Martina Uttenreuther-Fischer

Phase I Trial of the Irreversible EGFR and HER2 Kinase Inhibitor BIBW 2992 in Patients With Advanced Solid Tumors

PURPOSE Preclinical data have demonstrated that BIBW 2992 is a potent irreversible inhibitor of ErbB1 (EGFR/HER1) and mutated ErbB1 receptors including the T790M variant, as well as ErbB2 (HER2). A phase I study of continuous once-daily oral BIBW 2992 was conducted to determine safety, maximum-tolerated dose, pharmacokinetics (PK), food effect, and preliminary antitumor efficacy. PATIENTS AND METHODS Patients with advanced solid tumors were treated. PK evaluation was performed after the first dose and at steady-state. RESULTS Fifty-three patients received BIBW 2992 at 10 to 50 mg/d. BIBW 2992 was generally well-tolerated. The most common adverse effects included diarrhea, nausea, vomiting, rash, and fatigue. Dose-limiting toxicities included grade 3 rash (n = 2) and reversible dyspnea secondary to pneumonitis (n = 1). The recommended phase II dose was 50 mg/d. PK was dose proportional with a terminal elimination half-life ranging between 21.3 and 27.7 hours on day 1 and between 22.3 and 67.0 hours on day 27; BIBW 2992 exposure decreased after food intake. Three patients with non-small-cell lung carcinoma (NSCLC; two with in-frame exon 19 mutation deletions) experienced confirmed partial responses (PR) sustained for 24, 18, and 34 months, respectively. Two other patients (esophageal carcinoma and NSCLC) had nonconfirmed PRs. A patient with a PR at 10 mg/d progressed and developed symptomatic brain metastases, which subsequently regressed with an increased dose of 40 mg/d of BIBW 2992. A further seven patients had disease stabilization lasting > or = 6 months. CONCLUSION Continuous, daily, oral BIBW 2992 is safe and has durable antitumor activity. It is currently being evaluated in phase III trials.

Phase I trial of a human-mouse chimeric anti-disialoganglioside monoclonal antibody ch14.18 in patients with refractory neuroblastoma and osteosarcoma.

PURPOSE To evaluate the toxicity, immunogenicity, and pharmacokinetics of a human-mouse chimeric monoclonal antibody (mAb) ch 14.18 directed against disialoganglioside (GD2) and to obtain preliminary information on its clinical efficacy, we conducted a phase I trial in 10 patients with refractory neuroblastoma and one patient with osteosarcoma. PATIENTS AND METHODS Eleven patients were entered onto this phase I trial. They received 20 courses of mAb ch 14.18 at dose levels of 10, 20, 50, 100, and 200 mg/m2. Dose escalation was performed in cohorts of three patients; intrapatient dose escalation was also permitted. RESULTS The most prevalent toxicities were pain, tachycardia, hypertension, fever, and urticaria. Most of these toxicities were dose-dependent and rarely noted at dosages of 20 mg/m2 and less. Although the maximum-tolerated dose was not reached in this study, clinical responses were observed. These included one partial (PR) and four mixed responses (MRs) and one stable disease (SD) among 10 assessable patients. Biologic activity of ch 14.18 in vivo was shown by binding of ch 14.18 to tumor cells and complement-dependent cytotoxicity of posttreatment sera against tumor target cells. An anti-ch 14.18 immune response was detectable in seven of 10 patients studied. CONCLUSION In summary, with the dose schedule used, ch 14.18 appears to be clinically safe and effective, and repeated mAb administration was not associated with increased toxicities. Further clinical trials of mAb ch 14.18 in patients with neuroblastoma are warranted.

Diarrhea associated with afatinib: an oral ErbB family blocker

Gastrointestinal (GI) adverse events (AEs) are frequently observed in patients receiving EGF receptor (EGFR; also known as HER1 or ErbB1) tyrosine kinase inhibitor therapy. GI AEs are among the most common and most impactful on a patient’s quality of life. Severe diarrhea can result in fluid and electrolyte losses, leading to dehydration, electrolyte imbalances and renal insufficiency. Afatinib is an irreversible, oral, ErbB family blocker, inhibiting EGFR (ErbB1), HER2 (ErbB2) and ErbB4 receptor kinases. It also inhibits transphosphorylation of ErbB3. Similar to reversible tyrosine kinase inhibitors of EGFR, GI AEs – in particular, diarrhea – have frequently been observed in afatinib-treated patients. This article summarizes current data on afatinib-associated diarrhea and provides strategies for its management. Patient education, early identification, timely management and ongoing assessment will help to prevent aggravation, afatinib dose reductions or therapy discontinuation, encouraging patient compliance and allowing patients to obtain the maximum therapeutic benefit from this agent.

Afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with HER2-overexpressing metastatic breast cancer who had progressed on one previous trastuzumab treatment (LUX-Breast 1): an open-label, randomised, phase 3 trial

BACKGROUND Trastuzumab resistance is a key therapeutic challenge in metastatic breast cancer. We postulated that broader inhibition of ErbB receptors with afatinib would improve clinical outcomes compared with HER2 inhibition alone in patients who had progressed on previous trastuzumab treatment. LUX-Breast 1 compared afatinib plus vinorelbine with trastuzumab plus vinorelbine for such patients with HER2-positive metastatic breast cancer. METHODS We did this open-label trial at 350 hospitals in 41 countries worldwide. We enrolled female patients with HER2-overexpressing metastatic breast cancer who had progressed on or following adjuvant trastuzumab or first-line treatment of metastatic disease with trastuzumab. Participants were randomly assigned (2:1) to receive oral afatinib (40 mg/day) plus intravenous vinorelbine (25 mg/m(2) per week) or intravenous trastuzumab (2 mg/kg per week after 4 mg/kg loading dose) plus vinorelbine. Randomisation was done centrally and stratified by previous trastuzumab treatment (adjuvant vs first-line treatment), hormone receptor status (oestrogen receptor and progesterone receptor positive vs others), and region. The primary endpoint was progression-free survival, assessed in the intention-to-treat population. This trial is closed to enrolment and is registered with ClinicalTrials.gov, NCT01125566. FINDINGS Between Aug 26, 2010, and April 26, 2013, we enrolled 508 patients: 339 assigned to the afatinib group and 169 assigned to the trastuzumab group. Recruitment was stopped on April 26, 2013, after a benefit-risk assessment by the independent data monitoring committee was unfavourable for the afatinib group. Patients on afatinib plus vinorelbine had to switch to trastuzumab plus vinorelbine, afatinib monotherapy, vinorelbine monotherapy, or receive treatment outside of the trial. Median follow-up was 9·3 months (IQR 3·7-16·0). Median progression-free survival was 5·5 months (95% CI 5·4-5·6) in the afatinib group and 5·6 months (5·3-7·3) in the trastuzumab group (hazard ratio 1·10 95% CI 0·86-1·41; p=0·43). The most common drug-related adverse events of grade 3 or higher were neutropenia (190 [56%] of 337 patients in the afatinib group vs 102 [60%] of 169 patients in the trastuzumab group), leucopenia (64 [19%] vs 34 [20%]), and diarrhoea (60 [18%] vs none). INTERPRETATION Trastuzumab-based therapy remains the treatment of choice for patients with HER2-positive metastatic breast cancer who had progressed on trastuzumab. FUNDING Boehringer Ingelheim.

Use of BIBW 2992, a Novel Irreversible EGFR/HER1 and HER2 Tyrosine Kinase Inhibitor To Treat Patients with HER2-Positive Metastatic Breast Cancer after Failure of Treatment with Trastuzumab.

Background: BIBW 2992 (Tovok™*) is a novel, oral, irreversible inhibitor of the epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor (HER)1 and HER2 inhibitor, with preclinical activity in trastuzumab-resistant cell lines overexpressing HER2 and Phase I clinical activity. A Phase II study of BIBW 2992 in patients with HER2-positive breast cancer who have progressed following treatment with trastuzumab was conducted in the US and the UK.Methods: A multi-institutional, open-label, single-arm Phase II study was conducted. Eligible patients had stage IIIB or IV HER2-positive metastatic breast cancer, with progression following trastuzumab treatment or intolerance of trastuzumab, received no prior EGFR-targeted therapy, had measurable disease, Eastern Cooperative Oncology Group performance status of 0–2 and adequate organ function. Patients received 50 mg BIBW 2992 once-daily until disease progression. Tumor assessments were performed every two treatment courses (one course is 28 days). The primary endpoint was objective response rate (Response Evaluation Criteria In Solid Tumors). Safety data were also collected.Results: A total of 41 patients started treatment on the trial. Patients had received a median of three lines of prior therapy (range, 0–15). Thirty-four patients are evaluable for response. Of these, four patients had a partial response (PR) and eight patients had stable disease maintained for at least four cycles. One patient with confirmed PR remained on treatment until progression at 63 weeks. The most frequently observed side-effects to date are rash (Common Terminology Criteria for Adverse Events [CTCAE] Grade 3 in four patients [9.8%]) and diarrhea (CTCAE Grade 3) in nine patients. There have been 21 dose reductions in 18 patients.Conclusion: BIBW 2992 was safe and induced promising early clinical responses in HER2-positive breast cancer patients who have progressed following treatment with trastuzumab. Manageable cutaneous adverse events and diarrhea were the main side-effects.*Trade name not FDA approved. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5060.

A Neoadjuvant, Randomized, Open-Label Phase II Trial of Afatinib Versus Trastuzumab Versus Lapatinib in Patients With Locally Advanced HER2-Positive Breast Cancer

BACKGROUND Chemotherapy is standard neoadjuvant treatment of LA BC. Patients with HER2-positive BC require targeted therapy. Trastuzumab and pertuzumab, which target HER2, with chemotherapy are approved as neoadjuvant therapy, however, treatments with different mechanisms of action might provide a broader range of activity. In this study we evaluated the efficacy and safety of the irreversible ErbB family blocker afatinib, versus trastuzumab or lapatinib in the neoadjuvant treatment of HER2-positive, LA BC. PATIENTS AND METHODS Treatment-naive, HER2-positive BC patients with stage IIIA, B, C or inflammatory disease were randomized 1:1:1 to daily afatinib (50 mg), lapatinib (1500 mg), or weekly trastuzumab (4 mg/kg loading dose, then 2 mg/kg/wk) for 6 weeks until surgery or follow-up neoadjuvant treatment. The primary end point was objective response rate according to Response Evaluation Criteria in Solid Tumors (version 1.0). RESULTS Recruitment was stopped early because of slow patient enrollment; 29 patients were randomized to afatinib (n = 10), lapatinib (n = 8), or trastuzumab (n = 11). Objective response was seen in 8 afatinib-, 6 lapatinib-, and 4 trastuzumab-treated patients. Eleven patients had stable disease (best response); 1 lapatinib- and 1 trastuzumab-treated patient had progressive disease. All 10 afatinib-treated patients experienced drug-related adverse events (commonly diarrhea, dermatitis acneiform, and paronychia) versus 6 of 8 lapatinib- (diarrhea and rash) and 5 of 11 trastuzumab-treated patients (vomiting and arthralgia). CONCLUSION Afatinib demonstrated clinical activity that compared favorably to trastuzumab and lapatinib for neoadjuvant treatment of HER2-positive BC, with a safety profile consistent with epidermal growth factor receptor tyrosine kinase inhibitors.

Phase I Study to Assess the Combination of Afatinib with Trastuzumab in Patients with Advanced or Metastatic HER2-Positive Breast Cancer

Purpose: The HER2 mAb, trastuzumab, is a standard therapy for patients with HER2-positive breast cancer before acquired resistance. Afatinib, an irreversible, oral, small-molecule ErbB family blocker, shows clinical activity in trastuzumab-refractory HER2-positive breast cancer. Experimental Design: This phase I study used a 3+3 dose escalation to determine the MTD of oral once-daily afatinib in combination with the recommended dose of intravenous trastuzumab (4 mg/kg week 1; 2 mg/kg/wk thereafter). Adult women with confirmed advanced/metastatic HER2-positive breast cancer were eligible. Results: Of 18 patients treated, 16 received daily afatinib 20 mg and two 30 mg. Overall, 4 of 13 and 2 of 2 patients receiving afatinib 20 mg and 30 mg, respectively, experienced dose-limiting toxicity (DLT; all CTCAE grade 3 diarrhea). Most frequent treatment-related adverse events were diarrhea (94%), rash (56%), and fatigue (56%). Overall, pharmacokinetic profiles of afatinib and trastuzumab in combination were consistent with the known characteristics of each alone. Overall, objective response and disease control rates were 11% and 39%, respectively, with median progression-free survival 111.0 days (95% confidence interval, 56.0–274.0). Conclusions: The MTD of afatinib was 20 mg daily combined with the recommended weekly dose of trastuzumab, with 1 of 6 patients showing DLTs in the dose escalation. However, additional DLTs occurred in the dose-expansion phase meaning that this MTD cannot be recommended for phase II development without strict diarrhea management. There was no evidence suggesting relevant pharmacokinetic drug–drug interactions. Signs of clinical activity were seen in trastuzumab-resistant HER2-positive breast cancer, suggesting further investigation with optimal diarrhea management is warranted. Clin Cancer Res; 21(12); 2737–44. ©2014 AACR. See related commentary by Sledge and Pegram, p. 2663

Phase I dose-escalation study of afatinib, an ErbB family blocker, plus docetaxel in patients with advanced cancer

AIMS To determine the maximum tolerated dose (MTD), safety and anti-tumor activity of afatinib combined with docetaxel in advanced cancer. PATIENTS & METHODS The MTD was determined from dose-limiting toxicities in the first cycle. RESULTS Thirty-one patients received 10, 20 and 30 mg oral afatinib, plus 60 and 75 mg/m(2) intravenous docetaxel (six cohorts; 3-week cycles). The MTD of afatinib was 20 mg/day (days 2-21) with 75 mg/m(2) docetaxel (day 1). Dose-limiting toxicities were grade 3/4 diarrhea (n = 3) and febrile neutropenia (n = 6). Most frequently occurring adverse events were diarrhea, neutropenia and rash. Disease stabilization occurred in 14 patients. CONCLUSION Afatinib 20 mg/day plus docetaxel was suboptimal and the study could not yield Phase II dose recommendations. The combination resulted in a manageable safety profile.

A phase I study of daily afatinib, an irreversible ErbB family blocker, in combination with weekly paclitaxel in patients with advanced solid tumours.

BACKGROUND This phase I study evaluated afatinib, an irreversible ErbB family blocker, plus paclitaxel in patients with advanced solid tumours likely to express human epidermal growth factor receptor (HER1/EGFR) or HER2. METHODS Oral afatinib was combined with intravenous paclitaxel (80mg/m(2); days 1, 8 and 15 every four weeks) starting at 20mg once daily and escalated to 40 and 50mg in successive cohorts of ⩾3 patients. The primary objective was to determine the maximum tolerated dose (MTD) of afatinib combined with paclitaxel. Secondary objectives included safety, pharmacokinetics and antitumour activity. RESULTS Sixteen patients were treated. Dose-limiting toxicities with afatinib 50mg were fatigue and mucositis. The MTD was determined as afatinib 40mg with paclitaxel 80mg/m(2), which proved tolerable with repeated dosing. Frequent adverse events (AEs) included diarrhoea (94%), fatigue (81%), rash/acne (81%), decreased appetite (69%) and inflammation of mucosal membranes (69%); no grade 4 treatment-related AEs were observed. Five (31%) confirmed partial responses were observed in patients with non-small cell lung cancer (n=3), oesophageal cancer and cholangiocarcinoma; eight (50%) patients remained on study for ⩾6months. Pharmacokinetic parameters of afatinib and paclitaxel were similar for single administration or in combination. CONCLUSIONS The MTD and recommended phase II dose of once-daily afatinib combined with paclitaxel 80mg/m(2) (days 1, 8 and 15 every four weeks) was 40mg. AEs at or below this dose were generally manageable with repeated dosing. No pharmacokinetic interactions were observed. This combination demonstrated promising antitumour activity. TRIAL REGISTRATION ClinicalTrials.gov, NCT00809133.

BIBW 2992, a Novel Irreversible EGFR/HER1 and HER2 Tyrosine Kinase Inhibitor for the Treatment of Patients with HER2-Negative Metastatic Breast Cancer after Failure of No More Than Two Prior Chemotherapies.

Background: BIBW 2992 (Tovok™*) is a novel, oral, irreversible inhibitor of the epidermal growth factor receptor (EGFR)/ human epidermal growth factor receptor (HER)1 and HER2 inhibitor. It has promising preclinical activity in HER2-negative MDA-MB-453 and triple-negative SUM 149-PT cell lines, and showed clinical Phase I activity. First results of a Phase II study of BIBW 2992 in patients with HER2-negative, hormone receptor (HR)-positive or triple-negative breast cancer who have progressed following no more than two prior lines of chemotherapy are presented. The trial was conducted as a multi-institutional, open-label study in Germany and Belgium.Methods: Eligible patients had stage IIIB or IV HER2-negative metastatic breast cancer (MBC), with progression following no more than two prior lines of chemotherapy. No prior EGFR-targeted therapy was allowed and measurable disease, Eastern Cooperative Oncology Group performance status of 0–2 and an adequate organ function were required. Patients received 50 mg BIBW 2992 once-daily until disease progression. Tumor assessment was performed every other treatment course (one course is 28 days). The primary endpoint was objective response rate by Response Evaluation Criteria In Solid Tumors criteria in patients with HR-positive and triple-negative MBC. The latter was changed to clinical benefit, i.e. objective response (OR) or stable disease (SD) on treatment for at least four cycles for patients with triple-negative disease. Safety data were collected and analyses are still ongoing.Results: A total of 56 patients were enrolled with 50 actually starting treatment on the trial, including 29 patients with triple-negative and 21 patients with HER2-negative and HR-positive MBC. No ORs were observed in either cohort. Three patients in the triple-negative cohort had SD for at least 4 treatment cycles, one of them for 12 cycles. The most frequently observed side-effects at snapshot date (on 49 patients) are diarrhea (Common Terminology Criteria for Adverse Events Grade 3 in 18 patients [36.7%]) and Grade 3 skin rash in two patients [4.1%]). These were managed by symptomatic treatments and dose reductions.Conclusion: Long-term oral administration of BIBW 2992 was safe in HER2-negative MBC patients. Side effects mainly affected the skin and gastrointestinal tract, and were manageable. Clinical benefit was achieved in a fraction of triple-negative MBC patients.*Trade name not FDA approved. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5062.