Angela Zubel

Cetuximab Plus Irinotecan, Fluorouracil, and Leucovorin As First-Line Treatment for Metastatic Colorectal Cancer: Updated Analysis of Overall Survival According to Tumor KRAS and BRAF Mutation Status

PURPOSE The addition of cetuximab to irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for metastatic colorectal cancer (mCRC) was shown to reduce the risk of disease progression and increase the chance of response in patients with KRAS wild-type disease. An updated survival analysis, including additional patients analyzed for tumor mutation status, was undertaken. PATIENTS AND METHODS Patients were randomly assigned to receive FOLFIRI with or without cetuximab. DNA was extracted from additional slide-mounted tumor samples previously used to assess epidermal growth factor receptor expression. Clinical outcome according to the tumor mutation status of KRAS and BRAF was assessed in the expanded patient series. RESULTS The ascertainment rate of patients analyzed for tumor KRAS status was increased from 45% to 89%, with mutations detected in 37% of tumors. The addition of cetuximab to FOLFIRI in patients with KRAS wild-type disease resulted in significant improvements in overall survival (median, 23.5 v 20.0 months; hazard ratio [HR], 0.796; P = .0093), progression-free survival (median, 9.9 v 8.4 months; HR, 0.696; P = .0012), and response (rate 57.3% v 39.7%; odds ratio, 2.069; P < .001) compared with FOLFIRI alone. Significant interactions between KRAS status and treatment effect were noted for all key efficacy end points. KRAS mutation status was confirmed as a powerful predictive biomarker for the efficacy of cetuximab plus FOLFIRI. BRAF tumor mutation was a strong indicator of poor prognosis. CONCLUSION The addition of cetuximab to FOLFIRI as first-line therapy improves survival in patients with KRAS wild-type mCRC. BRAF tumor mutation is an indicator of poor prognosis.

MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study

BACKGROUND Patients with melanoma harbouring Val600 BRAF mutations benefit from treatment with BRAF inhibitors. However, no targeted treatments exist for patients with BRAF wild-type tumours, including those with NRAS mutations. We aimed to assess the use of MEK162, a small-molecule MEK1/2 inhibitor, in patients with NRAS-mutated or Val600 BRAF-mutated advanced melanoma. METHODS In our open-label, non-randomised, phase 2 study, we assigned patients with NRAS-mutated or BRAF-mutated advanced melanoma to one of three treatment arms on the basis of mutation status. Patients were enrolled at university hospitals or private cancer centres in Europe and the USA. The three arms were: twice-daily MEK162 45 mg for NRAS-mutated melanoma, twice-daily MEK162 45 mg for BRAF-mutated melanoma, and twice-daily MEK162 60 mg for BRAF-mutated melanoma. Previous treatment with BRAF inhibitors was permitted, but previous MEK inhibitor therapy was not allowed. The primary endpoint was the proportion of patients who had an objective response (ie, a complete response or confirmed partial response). We report data for the 45 mg groups. We assessed clinical activity in all patients who received at least one dose of MEK162 and in patients assessable for response (with two available CT scans). This study is registered with ClinicalTrials.gov, number NCT01320085, and is currently recruiting additional patients with NRAS mutations (based on a protocol amendment). FINDINGS Between March 31, 2011, and Jan 17, 2012, we enrolled 71 patients who received at least one dose of MEK162 45 mg. By Feb 29, 2012 (data cutoff), median follow-up was 3·3 months (range 0·6-8·7; IQR 2·2-5·0). No patients had a complete response. Six (20%) of 30 patients with NRAS-mutated melanoma had a partial response (three confirmed) as did eight (20%) of 41 patients with BRAF-mutated melanoma (two confirmed). The most frequent adverse events were acneiform dermatitis (18 [60%] patients with NRAS -mutated melanoma and 15 [37%] patients with the BRAF-mutated melanoma), rash (six [20%] and 16 [39%]), peripheral oedema (ten [33%] and 14 [34%]), facial oedema (nine [30%] and seven [17%]), diarrhoea (eight [27%] and 15 [37%]), and creatine phosphokinase increases (11 [37%] and nine [22%]). Increased creatine phosphokinase was the most common grade 3-4 adverse event (seven [23%] and seven [17%]). Four patients had serious adverse events (two per arm), which included diarrhoea, dehydration, acneiform dermatitis, general physical deterioration, irregular heart rate, malaise, and small intestinal perforation. No deaths occurred from treatment-related causes. INTERPRETATION To our knowledge, MEK162 is the first targeted therapy to show activity in patients with NRAS -mutated melanoma and might offer a new option for a cancer with few effective treatments. FUNDING Novartis Pharmaceuticals.

Randomized Phase II Study of the Anti–Epidermal Growth Factor Receptor Monoclonal Antibody Cetuximab With Cisplatin Versus Cisplatin Alone in Patients With Metastatic Triple-Negative Breast Cancer

PURPOSE Epidermal growth factor receptor is overexpressed in metastatic triple-negative breast cancers (mTNBCs), an aggressive subtype of breast cancer. Our randomized phase II study investigated cisplatin with or without cetuximab in this setting. PATIENTS AND METHODS Patients who had received no more than one previous chemotherapy regimen were randomly assigned on a 2:1 schedule to receive no more than six cycles of cisplatin plus cetuximab or cisplatin alone. Patients receiving cisplatin alone could switch to cisplatin plus cetuximab or cetuximab alone on disease progression. The primary end point was overall response rate (ORR). Secondary end points studied included progression-free survival (PFS), overall survival (OS), and safety profiles. Analyses included a significance level of α = .10 with no adjustments for multiplicity. RESULTS The full analysis set comprised 115 patients receiving cisplatin plus cetuximab and 58 receiving cisplatin alone; 31 patients whose disease progressed on cisplatin alone switched to cetuximab-containing therapy. The ORR was 20% (95% CI, 13 to 29) with cisplatin plus cetuximab and 10% (95% CI, 4 to 21) with cisplatin alone (odds ratio, 2.13; 95% CI, 0.81 to 5.59; P = .11). Cisplatin plus cetuximab resulted in longer PFS compared with cisplatin alone (median, 3.7 v 1.5 months; hazard ratio [HR], 0.67; 95% CI, 0.47 to 0.97; P = .032). Corresponding median OS was 12.9 versus 9.4 months (HR, 0.82; 95% CI, 0.56 to 1.20; P = .31). Common grade 3/4 adverse events included acne-like rash, neutropenia, and fatigue. CONCLUSION While the primary study end point was not met, adding cetuximab to cisplatin doubled the ORR and appeared to prolong PFS and OS, warranting further investigation in mTNBC.

A Phase Ib Dose-Escalation Study of the Oral Pan-PI3K Inhibitor Buparlisib (BKM120) in Combination with the Oral MEK1/2 Inhibitor Trametinib (GSK1120212) in Patients with Selected Advanced Solid Tumors

Purpose: MAPK and PI3K/AKT/mTOR pathways play important roles in many tumors. In this study, safety, antitumor activity, and pharmacokinetics of buparlisib (pan class PI3K inhibitor) and trametinib (MEK inhibitor) were evaluated. Experimental Design: This open-label, dose-finding, phase Ib study comprised dose escalation, followed by expansion part in patients with RAS- or BRAF-mutant non–small cell lung, ovarian, or pancreatic cancer. Results: Of note, 113 patients were enrolled, 66 and 47 in dose-escalation and -expansion parts, respectively. MTD was established as buparlisib 70 mg + trametinib 1.5 mg daily [5/15, 33% patients with dose-limiting toxicities (DLT)] and recommended phase II dose (RP2D) buparlisib 60 mg + trametinib 1.5 mg daily (1/10, 10% patients with DLTs). DLTs included stomatitis (8/103, 8%), diarrhea, dysphagia, and creatine kinase (CK) increase (2/103, 2% each). Treatment-related grade 3/4 adverse events (AEs) occurred in 73 patients (65%); mainly CK increase, stomatitis, AST/ALT (aspartate aminotransferase/alanine aminotransferase) increase, and rash. For all (21) patients with ovarian cancer, overall response rate was 29% [1 complete response, 5 partial responses (PR)], disease control rate 76%, and median progression-free survival was 7 months. Minimal activity was observed in patients with non–small cell lung cancer (1/17 PR) and pancreatic cancer (best overall response was SD). Relative to historical data, buparlisib exposure increased and trametinib exposure slightly increased with the combination. Conclusions: At RP2D, buparlisib 60 mg + trametinib 1.5 mg daily shows promising antitumor activity for patients with KRAS-mutant ovarian cancer. Long-term tolerability of the combination at RP2D is challenging, due to frequent dose interruptions and reductions for toxicity. Clin Cancer Res; 21(4); 730–8. ©2014 AACR.

Transient MEK Inhibitor-Associated Retinopathy in Metastatic Melanoma

BACKGROUND Melanoma is one of the most aggressive skin cancers. Recently, selective MEK inhibitors have shown efficacy in patients with advanced BRAF- and NRAS-mutant melanoma. Soon after the initiation of clinical oncology trials with MEK inhibitors, it was observed that some participants developed an eye condition resembling central serous chorioretinopathy. The present article addresses the clinical features and management of these MEK inhibitor-associated retinal syndromes. PATIENTS AND METHODS Thirty-two patients with advanced cutaneous melanoma were treated with the selective MEK inhibitor binimetinib (MEK162) in three different Phase 1b or 2 clinical trials. Twenty patients on binimetinib monotherapy and 12 on binimetinib plus RAF inhibitor [pan-kinase RAF inhibitor RAF265 (n = 7) or selective BRAF inhibitor encorafenib (LGX818) (n = 5)] combination therapy underwent ophthalmological examinations at regular intervals, including determination of best corrected visual acuity, perimetry, colour vision testing, dilated fundus examination, and multimodal imaging. RESULTS Grade 1-2 bilateral retinopathies with multiple lesions were observed in 13 of 20 patients on binimetinib monotherapy, 4 of 7 patients on binimetinib plus RAF265 combination therapy, and 2 of 5 patients on binimetinib plus encorafenib combination therapy. In this study population, the rate ranged from 40% to 65%. Retinopathy events appeared during the first 4 weeks, and in some cases, during the first few days of treatment. Patients reported mild and only short-lived visual symptoms. Optical coherence tomography revealed neuroretinal elevations. Central retinal thickness and volume showed dose-dependent increases after the start of treatment, followed by a marked decrease despite continued treatment, which was associated with symptom resolution. No vascular abnormalities were found with fluorescein and indocyanine green angiography. CONCLUSIONS Treatment with the selective MEK inhibitor binimetinib as a single agent or in combination with RAF inhibitors induced transient retinopathy with multiple bilateral lesions in some patients. Binimetinib-induced retinopathy was usually mild, self-limiting, and tolerable as visual function was not seriously impaired.BACKGROUND Melanoma is one of the most aggressive skin cancers. Recently, selective MEK inhibitors have shown efficacy in patients with advanced BRAF- and NRAS-mutant melanoma. Soon after the initiation of clinical oncology trials with MEK inhibitors, it was observed that some participants developed an eye condition resembling central serous chorioretinopathy. The present article addresses the clinical features and management of these MEK inhibitor-associated retinal syndromes. PATIENTS AND METHODS Thirty-two patients with advanced cutaneous melanoma were treated with the selective MEK inhibitor binimetinib (MEK162) in three different Phase 1b or 2 clinical trials. Twenty patients on binimetinib monotherapy and 12 on binimetinib plus RAF inhibitor [pan-kinase RAF inhibitor RAF265 (n = 7) or selective BRAF inhibitor encorafenib (LGX818) (n = 5)] combination therapy underwent ophthalmological examinations at regular intervals, including determination of best corrected visual acuity, perimetry, colour vision testing, dilated fundus examination, and multimodal imaging. RESULTS Grade 1-2 bilateral retinopathies with multiple lesions were observed in 13 of 20 patients on binimetinib monotherapy, 4 of 7 patients on binimetinib plus RAF265 combination therapy, and 2 of 5 patients on binimetinib plus encorafenib combination therapy. In this study population, the rate ranged from 40% to 65%. Retinopathy events appeared during the first 4 weeks, and in some cases, during the first few days of treatment. Patients reported mild and only short-lived visual symptoms. Optical coherence tomography revealed neuroretinal elevations. Central retinal thickness and volume showed dose-dependent increases after the start of treatment, followed by a marked decrease despite continued treatment, which was associated with symptom resolution. No vascular abnormalities were found with fluorescein and indocyanine green angiography. CONCLUSIONS Treatment with the selective MEK inhibitor binimetinib as a single agent or in combination with RAF inhibitors induced transient retinopathy with multiple bilateral lesions in some patients. Binimetinib-induced retinopathy was usually mild, self-limiting, and tolerable as visual function was not seriously impaired.

Abstract PD01-01: Cetuximab + Cisplatin in Estrogen Receptor-Negative, Progesterone Receptor-Negative, HER2-Negative (Triple-Negative) Metastatic Breast Cancer: Results of the Randomized Phase II BALI-1 Trial

Background: The epidermal growth factor receptor (EGFR) plays a role in triple-negative (estrogen receptor-, progesterone receptor-, HER2-negative) breast cancer (TNBC). This randomized, phase II study investigated the combination of the EGFR monoclonal antibody cetuximab and cisplatin in the treatment of metastatic (m) TNBC. Methods: Patients (pts) with mTNBC who had received ≥1 prior chemotherapy regimen for metastatic disease, were randomized 2:1 to treatment with either: cetuximab (400 mg/m 2 initial dose then 250 mg/m 2 weekly) + ≥6x 3-weekly cycles of cisplatin (75 mg/m 2 , d1); or ≥6x 3-weekly cycles of cisplatin alone. In the cisplatin arm, pts with disease progression (PD) during the 6 cisplatin cycles could switch to cetuximab plus cisplatin and those with PD after the 6 cycles could receive cetuximab alone. The primary endpoint was best overall response. Simultaneous null hypotheses assumed that the overall response rate (ORR) in the combination arm was ≥20% and that the ORRs were equal in both arms. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. All statistical tests were performed at alpha-level 0.1 Results: 173 pts were included in the intention-to-treat population: 115 were randomized to cetuximab/cisplatin and 58 to cisplatin. The cetuximab/cisplatin and cisplatin arms were well balanced for patient and disease characteristics (randomization strata, 73% first and 27% second line in both arms). Differences included: age ≥65 years (19.1% vs 12.1%) and lung metastases (55.7% vs 44.8%). 30 pts receiving cisplatin alone switched to cetuximab/cisplatin after first PD. 79.6% of patients on cetuximab/cisplatin and 73.7% on cisplatin received ≥90% of the relative dose intensity of cisplatin. Adverse events (AEs) were manageable and in line with what was expected from the different agents (grade 3/4 AEs are shown in the Table). Grade 3/4 AEs (%) Adding cetuximab to cisplatin nearly doubled the ORR: 20.0% (95% CI 13.1%, 28.5%) vs 10.3% (95% CI 3.9%, 21.2%) (p=0.5 for testing ORR against 20.0%), with an odds ratio of 2.126 (90% CI 0.945, 4.786, p=0.11). Cetuximab/cisplatin was associated with a significant 32.5% reduction in the risk of disease progression compared with cisplatin alone HR 0.675 (95% CI 0.470, 0.969, p=0.032). Median PFS times were 3.7 and 1.5 months, respectively. The benefits of cetuximab/cisplatin over cisplatin on ORR and PFS were observed consistently across sub-groups (according to patient, disease and treatment characteristics), but sample sizes were small. OS results will be presented at the meeting. Conclusions: Adding cetuximab to cisplatin increased the ORR compared with cisplatin alone and significantly improved PFS in mTNBC. Safety was manageable. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD01-01.

Abstract 2437: MEK162 (ARRY 438162), a MEK1/2 inhibitor, has activity in melanoma cells independent of BRAF and NRAS mutation status.

Background. Activation of the Ras/Raf/MEK/MAP kinase pathway is implicated in uncontrolled cell proliferation and tumor growth. Mutated, oncogenic forms of Ras are found in colon, pancreatic, and lung cancers; BRAF mutations have been identified in more than 60% of malignant melanomas and from 40-60% of papillary thyroid cancers. MEK, a dual specific kinase, is a key player in this pathway; it is downstream of both Ras and Raf and activates ERK1/2 through phosphorylation of key tyrosine and threonine residues. MEK162 (ARRY 438162) is a novel small molecule ATP-uncompetitive inhibitor of the kinases MEK1 and MEK2. MEK162 showed promising data in an ongoing Phase 2 Clinical Trial in patients with BRAF and NRAS mutated advanced melanoma. This is the first targeted therapy to show activity in patients with NRAS mutated melanoma. Methods and Results. The melanoma cell line panel was the most sensitive after investigating the growth inhibitory effect of MEK162 on 328 cancer cell lines from diverse histologies including melanoma, head and neck, colon, pancreas, lung, ovarian, liver, kidney, breast and endometrial. When a cutoff of IC50 70% Inhibition at 1uM after 6 days of culture was used 83% out of 47 melanoma cell lines were sensitive to the treatment with the MEK inhibitor. Sensitivity to MEK162 was independent of BRAFV600E andNRASQ61mutation status in this cell line panel. Cell cycle arrest and apoptosis was assessed upon exposure to MEK162 using flow cytometry. MEK162 led to a G1 arrest and marked increase in apoptotic cells in the majority of the sensitive melanoma cell lines regardless of their origin and oncogenic driver mutations. Western blots were used to characterize the changes induced by exposure to MEK162 in the MAPK and PI3K/mTOR pathways. MEK1/2 inhibition resulted in a decrease in pERK in all the cell lines tested regardless of their mutational status and the in vitro sensitivity. We observed an increase in pMEK more prominently in NRASQ61L mutant and wild type for NRAS and BRAF mutations cell lines than in BRAFV600Emutant cell lines. We found pAKT and pS6 decreased in the NRAS and BRAF mutant cell lines after treatment, suggesting that the inhibition of the mTOR pathway by MEK162 may be crucial for the sensitivity to the drug. Conclusion. These data provide evidence for supporting the use of MEK162 in the treatment of patients with melanoma. Citation Format: Erika M. Von Euw, Hong-Mei Rong, Neil O9Brien, Dylan Conklin, Veerauo Konkankit, Ke-Wei Gong, Angela Zubel, Ronald Linnartz, Richard Finn, Bartosz Chmielowski, Dennis Slamon. MEK162 (ARRY 438162), a MEK1/2 inhibitor, has activity in melanoma cells independent of BRAF and NRAS mutation status. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2437. doi:10.1158/1538-7445.AM2013-2437

Abstract 936: KRAS mutational subtypes and copy number variations are predictive of response of human pancreatic cancer cell lines to MEK162 in vitro.

Background: Activating mutations in KRAS have been observed in over 90% of pancreatic tumors and are thought to be a major mechanism of oncogenesis in pancreatic cancer. The EGFR signaling pathway serves as a potential target for cancer therapies. Although targeting KRAS itself has been difficult, targeting the downstream effector MEK1/2, a dual specific kinase required for activation of ERK1/2 has proven to be worthy in both preclinical cell lines and animal studies. MEK162 (ARRY-438192) is a potent, selective, ATP-uncompetitive inhibitor of MEK1/2 and was found to be effective at inhibiting growth in a cohort of solid tumors. The objective of this preclinical study was to assess the antitumor activity of MEK162 in pancreatic cancer comprehensively using a panel of 29 pancreatic cancer cell lines. Methods: MEK162 sensitivity in 29 pancreatic cancer cell lines was examined using a five day proliferation assay to assess growth inhibition in vitro. Array-comparative genomic hybridization (array-CGH) was performed on each cell line to determine genomic copy number variation (CNV). KRAS mutational status at codon 12 and 13 was determined by PCR. Results: Sensitivity of pancreatic cancer cell lines to MEK162 varied. There were 15 cell lines with IC50 values less than 500nm and 14 cell lines with IC50s greater than 500nM and 1 cell line (PATU8988T) in which the IC50 was not achieved at the maximum dose of 10uM. Although significant CNV was observed in many genes, only KRAS CNV was found to be significantly associated with sensitivity to MEK162 (p =0.007). In 15 cell lines with IC50 500nM (resistant lines), 10 had detectable KRAS copy number variations (gains and losses), and 4 had normal levels of KRAS. KRAS mutational subtypes were also associated with sensitivity. Although, the average IC50 of cells with wildtype KRAS (n=4) was not statistically different from those with mutant KRAS (n=25), those cell lines with a KRAS(V12) mutation (n=12) were significantly more resistant to MEK 162 than those with wildtype (n=4) or KRAS(D12) mutations (n=10). Activating mutations resulting in a polar amino acid [KRAS(D12), KRAS(R12) or KRAS(C12)] were more sensitive to MEK162 than nonpolar amino acids [KRAS(V12) (p-value=0.01466)]. Finally, we showed that cells with a KRAS CNV and KRAS(V12) mutation (n=7) were less sensitive than cells having neither KRAS CNV or KRAS(V12) mutation (n=14) (p-value=0.0007). The remaining 8 cell lines had moderate sensitivity to MEK inhibition. Conclusions: Our study has established that MEK162 sensitivity in pancreatic cancer cells lines is associated with KRAS CNV and mutational subtype. Clinical validation of these markers is required. Citation Format: Habib R. Hamidi, Richard Finn, Lee Anderson, Ming Lu, Marlena Fejzo, Charles Ginther, Ronald Linnartz, Angela Zubel. KRAS mutational subtypes and copy number variations are predictive of response of human pancreatic cancer cell lines to MEK162 in vitro . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 936. doi:10.1158/1538-7445.AM2013-936