The 2017 Genitourinary Cancers Symposium takes place in Orlando, FL, on February 16 – 18, and a press cast held in advance of the meeting featured 3 important abstracts, with these key findings:
Early Discontinuation of PD-1/PD-L1 Blockers May Not Compromise Efficacy
In a small study of 19 patients with metastatic renal cell carcinoma (RCC), discontinuation of anti-PD-1/PD-L1 immune checkpoint inhibitors due to side effects did not always lead to poor outcomes. The findings may challenge the current practice of continuing these drugs until (and sometimes after) the patient’s disease progresses.
Among 19 patients who initially responded to nivolumab but discontinued because of immune-related side effects, 42% had a durable response lasting for 6 months or longer, according to Rana R. McKay, MD, of the University of California San Diego School of Medicine.
“In medicine, we are constantly balancing the benefits and risks of any given treatment. This is a small study, and our findings need to be validated in a larger group of patients, but it underscores that in some cases, immunotherapy can have lasting benefits even after treatment discontinuation,” she said.
Two thirds of patients had received nivolumab as a single agent and the remainder received it in combination with other systemic treatments. The median time on immunotherapy was 5.5 months. All 19 discontinued treatment because of immune-related side effects, such as joint pain, rash, eye problems, diarrhea, and inflammation of the pituitary gland, muscle, heart, liver, pancreas, kidney or lung. Steroids were administered to 84% of patients and additional immunosuppressive agents were required for 11%. More than half the group had ongoing toxicity at the time of the analysis.
In 3 (16%) patients, the tumor progressed immediately after stopping treatment, but 8 (42%) patients had a continued response after being off treatment for at least 6 months. The remaining 8 (42%) were off treatment for 4 to 6 months or had follow-up for less than 6 months. The durable responders spent a median of 11 months on treatment and 20 months off treatment, reported Dr. McKay.
“We demonstrated that responders to anti-PD1/PD-L1 agents can have persistent clinical benefit despite treatment discontinuation for immune-related adverse events,” said Dr. McKay.
The prospective OMINIVORE study (Phase 2 study of Optimized Management of NIVOlumab based on Response) will further explore the efficacy of immunotherapy treatment discontinuation in treatment responders.
Press cast moderator and ASCO Expert Sumanta Pal, MD, reiterated the study’s message: that while the “unintended consequences of a reinvigorated immune response,” ie, immune-related adverse events, can be “serious,” patients with these side effects “can still have tangible benefit from these drugs.”
Recent Antibiotic Use May Negate Immunotherapy Benefits
In a retrospective analysis, patients with metastatic RCC who were treated with antibiotics within 1 month of starting treatment with immune checkpoint inhibitors had a significantly shorter progression-free survival, versus patients not taking antibiotics, according to French investigators.
The researchers attribute this to the ability of antibiotics to wipe out “good bacteria” in the gut, based on preclinical studies showing that certain microorganisms in the gut interact with the immune system in a way that facilitates the effect of immune checkpoint inhibitors.
The study is the first to analyze the impact of antibiotics on immune checkpoint inhibitors, and provides the first evidence of a relationship between the gut microbiome and patients’ response to immunotherapy.
The study included 80 patients with metastatic RCC enrolled in a trial of anti-PD-1/PD-L1 agents. Of these, 16 (20%) had been treated with broad-spectrum antibiotics (mostly beta-lactamases and fluoroquinolones) from baseline up to 1 month prior to the first injection.
Compared with patients not taking antibiotics, antibiotic users had significantly worse progression-free survival: 2.3 months vs 8.1 months, respectively (P< .001); their response rates to the checkpoint inhibitors were also lower.
This statistical association was maintained in a multivariate analysis that adjusted for age, gender, disease risk group, tumor burden and use of proton pump inhibitors. Antibiotic users’ risk for progression was increased more than four-fold vs non-users.
“Although it’s too early to conclude about overall survival, with median follow up of less than 6 months, there is already a negative trend in the antibody-positive group,” reported Lisa Derosa, MD, MD, a PhD candidate at the Gustave Roussy Cancer Institute, Paris-Sud University in Villejuif, France.
Dr. Derosa suggested that the findings may be applicable to other tumor types, since antibiotics are frequently used in cancer patients in general to prevent and treat treatment-related infections. At this time, she does not recommend withholding antibiotics from patients taking checkpoint inhibitors.
Dr. Pal agreed, stating, “While Dr. Derosa’s findings are very intriguing, they were retrospectively generated and therefore are hypothesis-generating. Having said that, the observations are consistent with preclinical observations. With further prospective validation, we may gain insight as to whether the bacterial composition of the gut affects clinical outcomes, and this could help guide us in our antibiotic usage. Meanwhile, we must consider that antibiotics are used under circumstances that are medically necessary.”
In Prostate Cancer, Liquid Biopsy Reveals Potential New Treatment Targets
Analysis of cancer DNA from blood samples is yielding some new leads for potential prostate cancer treatment targets. With a commercially available liquid biopsy — which examines cell-free circulating tumor DNA (ctNDA) in the bloodstream — researchers identified new genetic mutations in prostate cancers, some of which were associated with poor prognosis.
Cell-free DNA reveals a tumor’s genetic profile, for which targeted treatments can be designed. The genetic landscape, however, changes over time, rendering some drugs ineffective because resistance develops.
If the ctDNA can identify the evolving mutations, clinicians could discontinue futile treatments and switch therapies, explained Guru Sonpavde, MD, of the University of Alabama in Birmingham.
The study included blood samples from 514 patients with metastatic castration-resistant prostate cancer (mCRPC). The test, Guardant360, examined changes in 73 cancer-related genes.
In 163 patients, researchers explored associations between DNA changes and clinical outcomes, and in 64 patients they documented genetic changes over time through serial testing.
“Almost all the patients (94%) had some change detected, and most changes were associated with worse poor outcomes,” reported Dr. Sonpavde.
Higher number of ctDNA alterations was associated with shorter time to treatment failure (P=0.026). Patients with prior treatment for mCRPC had significantly more alterations in the androgen receptor gene (AR) than untreated patients (56% vs 37%; P=0.028).
Genes most often mutated were TP53, AR, APC, and NF1. Increased copy numbers were most common with AR, MYC and BRAF; increased cancer gene copy number can lead to proliferation of proteins that drive tumor growth.
Serial testing revealed that changes in AR over time were common. Importantly, patients with these mutations also trended toward shorter remissions (P=0.053) and shorter survival time (P=0.09).
“This indicates that developing salvage therapy with agents targeting AR alterations holds promise,” commented Dr. Sonpavde.
The findings via ctDNA were consistent with changes observed through traditional tissue biopsy, suggesting that noninvasive liquid biopsy may be a viable alternative. While there are currently no approved drugs targeting the most common mutations observed, some are in clinical trials noted investigators.
Dr. Sonpavde acknowledged that a controlled, prospective clinical trial is needed to confirm that treatment based on the molecular information from ctDNA improves patient outcomes.
Dr. Pal remarked that the study offers “one of the largest clinically annotated datasets describing features of ctDNA in advanced prostate cancer, which is a simple and convenient way to assess DNA composition and can reveal new mutations that clinicians can use to personalize therapy… The development of new agents targeting the androgen receptor is a good future direction of research.”
By Emily Benesh, Ph.D., Analyst, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Ph.D., Vice President, Clinical & Scientific Assessment, Kantar Health
It is an exciting time for patients and their doctors fighting advanced hepatocellular carcinoma (HCC). In mid-2016 the HCC community witnessed the first randomized trial to successfully improve survival outcomes in Nexavar® (sorafenib, Onyx/Amgen/Bayer)-pretreated HCC when the multikinase inhibitor Stivarga® (regorafenib, Bayer) demonstrated a 38% reduction in the risk of death compared with placebo in the Phase III RESOURCE trial.1 This led to submission of a supplemental new drug application with the U.S. Food and Drug Administration (FDA) in November 2016. Additionally, Opdivo® (nivolumab, BMS/Ono Pharmaceuticals) is showing very promising activity as treatment of advanced HCC, and the excitement around these results was palpable at the 2017 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium in San Francisco.
Historically, the unmet needs in HCC have been insurmountable. Even with the best therapeutic options available, the prognosis for advanced HCC has been quite poor; first-line patients receiving the standard of care, Nexavar, have a median overall survival of 10.7 months. In 2007, Nexavar, a multityrosine kinase inhibitor, was established as the first targeted agent FDA-approved in this indication. It achieved this by besting a placebo control with a 2.8-month improvement in overall survival,2 although patients did not experience improvements in time to symptomatic progression or complete responses with use of this agent. Additionally, use of Nexavar came at a high price. In the SHARP trial, 80% of Nexavar-recipient patients experienced serious adverse events including diarrhea, hand-foot skin reaction and others.2
The last nine years have seen novel therapeutic contenders struggle to improve outcomes and unseat Nexavar as front-line therapy. This is due, in part, to liver dysfunction (cirrhosis) present in many HCC patients as well as other comorbidities resulting from infection with hepatitis B or hepatitis C, and/or occurrence of non-alcoholic fatty liver disease. In practice, systemic therapies such as Nexavar are limited to patients with the least degree of cirrhosis (Child-Pugh A). Those with greatly impaired liver function (Child-Pugh C) are often unable to tolerate current therapeutic options and generally receive only best supportive care. Even those with reasonable liver function may struggle to tolerate combination therapies that include Nexavar as a backbone.
Thus, a novel agent is greatly needed that makes strides in both efficacy and tolerability in order to encompass more patients in the treatable population. Such an agent would find an open market with a reasonable patient base; in 2016 HCC ranked as the 14th most commonly diagnosed cancer in the United States with an incidence of roughly 30,000 newly diagnosed patients.3 In Eastern countries the population suffering from HCC is slightly larger; it ranked ninth in Japan with nearly 36,000 new cases reported in 2016.3
Against this backdrop of high unmet need and reasonable opportunity, BMS/Ono entered the competitive landscape in 2012. Opdivo is a human immunoglobulin IgG4 monoclonal antibody that binds to the programmed cell death protein-1 (PD-1) receptor on immune cells, releasing tumor-driven inhibition of immune reactions. Results of Opdivo trials have shown incredible promise with overall survival gains and remarkably durable responses in multiple tumors, leading to its FDA approval in metastatic melanoma (alone or in combination with Yervoy® (ipilimumab, BMS/Ono)), metastatic non-small cell lung cancer, advanced renal cell carcinoma, classical Hodgkin’s lymphoma and squamous cell carcinoma of the head and neck.
The CheckMate-040 Phase I/II trial (NCT01658878) was initiated to evaluate the safety, tolerability, dose-limiting toxicities and maximum tolerated dose of Opdivo in 1) uninfected HCC subjects, 2) HCC patients with hepatitis B, and 3) HCC patients with hepatitis C. Patients had unresectable advanced HCC, with a Child Pugh score of ≤7 (dose escalation) or ≤6 (dose expansion). Patients could not have active HBV or HCV and were required to be on antiviral therapy with a viral load of <100 IU/mL. Subpopulations of patients were Nexavar-naïve and Nexavar-refractory.
The patient characteristics between the dose escalation and expansion cohorts were well balanced; both cohorts favored male subjects (75% and 80%, respectively) and were enriched for Asians (38% and 47%, respectively). Seventy-six percent of patients were systemic therapy-experienced, two-thirds of whom had received prior Nexavar. In October 2016, interim data were presented for 48 patients treated in the dose escalation cohort and 214 patients in the dose-expansion cohort,4 and Friday at the ASCO Gastrointestinal Cancers Symposium in San Francisco updated results were presented.5 As of the data cut-off (August 8, 2016), investigators had treated 262 patients across the dose escalation and expansion phases of the trial. Twenty-five percent of patients experienced Grade 3/4 or greater adverse events, including AST increase (10%), ALT increase (6%) and lipase increase (13%). While hematologic liver parameters are of particular concern to the HCC patient population, these were considered manageable and did not result in hepatitis. Health-related quality of life outcomes, as measured by EQ-5D index scores, did not show differences in first- or second-line patients and were stable from baseline to week 25. Thus, the relatively mild toxicity profile of Opdivo monotherapy in these pretreated HCC patients was encouraging.
In second-line Nexavar-experienced patients, 37 patients were evaluable in the escalation cohort and 145 were evaluable in the expansion cohort. Investigator assessed objective response rate (ORR) were 16.2% and 18.6% in the escalation and expansion phases, respectively, including complete response (CR) rates of 8.1% and 2.1%. Blinded independent central review noted lower rates of CR (2.7% and 0.7%, respectively), but the ORR was only slightly lower than that reported by investigators (18.9% and 14.5, respectively). The duration of response was 17.1 months in the dose escalation cohort and had not been reached in the dose expansion cohort. The median overall survival of the dose escalation cohort was 15.0 months; it was 13.2 months in the dose expansion cohort. At nine months’ follow-up, 67% and 71% of patients were alive in the escalation and expansion cohorts, respectively. In the escalation cohort, 46% of patients were alive at 18 months. In the dose expansion Nexavar-naïve cohort (69 patients), 21.7% had an objective response (all partial). Six- and nine-month overall survival rates were 87% and 77%, respectively. Expression of PD-L1 did not correlate with response to Opdivo in either patient population. Despite PD-L1 level appearing inconsequential to outcomes in this population, the discussant stated that detailed biomarker analyses (e.g., mutational burden, tumor-infiltrating lymphocytes or immune gene signatures) would further enrich the population for responders and improve survival rates even more.6
Results from the CheckMate-040 trial were very promising. Cross-trial comparisons of Opdivo and Nexavar suggest that Opdivo far outstrips efficacy numbers put up by Nexavar in previous trials (in the SHARP trial, ORR was 2% and median overall survival was 10.7 months2). Based on these encouraging results, BMS is pursuing several avenues to establish and expand the reach of Opdivo in this space. In November 2015, BMS initiated a randomized global Phase III head-to-head trial (CheckMate-459) of Opdivo versus Nexavar. The trial is recruiting treatment-naïve, Child-Pugh A advanced HCC patients in the United States, EU, Asia and Australia. According to the presenter, patient recruitment for CheckMate-459 is almost finished. In addition, BMS is exploring Opdivo use as a monotherapy and in combination with Yervoy or other novel agents in Phase I and II trials in various HCC treatment settings.
While the BMS/Ono developmental program has a head start, they are not alone in pursuing opportunities in the HCC space. Merck also has a strong program for Keytruda® (pembrolizumab, Merck & Co.). An ongoing Phase III trial (Keynote-240, NCT02702401) is investigating Keytruda versus best supportive care in relapsed/refractory HCC. An ongoing randomized Phase II trial is pitting the PD-1 inhibitor durvalumab (AstraZeneca) monotherapy versus the CTLA4 inhibitor tremelimumab (AstraZeneca) monotherapy versus the durvalumab/tremelimumab combination in Nexavar-refractory patients (NCT02519348). Another agent in development is Pexa-Vec® (pexastimogene devacirepvec, SillaJen), an oncolytic virus that also delivers GM-CSF to tumor cells. Pexa-Vec is being paired with Nexavar versus Nexavar monotherapy as first-line therapy in Child-Pugh A advanced HCC in a Phase III trial (NCT02562755). Beyond immunotherapy approaches, other targeted therapy agents are in late-stage development in HCC: Stivarga has been filed for FDA approval in second-line HCC based on the positive RESOURCE trial results, and Phase III trials are ongoing for Cabometyx® (cabozantinib, Exelixis/Ipsen), Cyramza® (ramucirumab, Eli Lilly), and tivantinib (ArQule) in second-line, and Lenvima® (lenvatinib, Eisai) in first-line.
Thus, a host of agents are seeking entry into a space that promises to become increasingly crowded in the near future. It remains to be seen whether final results from the dose expansion cohort of CheckMate-040 might prompt an accelerated approval approach, or whether BMS will wait to file until CheckMate-459 data report. Nonetheless, the data that are unfolding continue to support a potential future scenario in which Opdivo emerges triumphant as a new leader in HCC management, potentially unseating Nexavar in the front-line and bringing a more effective and tolerable treatment to a very ill patient population greatly in need of some hope.
January 23, 2017 - 03:01 pm 0 Comments
Miriam J. Atkins, MD, Augusta Oncology
By the time you read this, the Obama Administration will be written about in the past tense. But there were no moving boxes in sight when I visited the White House on January 11 to participate in a discussion about a project that will live on past Inauguration Day: fighting cancer in our communities.
It was abundantly clear that Vice President Joe Biden’s “Cancer Moonshot” initiative was not going to stop. Nor was there any sense the vital work of the nation’s cancer leaders who are addressing disparities in care ranging from access, to prevention, to diagnosis, to treatment would grind to a halt. Indeed, what I heard was that America’s community oncologists are doubling down on how we can continue to make progress towards better, more accessible, and affordable cancer care.
On panels at the White House community oncologists shared their local efforts to close the disparity gap by putting boots on the ground, and going into neighborhood malls and churches to educate people about the importance of cancer screening. We heard about telemedicine and tele-survivorship programs that have successfully connected with people living in rural and remote areas providing them with care. And, we heard about how new technologies like a simple mobile phone health apps are being used to provide information, reduce skepticism, and encourage more people to participate in clinical trials.
Across the varying, practical, and preemptive strategies that were shared that day, it became crystal clear that we all face common challenges in our effort to reach and provide the best possible care to cancer patients in our communities. Those challenges are primarily patient engagement and education; disparities in access to care; navigating the healthcare system; and financial barriers. Those are some of the obstacles that the team of 12 nurses, 10 insurance navigators, 2 nurse navigators, 2 patient account representatives, 6 physicians and I face every single day in our community oncology clinic that treats approximately 200 patients from the Augusta, Georgia area.
But at the White House there was a strong voice of support for initiatives such as the recently launched Centers for Medicare & Medicaid Services’ Oncology Care Model (OCM). Currently underway with 190 oncology practices from around the country, the OCM encourages patient-oriented services that address the challenges we face to delivering the highest quality patient care. In return, the OCM reimburses the participating centers for providing these services, keeping patients safe while they fight cancer and away from expensive hospital visits.
The OCM is a terrific first step, providing a model of care that we believe is improving patient care. But we can’t stop there. The U.S. need to advance more public policies that adequately address the challenges our nation’s cancer patients and providers face every day. This includes looking beyond the OCM to new payment and delivery system reform models, and reversing some of the bad public policies and much-abused government programs that have made access to cancer care for rural, poor, and minority patients much harder.
Miriam Atkins, MD is a practicing medical oncologist at Augusta Oncology in Augusta, Georgia. She serves on the executive committee of the Community Oncology Alliance (COA).
By Tari Awipi, Ph.D., Associate Consultant, Clinical & Scientific Assessment, Kantar Health and Jay Grisolano, Ph.D., Senior Director, Clinical & Scientific Assessment, Kantar Health
Before Cyramza® (ramucirumab, Eli Lilly and Co) was approved by the U.S. Food and Drug Administration (FDA) in 2014, no targeted therapy regimens were approved for use in relapsed/refractory gastric cancer. Cyramza’s approval as a monotherapy or in combination with paclitaxel after prior fluoropyrimidine- or platinum-containing systemic therapy was based on the positive results of two Phase III studies in relapsed gastric patients: the REGARD trial, which showed a significant overall survival (OS) benefit of 5.2 months for Cyramza versus 3.8 months for placebo,1 and the RAINBOW trial, which compared Cyramza plus paclitaxel versus paclitaxel alone, demonstrating a significant progression free survival (PFS) and OS benefit for the Cyramza combination (OS: 9.63 months in Cyramza plus paclitaxel arm versus 7.36 months in paclitaxel alone arm).2 Cyramza had a significant first-to-market advantage in this indication and is currently highly utilized in this space (30.4% as monotherapy or with paclitaxel in second-line in the U.S.).3 However, given the limited number of treatment options, new agents still have a lot of potential, including immunotherapies, which have already made a splash in other solid tumor types.
While gastric cancer is a relatively rare tumor type in the United States (ranks 16th in terms of incidence), it is the most commonly diagnosed tumor type in Japan.3 In part due to this, Ono Pharmaceuticals took the lead in evaluating immunotherapy in gastric cancer in Asia Pacific. In 2014, Ono Pharmaceuticals (which is co-developing Opdivo along with Bristol-Myers Squibb) initiated a randomized (2:1), double-blind, Phase III trial of Opdivo® (nivolumab) in gastric and gastroesophageal junction (GEJ) cancer patients in Japan, Korea and Taiwan (ONO-4538-12; NCT02267343). In this trial, Opdivo (3 mg/kg q2w) was compared against placebo in patients refractory or intolerant to standard therapies. The primary endpoint was OS. In yesterday’s oral abstract session at the 2017 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, positive data from this trial were presented.4 The trial enrolled 493 patients with unresectable advanced or recurrent gastric/GEJ cancer who had failed two or more previous chemotherapy regimens, including Cyramza. As of the data cut-off on August 13, 2016, 5.6 months after the last patient was randomized, median OS was 5.32 months with Opdivo versus 4.14 months with placebo (hazard ratio, 0.63; 95% confidence interval (CI), 0.50-0.78; p<0.0001), and OS rates at six and 12 months were 46.4% versus 34.7% and 26.6% versus 10.9%, respectively. The overall response rate was 11.2% with Opdivo versus 0% with placebo (p<0.0001). Median PFS was 1.61 months with Opdivo versus 1.45 months with placebo (HR, 0.60; 95% CI, 0.49-0.75; p<0.0001). Grade ≥ 3 drug-related adverse events (AEs) occurred in 11.5% of Opdivo-treated patients and in 5.5% of placebo-treated patients; 2.7% and 2.5% of patients, in the respective arms, discontinued study treatment due to drug-related AEs (any grade). The most common AEs were pruritus, diarrhea, rash, fatigue, and decreased appetite. These data were well received by the conference audience. Of particular excitement was the characteristic OS plateau or “tail” in the Kaplan-Meier curve that we have come to expect from the checkpoint inhibitor class of immunotherapy agents; while the OS difference at the median was modest (1.18 months), a strong separation between the two curves that appears to be maintained long-term. Biomarker analysis was not reported, but is ongoing.
Not surprisingly, Ono has already filed for approval of Opdivo in gastric cancer in Japan with this data. Despite the Japanese filing, BMS has not stated that it has plans to file in the U.S. based on this data, perhaps given the enrollment was limited to Asian populations. Indeed during the discussion, Dr. Lenz of USC Norris Comprehensive Cancer Center took care to point out the molecular differences in gastric cancer between Asian and non-Asian populations citing reported differences in immune signatures.5 Furthermore, subgroup analysis in this trial showed a stronger magnitude of benefit (HR 0.59) in patients with intestinal histologic type (a better prognostic subset that is more common in Asian gastric cancer patients) compared with patients with diffuse histology type (HR 0.82; a worse prognostic subset that is more common in Caucasian gastric cancer patients). Together, this information raise doubts about the translatability of these data in Asian patients to a broader U.S. population. During the question-and-answer portion, however, the issue of U.S. filing based on these Asian data was raised, and some felt that, rather than wait for a new Phase III trial readout, a confirmatory Phase II trial in a U.S. population could warrant filing. Although not raised in yesterday’s session, an alternative scenario could be the National Comprehensive Cancer Network (NCCN) recommending Opdivo for use in relapsed/refractory gastric/GEJ. Such action (NCCN guideline recommendation for U.S. patients based strictly on Asian data) has not previously occurred but might not be entirely outside the realm of possibility given the unmet needs in gastric cancer and the well-established safety profile for Opdivo in other indications, even if balanced against the histologic subgroup data from the Japanese trial. In the absence of accelerated filing or NCCN recommendation, filing with the FDA may need to await the results of the ongoing global Phase III CheckMate 649 trial (NCT02872116) that is being conducted in the first-line setting and is investigating the combination of Opdivo plus Yervoy® (ipilimumab, BMS/Ono), data from which is not expected for several years.
Opdivo is not the only immunotherapy under late-stage development in gastric cancer. Keytruda® (pembrolizumab, MSD) has multiple Phase III trials underway in first-line and relapsed/refractory disease and may be the first immunotherapy agent to enter the gastric cancer market in the United States. Pfizer and Merck KGaA are also developing their PD-L1 inhibitor avelumab in relapsed/refractory gastric cancer. And of course non-immunotherapy approaches are also under late-stage development, including napabucasin (BBI608, Boston Biomedical/Sumitomo Dainippon) in second-line (NCT02178956), Lonsurf® (trifluorothymidine/tipiracil hydrochloride, Taiho) in third-line, GS-5745 (Gilead) in first-line, and Cyramza in first-line. Although the results of this Asian Phase III trial may not have an immediate impact in the U.S. gastric cancer market, these remain highly impactful results globally. Opdivo could gain approval in this indication in Japan as early as late 2017, putting it well-ahead of other competitors in this setting and bringing a new option to this population of high unmet need.