Primary Endpoint In Part Research Articles

Interim analysis of afatinib monotherapy in patients with metastatic NSCLC progressing after chemotherapy and erlotinib/gefitinib (E/G) in a trial of afatinib plus paclitaxel versus investigator’s choice chemotherapy following progression on afatinib monotherapy.

7557 Background: The benefit of sustained ErbB family blockade in NSCLC patients with acquired resistance (AR) to EGFR TKIs is unknown. We investigated afatinib, an irreversible blocker of EGFR (ErbB1), HER2 (ErbB2) and ErbB4 receptor tyrosine kinases, in patients with metastatic NSCLC, who had failed chemotherapy and E/G. Methods: This was a Phase III, randomized, open-label, multi-center trial. Patients with pathologically confirmed Stage IIIB/IV metastatic NSCLC after ≥1 line of chemotherapy who failed E/G received oral afatinib 50 mg until disease progression (Part A). After progression, patients with clinical benefit (≥12 wks) were eligible to continue afatinib 40 mg plus paclitaxel or receive investigator’s choice chemotherapy (Part B). Primary endpoint for Part A was PFS (RECIST 1.1; CT scan every 6 wks). Available tumor samples were collected for central EGFR mutation testing; local mutation data were also collected. An interim analysis of Part A, assessing afatinib monotherapy, is reported. Results: Part A enrolled April 2010 through to May 2011; 1154 patients received afatinib monotherapy. The majority had adenocarcinoma (85%), 57% were female, 43% were Asian, 54% were never smokers. Best response to prior E/G was CR (2%), PR (31%), SD (42%) and PD (20%). Median PFS for afatinib was 3.3 mths; 88 patients (8%) achieved an objective tumor response, 648 (56%) had SD. For EGFR mutation positive patients (n=49, centrally confirmed), PFS was 4.2 vs. 2.6 mths for EGFR mutation negative patients (n=35). When applying clinical enrichment criteria for AR, PFS was 4.2 mths for those with enrichment (n=597) vs. 2.8 mths for those without (n= 557; logrank test p<0.0001). The most common grade 3/4 adverse events were diarrhea (17%) and rash/acne (11%). In Part A, 99 patients remain on treatment. Conclusions: Afatinib monotherapy provided a clinically meaningful benefit in this large, treatment-refractory NSCLC trial, similar to LUX-Lung 1. Those clinically enriched for AR to EGFR TKIs achieved prolonged disease control upon continued ErbB blockade.

P1-12-09: Safety and Efficacy of Neratinib in Combination with Capecitabine in Patients with ErbB2-Positive Breast Cancer.

Abstract Background: Neratinib (HKI-272) is an irreversible pan-ErbB receptor tyrosine kinase inhibitor that has shown antitumor activity in patients with ErbB2+ breast cancer. Capecitabine has demonstrated efficacy and tolerability in combination with lapatinib, a reversible dual ErbB1/ErbB2 kinase inhibitor, in patients with ErbB2+ advanced breast cancer. The current study evaluated the safety and clinical activity of neratinib in combination with capecitabine. Methods: In part 1 of this open-label, phase 1/2 study, the maximum tolerated dose (MTD) of neratinib in combination with capecitabine was determined in adults with advanced solid tumors. Part 2 of the study further evaluated the safety and clinical activity of neratinib plus capecitabine at the MTD in adults with confirmed ErbB2+ metastatic or locally advanced breast cancer (ECOG Performance Status of 0–2). Eligible patients had received prior taxane treatment and ≥1 prior trastuzumab-containing regimen for ≥6 weeks for metastatic or locally advanced disease. The primary endpoint of part 2 was objective response rate (ORR); tumor responses were assessed by investigators using modified RECIST version 1.0 guidelines every 6 weeks. Results: In part 1 (n = 33), the MTD was determined to be neratinib 240 mg/day plus capecitabine 750 mg/m2 twice daily on Days 1 to 14 of each 21-day cycle. In part 2, as of April 2011, 72 female patients (median age of 52 years [range, 33–79 years]) with ErbB2+ breast cancer were enrolled and treated at the MTD; 7 patients had prior lapatinib exposure and all had prior trastuzumab and taxane exposure. As of the snapshot date, 56% of patients at the MTD were still participating in the study. The most common drug-related adverse events (AEs) in part 2 were diarrhea (89%), palmar-plantar erythrodysesthesia (57%), nausea (33%), vomiting (26%), and decreased appetite (22%). Grade 3/4 drug-related AEs in ≥5% of patients were diarrhea (25%) and palmar-plantar erythrodysesthesia (13%). Eight patients withdrew from part 2 due to AEs, including 4 who withdrew due to diarrhea. Dose interruptions of neratinib and capecitabine, respectively, due to AEs were required by 19 and 29 patients; dose reductions due to AEs were required by 8 and 22 patients. As of June 2010 (interim analysis), 22 patients were evaluable for efficacy in part 2 of the study. Of these 22 patients, 11 achieved a partial response for an ORR of 50%. An additional 2 patients maintained stable disease for ≥24 weeks, resulting in a clinical benefit rate of 59%, and 8 patients had stable disease for <24 weeks. One patient had progressive disease without achieving a response or stable disease. Updated efficacy data will be presented. Conclusions: The results of this study indicate that neratinib combined with capecitabine is tolerable and has promising antitumor activity in patients with ErbB2+ metastatic or locally advanced breast cancer pretreated with trastuzumab. This study supports further evaluation of this combination in ErbB2+ breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-09.

A randomized, phase Ib/II trial of rilotumumab (AMG 102; ril) or ganitumab (AMG 479; gan) with panitumumab (pmab) versus pmab alone in patients (pts) with wild-type (WT) KRAS metastatic colorectal cancer (mCRC): Primary and biomarker analyses.

3500 Background: Pmab, ril, and gan are fully human monoclonal antibodies against epidermal growth factor receptor, hepatocyte growth factor, and insulin-like growth factor receptor 1, respectively. This 3-part study examined the safety and efficacy of ril or gan with pmab in pts with mCRC expressing WT KRAS. Methods: Part 2 was a phase II, randomized, double-blinded, placebo-controlled trial of pmab (6 mg/kg) + placebo (Arm 1) vs pmab + ril (10 mg/kg, Arm 2) vs pmab + gan (12 mg/kg, Arm 3), all administered Q2W until disease progression or intolerance. Pts were ≥ 18 yrs old, had ECOG PS 0/1, and prior irinotecan and/or oxaliplatin. The primary endpoint for Part 2 was objective response rate (ORR). A Bayesian approach was undertaken to determine a meaningful improvement in ORR in the combination arms. Secondary endpoints included progression-free survival (PFS) and safety (adverse events [AEs]). Biomarker analyses including c-Met expression by immunohistochemistry (IHC) on archival tumor samples were completed. Correlation of c-Met expression with outcomes for the pmab + ril combination is ongoing. Results: 142 pts were enrolled; 58% were men; mean age was 59.7 yrs; 40%/59% had ECOG PS of 0/1, respectively. ORRs are shown (table). Median PFS (95% CI) was 3.7 (2.5-5.3), 5.2 (3.6-5.4), and 5.3 (2.7-5.7) months for Arms 1, 2, and 3, respectively. Grade ≥ 3 AEs were reported in 54%, 79%, and 72% of pts in Arms 1, 2, and 3, respectively and commonly included rash, dermatitis, and hypomagnesemia. c-Met IHC results were obtained for 134 of the142 pts (94%). Conclusions: Pmab + ril met the prespecified criterion for improvement in ORR (greater than Arm 1). Pmab in combination with ril or gan was well tolerated. Results of biomarker analyses of pmab/ril including c-Met staining will be presented. Arm 1 Arm 2 Arm 3 Best response, n (%) Pmab +placebo N = 48 Pmab +ril N = 48 Pmab +gan N = 46 Partial response 10 (21) 15 (31) 10 (22) Stable disease 17 (35) 19 (40) 18 (39) Progressive disease 16 (33) 11 (23) 15 (33) Unevaluable/not done 5 (10) 3 (6) 3 (6) Posterior probability of OR>1* 0.93 0.63 *Odds ratio relative to Arm 1 for ORR.

A randomized, phase I/II trial of AMG 102 or AMG 479 in combination with panitumumab (pmab) compared with pmab alone in patients (pts) with wild-type (WT) KRAS metastatic colorectal cancer (mCRC): Safety and efficacy results.

366 Background: Pmab is a fully human anti-epidermal growth factor receptor monoclonal antibody (mAb) approved as monotherapy for pts with mCRC. AMG 102 and AMG 479 are investigational, fully human mAbs against hepatocyte growth factor (HGF) and insulin-like growth factor receptor 1 (IGF1R), respectively. This 3-part study evaluated the safety and efficacy of AMG 102 or AMG 479 in combination with pmab. Methods: Part 1 was a phase 1b, open-label, dose-finding study to determine a tolerable dose of AMG 102 in combination with pmab. Part 2 was a phase II, randomized, blinded, placebo-controlled trial that explored pmab + the dose of AMG 102 selected in Part 1 vs pmab + AMG 479 vs pmab + placebo. Part 3 is a 2-arm randomized extension study for pts who developed disease progression (PD) or intolerability to pmab + placebo in part 2. Eligible pts were ≥ 18 years old with WT KRAS mCRC and ECOG PS 0/1. In part 1, all pts received 6 mg/kg pmab + 10 mg/kg AMG 102 Q2W IV until PD or intolerability. The primary endpoint of part 1 was the incidence of dose-limiting toxicities (DLTs). The primary endpoint for part 2 is objective response rate (ORR). Results: In part 1, no DLTs were reported for the first 6 DLT-evaluable pts. A total of 11 pts were enrolled in part 1 prior to the decision to use the 10 mg/kg Q2W AMG 102 dose in part 2; 5 pts were men; mean (range) age was 56 (37-75) yrs; ECOG 0/1 was 55%/45%. Grade 3 treatment-related adverse events (AEs) were acneiform dermatitis or rash (55%), paronychia (18%), infection (9%), capillary leak syndrome (9%), erythema (9%), nail disorder (9%), and pruritus (9%). There were no grade 4 or 5 treatment-related AEs. Serious AEs included acneiform dermatitis (n = 1), intestinal obstruction (n = 1), cerebrovascular accident (n = 1), capillary leak syndrome (n = 1), and anemia/general health deterioration (n = 1). One pt died on study from PD. In part 2, 142 pts received at least one dose of study drug; enrollment is complete, and data analyses are ongoing. Conclusions: In part 1, 6 mg/kg pmab + 10 mg/kg AMG 102 Q2W was well tolerated. Primary efficacy results from part 2, including ORR and progression-free survival, will be presented. [Table: see text]

Extended-Field Irradiation and Intracavitary Brachytherapy Combined With Cisplatin Chemotherapy for Cervical Cancer With Positive Para-Aortic or High Common Iliac Lymph Nodes: Results of ARM 1 of RTOG 0116

The Radiation Therapy Oncolology Group (RTOG) 0116 trial was designed to test the ability of Amifostine to reduce the toxicity of combined chemotherapy with extended-field radiotherapy and brachytherapy (Part 2), after first determining the toxicity rate for the regimen without Amifostine (Part 1). This manuscript reports the results of Part 1. Eligibility included patients with cervical carcinoma and high common iliac or para-aortic metastasis. Patients received extended-field radiotherapy to 45 Gy (1.8 Gy/fraction) with intracavitary irradiation. The final point A dose was 85 Gy LDR equivalent. Use of HDR was allowed. The positive para-aortic and high common iliac nodes were boosted to 54 to 59.4 Gy. Cisplatin (40 mg/m(2)) was delivered weekly during external beam and once with brachytherapy. The primary endpoint of Part 1 was acute Grade 3/4 toxicity, excluding Grade 3 leukopenia. A total of 26 eligible patients were entered between August 1, 2000, and December 3, 2003. Of these, 21 had para-aortic metastasis (15 also had high common iliac involvement), and 5 had high common iliac involvement only. The median follow-up was 17.1 months (range, 1.8-38.6 months) for all patients and 21.7 months (range, 11.4-38.6 months) for alive patients. The acute Grade 3/4 toxicity rate, excluding Grade 3 leukopenia was 81%. Late Grade 3/4 toxicity was 40%. Eight patients underwent surgery for complications. Sixteen (62%) patients had a complete response for both local and nodal disease. The complete local response was 92%, the complete overall nodal response rate was 62% and the regional and para-aortic nodal response rates were 60% and 71% respectively. Estimated disease-free and overall survival at 18 months are 46% and 60%. Extended field and intracavitary irradiation with cisplatin for para-aortic or high common iliac metastasis from cervical cancer is associated with significant acute and late toxicity.

Extended Field Irradiation and Intracavitary Brachytherapy Combined with Cisplatin Chemotherapy for Cervical Cancer with Positive Para-aortic or High Common Iliac Lymph Nodes: Results of Arm 1 of RTOG 0116

Extended Field Irradiation and Intracavitary Brachytherapy Combined with Cisplatin Chemotherapy for Cervical Cancer with Positive Para-aortic or High Common Iliac Lymph Nodes: Results of Arm 1 of RTOG 0116

Perioperative pain: other: Etoricoxib, a selective NSAID, reduces opioid use after knee or hip replacement surgery

The goal was to assess whether etoricoxib provides clinically important analgesic effect over several days to patients after knee or hip replacement surgery. Two double-blind, placebo-controlled studies randomized 264 (study 1) and 228 (study 2) patients with moderate or severe pain, within 72 hours after surgery, to etoricoxib 120mg, NAPRELAN™ 1000mg, and placebo (Day 1). On Days 2 to 7, etoricoxib patients received 60 or 120mg (study 1), or 120mg (study 2); placebo and NAPRELAN™ patients received placebo. On Day 1, patients reported pain relief, pain intensity, and a Global Evaluation at prespecified timepoints. On Days 2 to 7 patients reported rescue medication (LORTAB™) use, a Global Evaluation and worst, least, and average pain (study 2 only). The primary endpoint in Part I was total pain relief over 8 hours (TOPAR8) and the key endpoint in Part II was opioid use. On Day 1, compared with placebo, etoricoxib 120mg provided numerically greater (p=0.135; study 1) and significantly greater (p<0.001; study 2) overall analgesic effect (TOPAR8). Etoricoxib 120mg provided similar analgesic effect to NAPRELAN™ in both studies. On Days 2 to 7, compared with placebo, etoricoxib 120mg decreased opioid use significantly (p<0.001) in both studies; 41% (study 1) and 35% (study 2). Patients also rated etoricoxib superior to placebo on Patient Global Evaluation thus confirming that etoricoxib 120mg provided significantly greater (p<0.001) clinical benefit than placebo. Etoricoxib 60mg significantly decreased opioid use but the Global Evaluation was not different from placebo. Furthermore, etoricoxib 120mg significantly (p<0.001) decreased patients' worst and average pain (study 2). Etoricoxib was generally safe and well tolerated for 7 days. Etoricoxib 120mg provided pain relief and significantly reduced opioid use vs. placebo in patients after knee or hip replacements, and thus was identified as the optimal dose for the treatment of acute pain over several days.