum-containing chemotherapy and a PD-1/PD-L1 inhibitor. These analyses evaluated the PK of SG, Free SN-38, and Total Antibody (tAB) with SG administration. Population PK (PopPK) models were developed using data from 529 pts across 2 clinical studies, IMMU-132-01 (phase 1/2 in pts with advanced epithelial cancers including TNBC, UC, and lung cancer; PK n=276) and ASCENT (phase 3 in pts with mTNBC who received ≥2 prior therapies (>1 in the metastatic setting); PK n=253). Pts received SG at 8 to 18 mg/kg IV (IMMU-132-01) or 10 mg/kg IV (ASCENT) on d1 and d8, of every 21d cycle. Clinically relevant covariates were evaluated to assess their impact on exposure. The PopPK models of SG and tAB were developed independently. The model of Free SN-38 was developed in a sequential manner with a first-order release of Free SN-38 (payload) from SG (the ADC). The typical parameter estimates for clearance and steady-state volume of distribution were 0.133 L/hr and 3.68 L for SG and 0.0164 L/hr and 4.26 L for tAB. Bodyweight correlated with the clearance and volume parameters of all 3 analytes, but with limited impact on the exposure with the clinical regimen. There was no model-predicted accumulation of either SG or Free SN-38 with repeated dosing. Overall, mild to moderate renal impairment, mild hepatic impairment, age, sex, baseline albumin level, race, ECOG status, tumor type, UGT1A1 genotype or Trop-2 expression did not have a clinically relevant impact on exposure of any of the evaluated analytes. The PK of SG, Free SN-38, and Total Antibody were well characterized based on a robust dataset across two large trials. The analyses supported the approved 10 mg/kg clinical regimen and did not identify a need for dose-adjustment based on any of the evaluated patient demographics or disease characteristics.

HER2 IHC1+ or IHC2+ and in situ hybridization (ISH)-negative results are sometimes referred to as HER2-Low. SG is a novel antibody-drug conjugate composed of an anti–Trop-2 antibody coupled to SN-38 via a proprietary, hydrolyzable linker. SG is approved in mTNBC for the second line (2L) onwards. In the ASCENT study, SG had significant progression-free survival (PFS) and overall survival (OS) benefit vs chemotherapy of physician’s choice (TPC). This ASCENT post hoc subgroup analysis evaluates SG efficacy in HER2 IHC0 and HER2-Low mTNBC. Patients (pts) with mTNBC refractory/relapsing after ≥2 prior chemotherapies (≥1 in the metastatic setting) were randomized 1:1 to receive SG (10 mg/kg IV on d 1 and 8, every 21 d) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until unacceptable toxicity/progression. Primary endpoint was PFS per RECIST 1.1 by central review. Pts with known HER2-positive disease were ineligible, but HER2 status was not assessed centrally in ASCENT. Local HER2 IHC results were analyzed retrospectively. In the intent-to-treat (ITT) population (SG vs TPC), 149 vs 144, 63 vs 60, and 55 vs 58 pts had HER2 IHC0, HER2-Low, and missing HER2 IHC results, respectively; 79% of the ITT population was HER2-evaluable. Baseline characteristics between HER2 IHC0 vs HER2-Low were comparable and similar to the ITT population. Median PFS and OS were significantly improved, and objective response rate was numerically higher with SG vs TPC in the HER2 IHC0 and HER2-Low groups (Table). HER2-Low had numerically better outcomes vs HER2 ICH0 in both the SG and TPC arms. Clinical benefit with SG in HER2 IHC0 and HER2-Low mTNBC was consistent with that of the ASCENT ITT population, regardless of HER2 status. SG should be considered an effective treatment option for pts with mTNBC eligible for 2L or later therapy.Table: 168PHER2 IHC0HER2-Low∗HER2-Low defined as IHC1+ or ICH2+ and ISH-negSG (n=149)TPC (n=144)SG (n=63)TPC (n=60)mPFS, mo4.31.66.22.9HR (95% CI)0.38 (0.28-0.50)P<0.0010.44 (0.27-0.72)P=0.002mOS, mo11.35.914.08.7HR (95% CI)0.51 (0.39-0.66)P<0.0010.43 (0.28-0.67)P<0.001ORR, n (%)46 (31)5 (3)20 (32)5 (8)ISH, in situ hybridization; HR, hazard ratio; IHC, immunohistochemistry; mPFS, median progression-free survival; mOS, median overall survival, ORR, objective response rate; SG, sacituzumab govitecan; TPC, treatment of physician’s choice∗ HER2-Low defined as IHC1+ or ICH2+ and ISH-neg Open table in a new tab

Endocrine treatment is recommended by clinical guidelines as the preferred treatment option for premenopausal as well as postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer. In real-world clinical practice, however, a substantial number of patients are treated with chemotherapy. We aimed to compare the clinical antitumour activity and safety of palbociclib plus endocrine therapy with that of capecitabine chemotherapy in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer.This multicentre, open-label, randomised, phase 2 study was done in 14 academic institutions in South Korea. Premenopausal women aged 19 years or older with hormone receptor-positive, HER2-negative breast cancer that had relapsed or progressed during previous tamoxifen therapy and with an Eastern Cooperative Oncology Group performance status of 0–2 were included. One line of previous chemotherapy for metastatic breast cancer was allowed. Patients were randomly assigned, using a random permuted block design (with a block size of two), to receive palbociclib plus combination endocrine therapy (oral exemestane 25 mg per day for 28 days and oral palbociclib 125 mg per day for 21 days every 4 weeks plus leuprolide 3·75 mg subcutaneously every 4 weeks) or chemotherapy (oral capecitabine 1250 mg/m2 twice daily for 2 weeks every 3 weeks). Randomisation was stratified by previous chemotherapy for metastatic breast cancer and visceral metastasis. The primary endpoint was progression-free survival. All analyses were done in a modified intention-to-treat population that excluded patients who did not receive study medication. This study is registered with ClinicalTrials.gov, NCT02592746, and is ongoing for follow-up of overall survival.Between June 15, 2016, and Dec 10, 2018, 189 patients were enrolled, of whom 184 were randomly assigned to the palbociclib plus endocrine therapy group (n=92) or the capecitabine group (n=92). Six patients in the capecitabine group withdrew from the study before drug administration; therefore, 92 patients in the palbociclib plus endocrine therapy group and 86 patients in the capecitabine group were included in the modified intention-to-treat analyses. 46 (50%) of 92 patients in the palbociclib plus endocrine therapy group and 45 (51%) of 92 in the capecitabine group were treatment naive for metastatic breast cancer. During a median follow-up of 17 months (IQR 9–22), median progression-free survival was 20·1 months (95% CI 14·2–21·8) in the palbociclib plus endocrine therapy group versus 14·4 months (12·1–17·0) in the capecitabine group (hazard ratio 0·659 [95% CI 0·437–0·994], one-sided log-rank p=0·0235). Treatment-related grade 3 or worse neutropenia was more common in the palbociclib plus endocrine therapy group than in the capecitabine group (69 [75%] of 92 vs 14 [16%] of 86 patients). 2 (2%) patients in the palbociclib plus endocrine therapy group and 15 (17%) patients in the capecitabine group had treatment-related serious adverse events. No treatment-related deaths occurred.Exemestane plus palbociclib with ovarian function suppression showed clinical benefit compared with capecitabine in terms of improved progression-free survival in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer. Palbociclib plus exemestane with ovarian suppression is an active treatment option in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer who have been pretreated with tamoxifen.Pfizer, Shinpoong, and Daewoong Korea and Takeda.

Bevacizumab (Avastin®, Genentech, CA) was granted accelerated approval by the FDA for metastatic breast cancer in 2008. This occurred after the initial clinical trial, E2100, demonstrated an improvement in progression-free survival (PFS) and overall survival (OS) with the addition of bevacizumab to a standard chemotherapy. Unfortunately, the approval was rescinded in 2011 when two subsequent trials, AVADO and RIBBON-1, failed to show survival benefit. We compare and analyze the landmark trials E2100, AVADO and RIBBON-1, and suggest that the present-day clinical trial model may not be suited for the investigation of targeted therapies such as bevacizumab. The existing clinical trial model does not allow for modification of chemotherapeutic doses in a manner that maximizes the effect of biologic response modifiers and does not account for its “chemosensitizing” effect. The E2100, AVADO, and RIBBON-1 trials differed in the type and dose of chemotherapy, the dose and frequency of bevacizumab, and in the trial design, making it difficult to effectively compare and evaluate the results. The efficacy of combining bevacizumab with a maximum tolerated dose (MTD) of chemotherapy is also discussed in view of the observation that increased tumor response did not translate to an increase in survival. We suggest that even though angiogenesis inhibitors are non-toxic as monotherapies, they increase the toxicity of standard chemotherapy, and consequently a re-design of the now classic clinical trial model should be considered. Modifying the existing clinical trial model will lead to a more accurate evaluation of the safety and efficacy of bevacizumab and other biological agents in treating metastatic cancer.

Inhibition of phosphatidylinositol 3-kinase (PI3K) is a promising approach to overcome resistance to endocrine therapy in breast cancer. Pictilisib is an oral inhibitor of multiple PI3K isoforms. The aim of this study is to establish if addition of pictilisib to fulvestrant can improve progression-free survival in oestrogen receptor-positive, endocrine-resistant breast cancer.In this two-part, randomised, double-blind, placebo-controlled, phase 2 study, we recruited postmenopausal women aged 18 years or older with oestrogen receptor-positive, HER2-negative breast cancer resistant to treatment with an aromatase inhibitor in the adjuvant or metastatic setting, from 123 medical centres across 21 countries. Part 1 included patients with or without PIK3CA mutations, whereas part 2 included only patients with PIK3CA mutations. Patients were randomly allocated (1:1 in part 1 and 2:1 in part 2) via a computer-generated hierarchical randomisation algorithm to daily oral pictilisib (340 mg in part 1 and 260 mg in part 2) or placebo starting on day 15 of cycle 1, plus intramuscular fulvestrant 500 mg on day 1 and day 15 of cycle 1 and day 1 of subsequent cycles in both groups. In part 1, we stratified patients by presence or absence of PIK3CA mutation, primary or secondary aromatase inhibitor resistance, and measurable or non-measurable disease. In part 2, we stratified patients by previous aromatase inhibitor treatment for advanced or metastatic disease or relapse during or within 6 months of an aromatase inhibitor treatment in the adjuvant setting and measurable or non-measurable disease. All patients and those administering treatment and assessing outcomes were masked to treatment assignment. The primary endpoint was progression-free survival in the intention-to-treat population for both parts 1 and 2 and also separately in patients with PIK3CA-mutated tumours in part 1. Tumour assessment (physical examination and imaging scans) was investigator-assessed and done at screening and after 8 weeks, 16 weeks, 24 weeks, and 32 weeks of treatment from day 1 of cycle 1 and every 12 weeks thereafter. We assessed safety in as-treated patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT01437566.In part 1, between Sept 27, 2011, and Jan 11, 2013, we randomly allocated 168 patients to the pictilisib (89 [53%]) or placebo (79 [47%]) group. In part 2, between March 18, 2013, and Jan 2, 2014, we randomly allocated 61 patients to the pictilisib (41 [67%]) or placebo (20 [33%]) group. In part 1, we found no difference in median progression-free survival between the pictilisib (6·6 months [95% CI 3·9–9·8]) and placebo (5·1 months [3·6–7·3]) group (hazard ratio [HR] 0·74 [95% CI 0·52–1·06]; p=0·096). We also found no difference when patients were analysed according to presence (pictilisib 6·5 months [95% CI 3·7–9·8] vs placebo 5·1 months [2·6–10·4]; HR 0·73 [95% CI 0·42–1·28]; p=0·268) or absence (5·8 months [3·6–11·1] vs 3·6 months [2·8–7·3]; HR 0·72 [0·42–1·23]; p=0·23) of PIK3CA mutation. In part 2, we also found no difference in progression-free survival between groups (5·4 months [95% CI 3·8–8·3] vs 10·0 months [3·6–13·0]; HR 1·07 [95% CI 0·53–2·18]; p=0·84). In part 1, grade 3 or worse adverse events occurred in 54 (61%) of 89 patients in the pictilisib group and 22 (28%) of 79 in the placebo group. 19 serious adverse events related to pictilisib treatment were reported in 14 (16%) of 89 patients. Only one (1%) of 79 patients reported treatment-related serious adverse events in the placebo group. In part 2, grade 3 or worse adverse events occurred in 15 (36%) of 42 patients in the pictilisib group and seven (37%) of 19 patients in the placebo group. Four serious adverse events related to pictilisib treatment were reported in two (5%) of 42 patients. One treatment-related serious adverse event occurred in one (5%) of 19 patients in the placebo group.Although addition of pictilisib to fulvestrant did not significantly improve progression-free survival, dosing of pictilisib was limited by toxicity, potentially limiting its efficacy. For future assessment of PI3K inhibition as an approach to overcome resistance to hormonal therapy, inhibitors with greater selectivity than that of pictilisib might be needed to improve tolerability and potentially increase efficacy. No further investigation of pictilisib in this setting is ongoing.F Hoffmann-La Roche.

Abstract BackgroundThree multicenter, randomized, placebo-controlled Phase III trials of taxane (T), or capecitabine (Cape), or anthracycline (Anth) chemotherapy plus or minus bevacizumab (B) established that the addition of B improves progression-free survival (PFS). Outcomes in clinically important subsets are important to demonstrate the consistency of treatment effect and may guide physicians when considering treatment options for patients. Here we compare various clinically relevant subgroups across three studies to assess the activity of B in patients for these subgroups.MethodsResults for PFS based upon investigator assessments were used from all trials. Kaplan-Meier methodology was used to estimate median PFS for chemo+placebo and chemo+B for patient subgroups from the E2100, AVADO, and RIBBON-1 studies. For the overall study results, stratified hazard ratios (HRs) are presented with the same stratification factors as the variables that were used for the randomization, while unstratified HRs are presented here for the subgroups.ResultsIn all 3 studies we observed an improvement in PFS upon addition of B to chemotherapy. For patients with triple-negative (ER-, PR-, HER2-) tumors, the addition of B led to an increase in median PFS (mPFS) from 4.7 mo to 10.2 mo (HR=0.45; 95% confidence interval [CI], 0.33-0.61) in E2100, from 6.0 to 8.1 mo in the AVADO 15 mg/kg B arm (HR=0.60, 95% CI, 0.39-0.92); from 4.2 to 6.1 mo in the RIBBON-1 Cape cohort (HR=0.72, 95% CI, 0.49-1.06); and from 8.2 to 14.5 mo in the RIBBON-1 T/Anth cohort (HR=0.78, 95% CI, 0.53-1.15).For patients ≥65 yr, the addition of B led to an increase in mPFS from 7.4 to 10.4 mo (HR=0.69, 95% CI, 0.46-1.03) in E2100, from 7.6 to 8.4 mo in the AVADO 15 mg/kg B arm (HR=0.62, 95% CI, 0.36-1.08); from 6.2 to 9.1 mo in the RIBBON-1 Cape cohort (HR=0.69, 95% CI, 0.47-1.02); and from 8.5 to 10.1 mo in the RIBBON-1 T/Anth cohort (HR=0.83, 95% CI, 0.52-1.34).For patients who had received prior adjuvant T, the addition of B led to an increase in mPFS from 4.4 to 13.3. mo in E2100 (HR=0.29; 95% CI, 0.19-0.46), 6.6 to 8.5 mo in the AVADO 15 mg/kg B arm (HR=0.42; 95% CI, 0.23-0.77), 4.2 to 8.7 mo in the RIBBON-1 Cape cohort (HR=0.62; 95% CI, 0.45-0.84); and from 6.7 to 9.1 mo in the RIBBON-1 T/Anth cohort (HR=0.65; 95% CI, 0.39-1.09).ConclusionsAlthough the addition of bevacizumab consistently improved mPFS across a number of clinically relevant subsets, regardless of the chemotherapy backbone used, absolute improvements in HRs and median PFS varied within subsets and across the three trials. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 207.

Abstract BackgroundA number of chemotherapy agents are used in the first-line treatment of patients with HER2-negative MBC. Three multicenter, randomized Phase III trials have demonstrated significant improvements in progression-free survival (PFS) when adding B to chemotherapy (C) in the first line treatment of women with MBC. These include E2100 (n=722), an open-label trial evaluating weekly paclitaxel (P) +/- B 15 mg/kg; AVADO (n=736), a placebo-controlled, double-blind trial evaluating docetaxel every 3 weeks +/- B 7.5mg/kg or B 15 mg/kg; RIBBON-1 (n=1237), a placebo-controlled, double-blind trial assessing capecitabine (C), Taxane (T) or Anthracycline (A) +/- B 15 mg/kg.Bevacizumab has a characteristic safety profile across a number of different tumor types when used as either a single agent or in combination with chemotherapy. Selected adverse events from breast cancer phase III trials will be summarized to show how different types of chemotherapy affect the adverse event (AE) rates in the first-line MBC setting.MethodsGrade 3–5 non-hematological events and Grade 4 or 5 hematological events using the NCI-CTC Version 2 (E2100) and the NCI CTCAE Version 3 (AVADO and RIBBON-1) are recorded and are summarized for B-related AEs by individual treatment arm from these three studies. These AEs included arterial tumor embolism (ATE), gastrointestinal perforation, hypertension, left ventricular systolic dysfunction, venous thromboembolism, proteinuria, bleeding, and wound-healing complications.ResultsAnalyzing the incidence of known B-related AEs in the placebo arms and B-containing arms of the E2100, AVADO, and RIBBON-1 studies, we found that hypertension ranged from 0 to 2% for patients in the placebo arms and from 2.8 to 16% for patients in the B-containing arms (E2100, 16.0%; the AVADO study, B 7.5 mg/kg cohort, 0%; the AVADO study B 15 mg/kg cohort, 2.8% for; the RIBBON-1 capecitabine cohort, 9.4%; the RIBBON-1 taxane cohort, 8.9%; and the RIBBON-1 anthracycline cohort, 10.0%). For all other B-related AEs the differences between the placebo arms and the B-containing arms were of smaller magnitude. Treatment discontinuation rates in the B-containing arms varied across trials, ranging from 11.9% to 27.9% compared with 4.0 to 19% for the placebo arms. By chemotherapy backbone, treatment discontinuation rates for patients receiving B were higher relative to the placebo arm for the taxane cohort (7.8% vs. 24.1%) and the anthracycline cohort (4.0% vs. 14.3%). There was no difference in treatment discontinuations for patients in the capecitabine cohort (11.9% for both arms).ConclusionsThe addition of B to chemotherapy is associated with an increased frequency of selected adverse events that have been observed across randomized MBC studies. Treatment discontinuation rates for adverse events vary across trials and may be a function of the chemotherapy agent, dose, and schedule. With the exception of hypertension, bevacizumab-related Grade 3–5 adverse events occurred in fewer than 5% of patients. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6083.

1030 Background: Aromatase inhibitors (AIs) are highly active in postmenopausal women with hormone receptor positive breast cancer. However, the AIs do not suppress ovarian estrogen synthesis and are not effective in premenopausal women. This phase II study was initiated to estimate the activity of anastrozole when given with ovarian suppression by goserelin in premenopausal women with ER and/or PgR positive metastatic breast cancer. Methods: Premenopausal women with measurable recurrent or metastatic, ER and/or PgR positive breast cancer; no prior AI or LH-RH agonist/antagonist; no adjuvant chemotherapy within 6 months; ECOG performance status of 0–2; adequate organ function; and who provided signed, informed consent were eligible. A 2 stage phase II design was utilized. Treatment was with goserelin 3.6 mg SQ q4wk and anastrozole 1 mg/day begun on day 22 of protocol treatment. Treatment was continued to disease progression. Results: 35 patients (pts) were enrolled. Three were excluded from analysis for the following: 1 postmenopausal, 1 consent withdrawal, 1 early oophorectomy. Of the remaining 32 pts, median age was 43 yrs (range 26–51 yrs), 18 (56%) had prior chemotherapy, and 9 (28%) had prior SERM. Pts were Asian/Middle Eastern 22%, Caucasian 62%, Black 13%, Hispanic 3%. Disease sites were lymph node 50%, breast 44%, bone 81%, lung 41%, liver 22%, pleural effusion 6% and soft tissue 6%. Receptor status was ER+/PgR+ 75%, ER+/PgR- 22% and ER-/PgR+ 3%. Response: Treatment resulted in complete response (CR) in 1(3%), partial response (PR) in 11(34%), stable disease 6+ mos (SD) in 11(34%), and clinical benefit (CR+PR+SD) 23 (72%). Median TTP was 8 mos (range 2 - 63+ mos); median OS was 26 mos (range 11 - 63+ mos). Estradiol levels were detectable in 30/31 pts at baseline (median 56 pg/ml, range <10 - 273 pg/ml). Mean estradiol levels (pg/ml) were 75 at baseline, 21 at 1 mos, 19 at 3 mos, and 15 at 6 mos. TOXICITY: One grade 3 weight loss. All other toxicities were grade 1–2. Conclusions: Ovarian suppression with goserelin in combination with anastrozole is well tolerated and highly active in the treatment of premenopausal, hormone receptor-positive metastatic breast cancer. Support provided by AstraZeneca Pharmaceuticals No significant financial relationships to disclose.

3138 Background: MGd is a novel anti-neoplastic agent that targets tumors and generates reactive oxygen species (ROS) by redox cycling. Pre-clinical models show that MGd enhances the cytotoxic activity of several chemotherapy drugs including taxanes in lung cancer. This phase I trial evaluated safety and response rate of MGd in combination with docetaxel in patients (pts) with recurrent solid tumors. Methods: Pts with progressive recurrent solid tumors, adequate bone marrow, hepatic and renal function and performance status (PS 0,1)were eligible. Cohorts of 3 pts were treated with increasing doses of MGd, starting at 2.5 mg/kg IV followed by docetaxel 75 mg/m2 30 minutes later. Treatments were repeated q3wks. Results: Ten pts were treated with MGd (2.5–10 mg/kg) and docetaxel. There were 4 males/6 females with a median age of 62 yrs (range 45 -75). Diagnoses included non-small cell lung (6, NSCLC); ovarian (2); breast (1); prostate (1). Pts had a median of 3 prior chemotherapy regimens (range 0–13), 5 pts had previously received a taxane. In pts with NSCLC, 2 had failed >=2 therapies, 2 pts had failed taxanes. Reported toxicities in more than one patient include asthenia, leukopenia, diarrhea, skin discoloration, urine discoloration, injection site reaction, nausea, and stomatitis, without reaching dose limiting toxicity. Partial responses (PR) were observed in 5 of the first 9 evaluable pts. Three pts with NSCLC (3/5) had a PR including two that failed prior taxanes. PRs also were seen in prostate (1/1) and in breast previously treated with paclitaxel (1/1). Pts received a median of 2 cycles (range 1–11) and responses had a median duration of 12 weeks (range 6–33). Conclusions: MGd in combination with docetaxel was well-tolerated and did not increase expected docetaxel toxicity. Responses in heavily pre-treated pts including those having failed taxanes were seen. This combination should be studied further, especially in NSCLC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pharmacyclics Pharmacyclics Pharmacyclics

PURPOSESix of the most active chemotherapy agents in small cell lung cancer were administered sequentially in a weekly fashion in an attempt to optimize the dose and the number of agents received over a 12-week period. The purpose of this study was to estimate the efficacy and to characterize the toxicity of this approach.PATIENTS AND METHODSThirty-six patients with extensive-stage small cell lung cancer received weekly treatments with cisplatin and etoposide (weeks 1, 5, and 11), cyclophosphamide (weeks 2, 7, and 10), vincristine (weeks 2, 4, 7, 8, 10, and 12), methotrexate (weeks 3, 6, and 9), and doxorubicin (weeks 4, 8, and 12). Patients achieving a partial response received a second 12-week course. Patients achieving a complete response received prophylactic cranial radiation.RESULTSTwenty-nine of the 36 patients completed the initial 12-week program over a median of 16 weeks. Hematologic toxicity was most prominent, with two deaths from sepsis and 31 patients having grade 3 or 4 neutropenia The overall response rate was 85%, with 33% of patients achieving a complete response. The median survival was 10.5 months, and the median time to progression was 8.2 months.DISCUSSIONThis 12-week program, consisting of administration of six active agents for small cell lung cancer, caused significant myelosuppression that resulted in significant treatment delays and dose reductions. Although a high response rate was achieved, the median overall survival of 10.5 months was not significantly longer than expected from other standard two- to three-drug regimens.