Chester Clinic

Stage iiib epithelial ovarian cancer: recurrent 13 months following completion of induction chemotherapy

prIME LINES
September 2016
TABLE OF CONTENTS
 PHARMA NEWS
 FROM THE LITERATURE
 ADDITIONAL PUBLICATIONS WORTH READING
 UPCOMING prIME EVENTS
 OTHER prIME ACTIVITIES
prIME Lines – September 2016 Issue
PHARMA NEWS
FDA Approves Extended-Release Granisetron for Chemotherapy-Induced Nausea
and Vomiting
On 9 August 2016, the United States (US) Food and Drug Administration (FDA) approved an extended-release subcutaneous injection formulation of granisetron (Sustol®, Heron Therapeutics) for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) associated with initial and repeat courses of moderately emetogenic chemotherapy or anthracycline and cyclophosphamide combination regimens. In contrast to other serotonin (5-HT3) receptor antagonists, this long-lasting formulation utilizes a novel polymer-based drug delivery technology known as Biochronomer™ (Heron Therapeutics) to maintain therapeutic levels of granisetron for at least 5 days. This extended release time allows granisetron to be effective in preventing both acute and delayed phases of CINV, as demonstrated in two large phase III trials. The most common adverse events (AEs) associated with granisetron, seen in at least 10% of patients, are injection site reaction, constipation, fatigue, and headache.

Blinatumomab Now Available for Pediatric Patients With Relapsed Acute
Lymphoblastic Leukemia
On 1 September 2016, the FDA granted accelerated approval to a supplemental indication for blinatumomab (Blincyto®, Amgen) for use in pediatric patients with Philadelphia chromosome (Ph)-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). Blinatumomab is a bispecific, CD19-directed, CD3 T- cell engager (BiTE) antibody that binds to CD19 on B-lineage cells and to CD3 on T- cells. It has previously been approved in the US for adults with Ph-negative relapsed or refractory B-cell precursor ALL. This expansion to pediatric populations was granted based on achievement of complete remission (CR) within the first two cycles of blinatumomab in the single arm, open-label phase I/II trial, Study 205. In phase I the CR rate among 41 patients with relapsed/refractory ALL was approximately 32% and preliminary results for 39 patients from the phase II part of the study showed a CR rate of 31%. The trial has been completed and patients are currently being assessed for long-term efficacy. AEs in pediatric patients were comparable to those previously reported in adults, with the most common grade ≥3 AEs being anemia, thrombocytopenia, febrile neutropenia, hypokalemia, and neutropenia. New Ofatumumab Combination Approved for Relapsed Chronic Lymphocytic
Leukemia
On 31 August 2016, the FDA granted approval to expand the indication for ofatumumab (Arzerra®, Novartis) to include use in combination with fludarabine and cyclophosphamide (FC) for patients with relapsed chronic lymphocytic leukemia (CLL). This approval was based on results from the phase III COMPLEMENT 2 study, which compared ofatumumab plus FC to FC alone in 365 patients with relapsed CLL. In this study, addition of ofatumumab to FC resulted in a statistically significant increase in progression-free survival (PFS), from 18.8 months with FC alone to 28.9 months with ofatumumab plus FC (HR 0.67, P = .0032), with no newly observed safety signals. This

is the fourth indication for ofatumumab in the US. It has previously been approved for use in combination with chlorambucil for initial treatment of CLL in patients considered ineligible for fludarabine-based therapy, for maintenance treatment of patients in CR or partial remission (PR) after at least two lines of therapy for recurrent or progressive CLL, and for patients refractory to fludarabine and alemtuzumab. FROM THE LITERATURE
What is the Benefit of 70-Gene Signature in Early Breast Cancer?
Results of the European randomized phase III MINDACT trial demonstrated that 70-gene signature profiling may identify women with clinically high-risk early breast cancer who are unlikely to benefit from adjuvant chemotherapy. The MINDACT trial prospectively evaluated the addition of a 70-gene signature assay to standard clinical-pathological criteria as a tool for selecting patients for adjuvant chemotherapy. The risk of breast cancer recurrence following breast cancer surgery was evaluated by using the 70-gene assay to determine genomic risk (centrally assessed) and by Adjuvant! Online. Of the 6693 women evaluated, 2745 (41%) had low clinical and low genomic risk, 1806 (27%) had high clinical and high genomic risk, 592 (8.8%) had low clinical risk and high genomic risk, and 1550 (23.2%) had high clinical and low genomic risk. For patients identified as high-risk by both methods, adjuvant chemotherapy was recommended, while patients with low risk were spared from chemotherapy. Patients with discordant results were randomized to either adjuvant chemotherapy or no chemotherapy. The primary focus of this analysis was the group of patients with clinically high-risk disease and low genomic risk according to the 70-gene assay. Investigators sought to determine if these patients would have a 5-year rate of survival without distant metastases of 92% or higher, which was identified as the cutoff benefit for chemotherapy (noninferiority boundary). Survival without distant metastases at 5 years in patients with high clinical risk and low genomic risk for breast cancer recurrence who did not receive chemotherapy was 94.7%, meeting the primary endpoint of the study. Survival without distant metastases rates

differed by 1.5 percentage points between the groups of women who received chemotherapy and those who did not (95.5% vs 94.4%; HR; 0.78; P = .27); however, the study was not powered to determine significance of differences between the groups. Similar results were observed in the subgroup of patients with estrogen receptor-positive (ER-positive), human epidermal growth factor receptor 2-negative (HER2-negative) tumors, as well as in patients with node-negative disease or those with 1 to 3 positive lymph nodes. The investigators concluded that with the addition of the 70-gene signature assay to traditional clinical and pathological factors, approximately 46% of women with high clinical but low genomic risk for breast cancer recurrence may avoid chemotherapy and be spared from its toxic effects, but at the cost of a 1.5 percentage point higher risk of distant metastases at 5 years. In the accompanying editorial, the authors highlighted that "a difference of 1.5 percentage points, if real, might mean more to one patient than to another" and that "adequately powered randomization or higher threshold for 5-year metastasis-free survival might have provided a more convincing result." ESR1 Mutations Predict Poor Outcomes in Metastatic Breast Cancer
Mutational analysis of cell-free (cf) plasma DNA samples from patients enrolled in the BOLERO-2 trial revealed that 28% of women with ER-positive, HER2-negative metastatic breast cancer harbor mutations in the hormone binding domain of estrogen receptor α (ESR1), and these women have significantly shorter survival compared to those with wild-type ESR1. The BOLERO-2 trial demonstrated a significant PFS benefit with the addition of everolimus to the steroidal aromatase inhibitor (AI) exemestane in postmenopausal women with hormone-receptor positive (HR-positive), HER2-negative metastatic breast cancer having received prior treatment with a nonsteroidal AI. This retrospective analysis used archival baseline plasma specimens available from 541 patients enrolled in this trial, analyzing cfDNA for presence of the two most common

ESR1 mutations (Y537S and D538G) by digital drop polymerase chain reaction (ddPCR). Mutations were identified in 28.8% of the analyzed BOLERO-2 population, consistent with the overall reported frequency of ESR1 mutation in 20% of metastatic breast cancer. Interestingly, mutations occurred more frequently in women who had received prior AI treatment for metastatic breast cancer versus those who had received AI only in the adjuvant setting (33% vs 11%). Patients with ESR1 mutations had lower rates of overall survival (OS; 20.7 months) compared with patients who had wild-type ESR1 (32.1 months). Survival was lowest in patients harboring both Y537S and D538G mutations (15.15 months), compared with 25.99 months and 19.98 months for patients with only D538G or Y537S mutations, respectively. There were not adequate samples to accurately compare outcomes on everolimus in mutated versus wild-type patients. However, preliminary data suggest that among patients with mutations, those with D538G mutation alone benefited most from everolimus while the benefit was less evident in patients with either Y537S mutations or both Y537S and D538G mutations. The authors concluded that ESR1 mutations may represent a potential poor prognostic factor in breast cancer and should be investigated further. An accompanying editorial agreed, highlighting that metastases can harbor multiple ESR1 mutations and thus incomplete ESR1 mutation testing in this study may be just the "tip of the iceberg" in predicting treatment response. Prophylactic Dexamethasone May Reduce Regorafenib-Associated Fatigue in
Metastatic Colorectal Cancer
In a retrospective analysis of patients with metastatic colorectal cancer (mCRC) treated with regorafenib at a single institution, oral dexamethasone at a dose of 2 mg/day significantly reduced rates of regorafenib-associated AEs including fatigue, appetite loss, and hand-foot skin reaction. The primary objective of this study was to evaluate the effect of prophylactic use of low dose dexamethasone on fatigue during regorafenib therapy in

mCRC. Fatigue is one of the most common regorafenib-associated toxicities leading to dose modification. Of 105 patients included in this analysis, 74 received regorafenib alone and 31 received regorafenib plus dexamethasone. While addition of dexamethasone did not impact the need for regorafenib dose modifications, time to dose modification was significantly longer in patients receiving dexamethasone (15 days with dexamethasone vs 9 days without; P = .009). Incidence of grade ≥1 fatigue was significantly lower in patients receiving dexamethasone (25.8% vs 50%; P = .022). Patients treated with dexamethasone also had lower rates of decreased appetite of grade ≥1 (3.2% vs 35.1%; P<.001) and hand-foot skin reaction of grade ≥3 (3.2% vs 25.7%; P = .002). Although dexamethasone treatment is known to increase rates of opportunistic infections, oral candidiasis was the only observed infection associated with dexamethasone (16.2% vs 0%; P<.001), and most cases were resolved within a week by using antifungal agents. There were no significant differences in regorafenib efficacy between the two treatment groups. The authors concluded that these results support the potential role of prophylactic dexamethasone in reducing the incidence of regorafenib- related fatigue and other AEs and may improve quality of life of patients receiving this agent. Recognizing the limitations of this single institution retrospective analysis, a prospective, multicenter, randomized, placebo-controlled study is currently underway that will provide more robust data supporting the use of prophylactic dexamethasone in patients with mCRC who are treated with regorafenib. Discordant Efficacy of PD-1 Blockade in Rare Melanoma Subtypes
Two retrospective cohort analyses, one in patients with advanced acral or mucosal melanoma and another in patients with uveal melanoma, found that programmed death (PD)-1 blockade in patients with acral/mucosal melanoma resulted in durable responses similar to those seen in patients with cutaneous melanoma, while PD-1 blockade in metastatic uveal melanoma rarely yielded durable remissions. Acral and mucosal

melanoma are rare subtypes of melanoma often either excluded from clinical trials or poorly represented in trial populations. This analysis pooled data from 25 patients with acral melanoma and 35 patients with mucosal melanoma who were treated in clinical trials and expanded access programs with a variety of doses and schedules of pembrolizumab (67%) or nivolumab (33%). The majority of patients had received prior treatment, including previous ipilimumab. Objective response rates (ORR) were 32% in patients with acral melanoma and 23% in mucosal melanoma. With a median 20 months of follow-up, patients with acral melanoma treated with PD-1 inhibitors had a median PFS of 4.1 months and a median OS of 31.7 months. The mucosal melanoma cohort had a median PFS of 3.9 months; however, with only 10.6 months of follow-up, the OS data were not yet mature. The investigators concluded that even in this retrospective and pooled analysis, the strong similarity between the ORR results in acral and mucosal melanoma to those seen with PD-1 inhibitors in cutaneous melanoma support the use of PD-1 blockade in these melanoma subtypes. In contrast, a second retrospective analysis was published simultaneously with this paper where similar results were not seen in uveal melanoma. In this second study, 56 patients with metastatic uveal melanoma treated with anti–PD-1 (nivolumab, pembrolizumab), or anti–PD-L1 (atezolizumab) antibodies achieved an ORR of only 3.6%, with median PFS of 2.6 months and median OS of 7.6 months. In the accompanying editorial, the authors indicated that these results provide useful insight to the therapeutic value of PD-1 blockade in these rare melanoma subtypes. They highlighted that the differences in results between the three subtypes point to important immunologic differences tied to unique pathogenesis of these malignancies; an important reminder that even immunotherapy is not a "one size fits all" treatment.

Active Surveillance Safe for Selected Patients With Metastatic Renal Cell
Carcinoma
The results of a small, prospective phase II trial suggest that selected patients with metastatic renal cell carcinoma (mRCC) with good performance status and indolent growth of metastasis can safely undergo active surveillance before the start of systemic treatment. The investigators sought to determine the time to initiation of systemic therapy in 48 patients with evaluable treatment-naïve, asymptomatic, metastatic RCC. Most patients had one metastatic site and a relatively low tumor burden at baseline. Patients were radiographically assessed at baseline, every 3 months for the first year, every 4 months for the second year, and every six months thereafter. Observation continued until initiation of systemic therapy at the discretion of the physician and patient. At a median follow-up of 38.1 months, the time to initiation of systemic therapy was 14.9 months. The median time to progression was 9.4 months, and 53% of patients with progressive disease immediately began systemic therapy while 47% continued active surveillance (median additional surveillance time for these patients was 15.8 months). Higher numbers of International Metastatic Database Consortium (IMDC) adverse risk factors (P = .043) and higher numbers of metastatic disease sites (P = .0414) were both independently associated with a shorter surveillance period. The median OS from start of surveillance was 44.5 months. Twenty-two patients (46%) died during the study period due to mRCC and only one died (from brain metastases) without ever receiving systemic therapy. Quality of life, anxiety, and depression were not negatively impacted by active surveillance. The investigators concluded that this study suggests active surveillance might be a viable initial strategy in some patients with mRCC. However, appropriate selection of patients and adequate monitoring, including central nervous system surveillance, is crucial for applying this approach in practice. Additional studies to understand the full risks and benefits of active surveillance are warranted. In an accompanying editorial, the author highlighted that this study provides guidance to oncologists to identify newly diagnosed patients with mRCC who may benefit from a period of active surveillance. Hopefully ongoing genomic research will identify biomarkers that can further refine patient selection for this approach. ADDITIONAL PUBLICATIONS WORTH READING
 Neoadjuvant Chemotherapy for Newly Diagnosed Advanced Ovarian
Cancer. A new practice guideline from the Society of Gynecologic Oncology
(SGO) and the American Society of Clinical Oncology (ASCO) evaluates the utility of neoadjuvant chemotherapy and interval cytoreduction in women with either stage IIIC or IV epithelial ovarian cancer. Based on four phase III clinical trials, an expert panel provides commentary about and recommendations for the use of neoadjuvant chemotherapy in place of primary cytoreduction as a means to reduce perioperative morbidity and mortality in select groups of women with high perioperative risk or low likelihood of achieving cytoreduction to <1 cm of  Challenges and Opportunities in Triple-Negative Breast Cancer. This
interesting article reviews the heterogeneous landscape of triple-negative breast cancer (TNBC) and potentially actionable molecular targets for therapy in a disease with few treatment options and poor prognosis. The authors discuss targeted agents currently under investigation in TNBC, including PARP inhibitors, PI3K and MEK inhibitors, anti-androgen therapies, and their combinations. In addition, they evaluate breast cancer immunogenicity in TNBC subtypes and the potential role of immune checkpoint inhibitors. UPCOMING prIME EVENTS
7 October 2016 Copenhagen, Denmark 8 October 2016 Copenhagen, Denmark 8 October 2016 Copenhagen, Denmark
11 October 2016 Barcelona, Spain

18 October 2016 Barcelona, Spain
23 October 2016 Cologne, Germany

28 October 2016 Estoril, Portugal
18-19 November 2016 Memphis, Tennessee 2 December 2016 San Diego, California 5 December 2016 Vienna, Austria 6 December 2016 Vienna, Austria 9 March 2017 Atlanta, Georgia
OTHER prIME ACTIVITIES

Source: http://www.primeoncology.org/app/uploads/prime_activities/28387/prIME_Lines_September_2016_issue_PDF.pdf