Clovis Oncology Inc (NASDAQ:CLVS) announced updated phase 2 results from Part 1 of the ongoing ARIEL2 study in patients with advanced ovarian cancer as well as the final results of the RUCAPANC study of rucaparib in pancreatic cancer at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago. Rucaparib is the Company’s oral, potent, small molecule inhibitor of PARP1, PARP2 and PARP3 currently being developed for the treatment of ovarian cancer, specifically in patients with tumors with BRCA mutations and other DNA repair deficiencies beyond BRCA, including those with high genomic loss of heterozygosity (LOH) also known as “BRCA-like.”
“We are pleased to present our mature dataset from Part 1 of the ARIEL2 study for rucaparib in ovarian cancer at ASCO, which demonstrates its encouraging clinical activity in selected patients and its potential in the treatment of advanced ovarian cancer,” said Patrick J. Mahaffy, CEO and President of Clovis Oncology. “We are also encouraged by the results of the RUCAPANC study of rucaparib in advanced pancreatic cancer patients with mutations of BRCA, and look forward to exploring rucaparib in additional tumor types in which mutations in BRCA and other DNA repair deficiencies play a significant role.”
Study objectives of the global, two-part single-arm open-label ARIEL2 trial in patients with advanced ovarian cancer include determining rucaparib activity in prospectively defined molecular subgroups through the assessment of progression-free survival (PFS) in patients with tumors that have germline and somatic BRCA mutations, those with a BRCA-like signature (patients whose tumors have other DNA repair deficiencies, including those with high genomic LOH but with normal BRCA genes (BRCAwt/LOHhigh)), and patients whose tumors are biomarker negative (those with low genomic LOH, or BRCAwt/LOHlow). Objective response rate (ORR), safety and pharmacokinetics were also analyzed. Patients in ARIEL2 were treated with the recommended phase 2 dose (RP2D) of 600mg twice daily (BID). ARIEL2 Part 1 was initiated in October 2013 and completed enrollment in 2014. At the data cutoff date of January 18, 2016, 28 of the 204 patients enrolled in ARIEL2 Part 1 remained on study. These patients were required to be platinum-sensitive for enrollment and received a median of one prior treatment regimen and a median of one prior platinum-based chemotherapy regimen. Enrollment continues for ARIEL2 Part 2, which expanded the ARIEL2 study in early 2015 into up to 300 additional patients with recurrent disease after at least three prior lines of chemotherapy. Enrollment into ARIEL2 Part 2 is not limited to platinum-sensitive disease, but also includes patients with platinum-resistant or platinum-refractory disease. Presentation of ARIEL2 Part 2 data will follow at a future medical meeting.
A NGS-based assay developed with Foundation Medicine, Inc. was used to determine the percentage of genomic LOH, mutations in BRCA, and other homologous recombination genes in archival tumor tissue and pretreatment biopsies for patients enrolled in ARIEL2. A prespecified cutoff of ≥14% for LOHhigh was determined through analysis of microarray and survival data for patients in The Cancer Genome Atlas who had ovarian carcinoma and had received platinum-based chemotherapy. A planned post hoc analysis using outcome data from ARIEL2 Part 1 was performed to refine the genomic cutoff. The data for both the prespecified and refined cutoff percentages are presented in today’s poster presentation.
Updated Results of ARIEL2 Part 1
Data presented from the ARIEL2 Part 1 study demonstrated clinical activity in patients with tumors with germline and somatic BRCA mutations as well as those with tumors classified as BRCAwt/LOHhigh.
Using the prespecified ≥14% cutoff, patients in the BRCAmut subgroup demonstrated a 73 percent reduction in the risk of progression, and patients in the BRCAwt/LOHhigh subgroup demonstrated a 38 percent reduction in the risk of progression, both compared to the BRCAwt/LOHlow subgroup (hazard ratio: 0.27 [95% CI: 0.16, 0.44; p<0.001] and hazard ratio: 0.62 [95% CI: 0.42, 0.90; p=0.01], respectively). Median PFS for the BRCAmut, BRCAwt/LOHhigh, and BRCAwt/LOHlow subgroups was 12.8 months, 5.7 months and 5.2 months, respectively.
An analysis of platinum-sensitive patients from ARIEL2 Part 1 identified a refined LOH cutoff of ≥16% that provided further discrimination of PFS, objective response rate and duration of response in patients with LOHhigh and LOHlow tumors who received a median of one prior treatment regimen. Using the refined LOH cutoff of ≥16%, patients in the BRCAmut subgroup demonstrated a 75 percent reduction in the risk of progression, and patients in the BRCAwt/LOHhigh subgroup demonstrated a 49 percent reduction in the risk of progression, both compared to the BRCAwt/LOHlow subgroup (hazard ratio: 0.25 [95% CI: 0.15, 0.42; p<0.001] and hazard ratio: 0.51 [95% CI: 0.34, 0.74; p<0.001], respectively). Median PFS for the BRCAmut, BRCAwt/LOHhigh, and BRCAwt/LOHlow subgroups was 12.8 months, 7.2 months and 5.0 months, respectively.
The confirmed investigator-assessed ORR based on RECIST criteria was significantly higher in the BRCAmut subgroup than in the BRCAwt/LOHlow with the prespecified LOH cutoff. As expected, the most robust clinical responses were observed in patients with tumor (germline and somatic) BRCA mutations: 80 percent (32/40) of BRCAmut patients achieved a response. Responses were observed in both germline and somatic BRCAmut tumors, including 85 percent (17/20) of patients with a gBRCA mutation and 74 percent (14/19) of patients with a sBRCA mutation. One patient with a BRCA mutation was indeterminate for mutation type. In the BRCAwt/LOHhigh subgroup, the ORR was 29 percent (24/82) and 33 percent (23/69) based on the prespecified and refined cutoff, respectively. In the BRCAwt/LOHlow subgroup, the ORR was 10 percent for both the prespecified and refined cutoffs, representing responses in 7 of 70 and 8 of 83 patients, respectively. Median duration of response for the prespecified and refined LOH cutoffs for the BRCAmut and BRCAwt/LOHhigh subgroups were the same at 9.2 months and 10.8 months, respectively, and highly similar for the BRCAwt/LOHlow subgroup at 5.6 months and 5.5 months, respectively.
The most common treatment-emergent AEs reported in ≥20 percent of all patients included nausea (80%), asthenia/fatigue (78%), constipation (46%), vomiting (44%) and dysgeusia (43%). These events were mostly Grade 1/2. The most common Grade 3/4 treatment-emergent AEs were anemia/decreased hemoglobin (21%) and ALT/AST elevations (12%). No treatment-related deaths were reported. Nineteen patients (9%) discontinued treatment because of an adverse event.
These results support the predictive utility of an HRD signature to identify patients with platinum-sensitive ovarian cancer who may benefit from rucaparib treatment. The NGS-based HRD assay will be prospectively applied to assess the utility of a rucaparib treatment-based LOHhigh cutoff in predicting response to rucaparib in the phase 3 ARIEL3 study investigating rucaparib in the maintenance setting in platinum-sensitive ovarian cancer.
Feasibility of Monitoring Response to Rucaparib with ctDNA
A study at the University of Cambridge was conducted to assess TP53 mutant allele fraction (MAF) in circulating tumor DNA (ctDNA) from a subset of 18 patients in ARIEL2 Part 1 and will be presented in a poster session this afternoon. Plasma samples were collected from 18 patients in the ARIEL2 Part 1 study during screening, on day 1 of each cycle, and at the end of rucaparib treatment. The objective was to assess monitoring responses to rucaparib with targeted amplicon deep sequencing (TADS) of ctDNA. Seven of 9 patients with a >50% reduction of TP53 MAF in ctDNA at cycle 2 achieved a RECIST PR; this included 5/6 patients with either a germline or somatic BRCA mutation. No patients with a <50% reduction at cycle 2 (n=5) achieved a RECIST response. TADS detected different types of TP53 mutation in plasma including substitutions (n=12) and indels (n=6) across a wide spectrum of allele fractions (0.01–42.3%) with 100% concordance for TP53 mutation status in matched tumor-plasma samples. ctDNA is a potential biomarker for monitoring responses to the PARP inhibitor rucaparib.
Final Results of RUCAPANC
The open-label phase 2 RUCAPANC study investigated the safety and efficacy of rucaparib in patients with advanced pancreatic cancer and a known deleterious germline or somatic BRCA mutation and final results were presented in a poster session on June 4. A total of 19 patients were enrolled and received one or more doses of rucaparib, with a median of three cycles (range 1-18) of treatment started. The confirmed investigator-assessed ORR based on RECIST criteria was 16%, in which two partial responses (PR) and one complete response (CR) were observed. The disease control rate was 32% for all patients (6/19) and 50% for patients with one prior chemotherapy (3/6). All three patients with a confirmed response received only one prior line of therapy. Common treatment-emergent AEs included nausea (63%) and anemia (47%). These findings are expected to inform future rucaparib study designs in patients with advanced BRCAmut pancreatic cancer. (Original Source)
Shares of Clovis Oncology closed last Friday at $16.30, down $0.97 or -5.62%. CLVS has a 1-year high of $116.75 and a 1-year low of $11.58. The stock’s 50-day moving average is $14.41 and its 200-day moving average is $21.41.
On the ratings front, Clovis has been the subject of a number of recent research reports. In a report issued on May 23, Credit Suisse analyst Kennen MacKay reiterated a Hold rating on CLVS, with a price target of $14, which represents a potential downside of 14.1% from where the stock is currently trading. Separately, on May 6, Piper Jaffray’s Steven Breazzano reiterated a Hold rating on the stock and has a price target of $14.
According to TipRanks.com, which ranks over 7,500 financial analysts and bloggers to gauge the performance of their past recommendations, Kennen MacKay and Steven Breazzano have a total average return of 15.1% and -18.9% respectively. MacKay has a success rate of 83% and is ranked #262 out of 3894 analysts, while Breazzano has a success rate of 0% and is ranked #3397.
Overall, 4 research analysts have assigned a Hold rating and 2 research analysts have given a Buy rating to the stock. When considering if perhaps the stock is under or overvalued, the average price target is $14.00 which is -14.1% under where the stock closed last Friday.
Clovis Oncology, Inc. is a biopharmaceutical company which focuses on acquiring, developing and commercializing cancer treatments in the United States, Europe and other international markets. The company has three product candidates in its clinical development pipeline: Rociletinib, Rucaparib and Lucitani.