Background Continuous combination of MAPK pathway inhibition (MAPKi) and anti-programmed death-(ligand) 1 (PD-(L)1) showed high response rates, but only limited improvement in progression-free survival (PFS) at the cost of a high frequency of treatment-related adverse events (TRAE) in patients with BRAF V600 -mutated melanoma. Short‐term MAPKi induces T-cell infiltration in patients and is synergistic with anti-programmed death-1 (PD‐1) in a preclinical melanoma mouse model. The aim of this phase 2b trial was to identify an optimal regimen of short-term MAPKi with dabrafenib plus trametinib in combination with pembrolizumab. Methods Patients with treatment-naïve BRAF V600E/K -mutant advanced melanoma started pembrolizumab 200 mg every 3 weeks. In week 6, patients were randomized to continue pembrolizumab only (cohort 1), or to receive, in addition, intermittent dabrafenib 150 mg two times per day plus trametinib 2 mg one time per day for two cycles of 1 week (cohort 2), two cycles of 2 weeks (cohort 3), or continuously for 6 weeks (cohort 4). All cohorts continued pembrolizumab for up to 2 years. Primary endpoints were safety and treatment-adherence. Secondary endpoints were objective response rate (ORR) at week 6, 12, 18 and PFS. Results Between June 2016 and August 2018, 33 patients with advanced melanoma have been included and 32 were randomized. Grade 3–4 TRAE were observed in 12%, 12%, 50%, and 63% of patients in cohort 1, 2, 3, and 4, respectively. All planned targeted therapy was given in 88%, 63%, and 38% of patients in cohort 2, 3, and 4. ORR at week 6, 12, and 18 were 38%, 63%, and 63% in cohort 1; 25%, 63%, and 75% in cohort 2; 25%, 50%, and 75% in cohort 3; and 0%, 63%, and 50% in cohort 4. After a median follow-up of 43.5 months, median PFS was 10.6 months for pembrolizumab monotherapy and not reached for patients treated with pembrolizumab and intermittent dabrafenib and trametinib (p=0.17). The 2-year and 3-year landmark PFS were both 25% for cohort 1, both 63% for cohort 2, 50% and 38% for cohort 3 and 75% and 60% for cohort 4. Conclusions The combination of pembrolizumab plus intermittent dabrafenib and trametinib seems more feasible and tolerable than continuous triple therapy. The efficacy is promising and appears to be favorable over pembrolizumab monotherapy. Trial registration number NCT02625337 .

Background: Continuous combinations of targeted therapy (TT), e.g. BRAF+MEK inhibitors(BRAFi+MEKi), with immunotherapy (IT), e.g. CTLA-4 or PD-1 blockade are currently tested in several phase1/2 trials with the aim to improve response rate and response duration in melanoma patients with a BRAFV600 mutation. However, high toxicity rates have been observed, revealing PD-1 blockade currently being the only possible combination partner for TT. Recently we have published preclinical data, showing that short-time TT induces strong T cell infiltration and is synergistic with PD-1 blockade. Analysis of biopsies of patients during TT indicate that long-term TT might be counterproductive, as T cell infiltration decreases in some patients already beyond 2 weeks. This raises the question which time period of MAPK pathway inhibition is optimal for combination with anti-PD-1. The IMPemBra trial will address this question, comparing PEM monotherapy with combination schemes of intermittent/short-term BRAFi + MEKi plus PEM. The primary objective is to explore safety, feasibility and the immune-activating capacity of the different regimens. Trial design: Stage IV BRAFV600E/K mutation positive melanoma patients, naïve for IT and TT, will start treatment with PEM 200mg q3wk. After 6 wks the patients will be randomized (stratified according their LDH level) to continue PEM for up to 2 years (cohort 1), or to one of the experimental cohorts receiving either dabrafenib 150mg BID + trametinib 2mg QD two times intermittent for 1 wk (cohort 2), two times intermittent for 2 wks (cohort 3), or continuous for 6 wks (cohort 4). All cohorts continue afterwards with PEM for up to 2 years. Each cohort will consist of 8 patients. Primary endpoints are SUSARs and adherence to the study timeline, the intra-patient alteration in intratumoral CD8+ T cells and the percentage PD1+ CD8+ T cells in the peripheral blood. Tumor biopsies and blood samples including PBMCs are taken at baseline, wk 6, 9, 12, 18 and in case of progression. Secondary endpoints are objective response rate and progression free survival. Enrollment started in May 2016, 11 patients have been included so far. Clinical trial identification: NCT02625337 Legal entity responsible for the study: NKI-AVL Funding: MSD Disclosure: J.V. Thienen: Advisory board: MSD and Bristol-Myers Squib. J.B. Haanen: Advisory role: Bristol-Myers Squib. MSD, Pfizer, Roche, Novartis, Neon Therapeutics Research grants: Bristol-Myers Squib, MSD, GSK. C.U. Blank: Advisory board: Bristol-Myers Squib, MSD, Novartis, GSK, Pfizer, Lilly, Roche Research grants: Bristol-Myers Squib, Novartis. All other authors have declared no conflicts of interest.

Purpose: To study the safety, pharmacokinetics, and recommended dose of the combination of pertuzumab, a humanized monoclonal antibody HER2-dimerization inhibitor, and capecitabine in patients with advanced malignancies. Experimental Design: Patients that had progressed to standard treatment were treated with pertuzumab at a fixed dose of 1,050 mg given i.v. on day 1 plus capecitabine at doses of 825-1,000-1,250 mg/m2, twice daily orally on days 1 to 14 of each 21-day treatment cycle, in three sequential cohorts. The pharmacokinetics of capecitabine and pertuzumab were studied. Patients received a single dose of capecitabine in a pretreatment phase (day −7) followed by serum sampling for capecitabine and its metabolites. Results: Nineteen patients were accrued and 18 were assessable. The combination of capecitabine and pertuzumab was well tolerated at all dose levels and no dose-limiting toxicities were observed. The most frequent adverse event was asthenia, which was grade 3 in two patients. One asymptomatic pulmonary embolism occurred. No other grade 3 or 4 adverse events or cardiac or left ventricular ejection fraction events were reported. There was no apparent change in the pharmacokinetics of capecitabine and its metabolites when combined with pertuzumab. The pharmacokinetics of pertuzumab was apparently not modified when administered with capecitabine. Disease stabilization was observed in 11 patients. Conclusions: Pertuzumab and capecitabine were well tolerated at all dose levels. Escalation beyond the highest dose level tested was not planned, as this included the recommended doses of monotherapy for both drugs. In conclusion, this combination is ready for phase II testing.

3166 Background: P represents the first in a new class of targeted therapeutics known as HER dimerization inhibitors (HDIs). It blocks ligand-associated heterodimerization of HER2 with other HER-kinase family members, thereby inhibiting intracellular signaling. Study endpoints: determine the maximum tolerated dose (MTD) and the dose limiting toxicities (DLTs) of P and D, and the pharmacokinetic (PK) interaction. Methods: DLTs are assessed in cycle 1 and defined as non-hematological toxicity ≥ grade 3, grade 4 neutropenia of > 7 days, thrombocytopenia grade 4. If DLT is observed in ≥ 2/6 pts at a dose level, MTD is exceeded. Pts are treated with a fixed dose of 1050 mg of P and an escalating dose of D as an IV infusion on day 1, q 3 weeks. Three dose levels of D are explored: 60, 75, and 100 mg/ m2. Results: To date, a total of 8 pts (6 males) have received 36 cycles, median 5 (range 1–9). Mean age: 59.5 years, PS 0/1: 5/3 pts. Tumor types: prostate (4), ovarian (2), head & neck (1) and melanoma (1). At dose level D 75 mg/ m2, 2 pts developed DLTs: grade 3 diarrhea and fatigue, and febrile neutropenia, respectively. None of 6 pts treated at dose level 1 developed DLTs. Most frequent grade 1/2 toxicities per cycle included: diarrhea 36% (grade 3 6%), fatigue 31% (grade 3 6%), mucositis 17%, and nausea 8%. Neutropenia and leukopenia grade 3/4 occurred in 28% and 19% of cycles, respectively. Preliminary data from 8 pts suggest that PK parameters of D are not altered in combination with P. Mean clearance of D single agent versus D combined with P is 59 L/h ± 14 and 68 L/h ± 16, respectively. Tumor assessment: 1 PR, 5 SD and 1 progression. Conclusions: The RP2D will be 60 mg/m2 D and 1050 mg of P but further evaluation of D at 75 mg/m2 and P at 420 mg (840 mg loading dose) q 3 weeks is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Hoffmann-La Roche Ltd., Hoffmann-La Roche Boehringer Ingelheim, Celgene, Novartis, Oncolytics Biotech, Topotargets Hoffmann-La Roche, GlaxoSmithKline Hoffmann-La Roche, Novartis, Quintiles Oncology

The HER family is composed of four receptors, HER1 to HER4, is dysregulated, and/or shows abnormal signaling activity in a broad range of human tumors. The essential role of HER2 in the HER signaling network led to the development of anti-HER2 monoclonal antibodies (mAb) for cancer therapy. In particular, the humanized antibody trastuzumab (Herceptin™) has antitumor activity against HER2-overexpressing breast tumors and is widely used for the treatment of women with HER2-overexpressing breast cancers. However, trastuzumab activity relies on the presence of HER2 overexpression and it is not active against tumors that express moderate or normal levels of HER2. Importantly, there is a large population of breast cancers and many other tumors that have normal (nonoverexpressed) HER2 expression yet show abnormal HER signaling activity. In such tumors, HER2 functions as a preferred coreceptor to form heterodimers with HER1 (EGFR), HER3, or HER4. For this reason, a humanized mAb, called pertuzumab (2C4; Omnitarg™), that targets HER2—the preferred pairing partner—was developed and is now in clinical development. Importantly, pertuzumab is directed at an extracellular region of HER2—the dimerization domain—and blocks HER2 from dimerizing with other receptors and prevents the activation of HER signaling cascades. Pertuzumab represents the first in a new class of targeted therapeutics known as HER dimerization inhibitors (HDIs). Given the good preclinical activity of pertuzumab and its potential to target a broad range of human tumors, including those with low HER2 expression, the antibody was recently moved to the clinic. Phase I trials with pertuzumab have shown promising results and phase Ib and II trials are ongoing against a variety of tumor types. Current results and ongoing strategies with these anti-HER2 antibodies are discussed.

Background We conducted a phase I/II study of weekly irinotecan [30 min intravenous (i.v.) infusion] combined with 5-fluorouracil (5-FU 3 g/m2 weekly 48 h i.v. infusion, TTD regimen) as first-line chemotherapy for patients with advanced colorectal cancer (CRC). Patients and methods The maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) in the treatment of gastrointestinal solid tumors (in phase I), and the antitumor activity and toxicity of the recommended phase I dose (in phase II) were determined. Results Diarrhea was the DLT, and irinotecan 80 mg/m2 plus 5-FU 3 g/m2 was the recommended phase I dose. In phase II, the confirmed response rate was 44% [95% confidence interval (CI) 29% to 59%] and the median overall survival was 23.8 months. However, grade 3/4 diarrhea affected 59% of patients and led to withdrawal of three patients. A second cohort of patients studied using the same schedule but with a reduced 5-FU starting dose of 2.25 g/m2 showed improved tolerance (the incidence of grade 4 diarrhea decreased from 28% to 11% and overall grade 3/4 diarrhea to 56%, with no patient withdrawals) but the confirmed response rate was 28% (95% CI 14% to 45%) and median overall survival was 17.2 months. Conclusions We found weekly irinotecan 80 mg/m2 plus TTD regimen (5-FU 2.25 g/m2 given as 48-h i.v. infusion) to be a feasible and active combined chemotherapy for the first-line treatment of advanced colorectal cancer.

The aims of this study were to evaluate the efficacy and safety of docetaxel (Taxotere®) in patients with progressive locally advanced or metastatic breast cancer, previously treated with at least one chemotherapy regimen, and the effect of the number of previous chemotherapy lines on response rate, progression-free survival and overall survival. Two-hundred and fifty-three patients from 10 hospitals in The Netherlands received docetaxel as part of a compassionate use program. The majority had received prior anthracycline-containing chemotherapy (84.2%). The recommended starting dose was 100 mg/m2 i.v. every 3 weeks. All patients received corticosteroid premedication. Two-hundred and thirty patients were evaluable for response. The overall response rates (ORR) to docetaxel when used as second-, third- or fourth-line treatment were, respectively, 40.2, 26.0 and 34.6% (p value 0.30). The median progression-free survival for this population was 4.9 months and the median overall survival of the whole group was 8.5 months, and both were not related to the number of previous chemotherapy regimens (p value, respectively, 0.71 and 0.16). The toxicity of docetaxel was manageable and neutropenia was the most frequently noted toxicity. This study confirms that docetaxel is an active cytotoxic agent in pretreated patients with progressive locally advanced or metastatic breast cancer and is still active when used as third- or fourth-line treatment.

The pharmacokinetics of the combination of docetaxel and ifosfamide were studied in a phase I study. Docetaxel was given to cancer patients as a 1-hour infusion followed by a 24-hour infusion of ifosfamide (schedule A). After the dose-limiting toxicity of the combination was reached, ifosfamide was administered as a 24-hour infusion followed after 24 hours by a 1-hour infusion of docetaxel (schedule B). Cycle duration was 21 days. Docetaxel was determined by high-performance liquid chromatography, and ifosfamide and its metabolites, by gas chromatography-mass spectrometry. Twenty-seven patients were treated according to schedule A, and 6 according to schedule B. Combining the two drugs did not change their respective plasma half-lives. The sequence of drug administration did not affect the clearance and the area under the curve (AUC) of docetaxel. There was a decrease in the AUC of ifosfamide in schedule A compared with schedule B, resulting from an increase in the clearance of ifosfamide. The pharmacokinetics of docetaxel are not influenced by combination with ifosfamide, regardless of the drug sequence, but ifosfamide pharmacokinetics are changed by docetaxel, depending on the sequence of administration. The increase of clearance in schedule A may be due to the pretreatment with corticosteroids.

Background. In most patients with recurrent glioma chemotherapy is the only remaining treatment option. In general results of chemotherapy in these patients are poor, and trials on new regimens are indicated. Because relatively good results have been achieved with combinations of platin compounds and etoposide, we investigated a dose-intensified cisplatin regimen with oral etoposide.