On June 3, 2017 TESARO, Inc. (NASDAQ:TSRO), an oncology-focused biopharmaceutical company, reported initial data from the TOPACIO trial of niraparib plus KEYTRUDA (pembrolizumab) and results of a Phase 1 trial of TSR-042 during an investor briefing held in conjunction with the American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2017 Annual Meeting (Press release, TESARO, JUN 3, 2017, View Source [SID1234519444]). The Company also provided an update on its commercial businesses in the U.S. and Europe.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"ASCO represents an opportunity to showcase ZEJULA and the potential for it to positively impact the lives of women with recurrent ovarian cancer. Data presented earlier today during the conference further characterize the positive, durable treatment effects of ZEJULA and the clinical benefit in women who have residual disease following treatment with platinum-based chemotherapy. We are excited that the initial data from TOPACIO suggest a potential synergy between niraparib and an anti-PD-1 antibody, and look forward to evaluating this combination further in ovarian cancer and additional tumor types," said Lonnie Moulder, CEO of TESARO. "To date, there has been an overwhelmingly positive response by prescribers, patients and payors related to our U.S. launch and the potential for ZEJULA to benefit women with recurrent ovarian cancer. Our European organization has started filling orders for VARUBY in Germany, with other countries soon to follow. Pre-launch preparations are also underway to support the introduction of ZEJULA in Europe later this year, pending European Commission approval. In the U.S., demand for the oral formulation of VARUBI continues to increase and we look forward to a fourth quarter launch of VARUBI IV to extend our offering for patients who are undergoing emetogenic chemotherapy. Finally, our immuno-oncology programs are advancing at a rapid pace, led by the clinical study of TSR-042, our anti-PD-1 antibody, which we believe will form the basis for a registration of the drug in patients with MSI-H tumors, including endometrial cancer."

TOPACIO Data Demonstrate Activity in Platinum-Resistant Ovarian Cancer
TOPACIO is a Phase 1/2 clinical trial designed to evaluate the preliminary safety and efficacy of niraparib plus KEYTRUDA (pembrolizumab) in patients with recurrent, platinum-resistant ovarian cancer or triple negative breast cancer. Phase 1 of TOPACIO consisted of a dose escalation study to evaluate an oral, once-daily dose of niraparib (200 milligrams or 300 milligrams) plus 200 milligrams of pembrolizumab administered intravenously on day one of each 21-day treatment cycle. Endpoints included tolerability assessments, pharmacokinetic measures, and RECIST response rate.

In the dose escalation phase, a disease control rate of 69% was observed (9 of 13 evaluable patients), including 3 PRs and 1 CR, in patients with platinum-resistant ovarian cancer. The most common grade ≥3 adverse events included thrombocytopenia, anemia and neutropenia. At the recommended Phase 2 dose, one of seven patients experienced grade 3 thrombocytopenia and no significant overlapping toxicities were observed. A dose of 200 milligrams of niraparib once daily was selected for evaluation with pembrolizumab in Phase 2 of this study.

The first expansion cohorts of patients with platinum-resistant ovarian cancer (n=24) and triple-negative breast cancer (n=24) are now fully enrolled, and the second expansion cohorts for each tumor have been opened. Additional data from this trial are anticipated to become available during the second half of 2017.

The TOPACIO trial is being conducted in collaboration with Merck Sharp & Dohme B.V., a subsidiary of Merck & Co., Inc., which is providing support for the trial.

TSR-042 Phase 1 Results Show Anti-PD-1 Activity
The Phase 1 study of TSR-042, TESARO’s anti-PD-1 antibody, is now complete. No dose limiting toxicities were observed. Among the 21 heavily pretreated patients in Part 1 of the study, two had a partial response (PR) and five had stable disease. Adverse events were commensurate with commercially-available anti-PD-1 therapies.

Following the identification of a fixed dose and patient-centric dosing schedule, the ongoing clinical trial of TSR-042 was expanded to enroll patients with metastatic microsatellite instability-high (MSI-H) endometrial cancer who have progressed following one or two prior chemotherapy treatments. During the first 12 weeks of treatment, TSR-042 is administered once every three weeks, followed by administration every six weeks until disease progression. The intent of this study is to support a request for accelerated approval and Biologics License Application (BLA) submission to the U.S. Food and Drug Administration (FDA). The primary endpoints of this trial are overall response rate (ORR) and duration of response, and secondary endpoints include disease control rate, progression free survival (PFS), and overall survival (OS). The addition of cohorts for patients with other tumor types, including those with MSI-H tumors, is also planned. This is the first clinical development program within a broader plan that includes potential label expansion trials of TSR-042 in multiple cancers in combination with ZEJULA, TSR-022, TESARO’s anti-TIM-3 antibody, and TSR-033, TESARO’s anti-LAG-3 antibody.

Niraparib Data Presentations at ASCO (Free ASCO Whitepaper) Demonstrate Positive, Durable Treatment Effect
Three posters describing additional data analyses from the Phase 3 ENGOT-OV16/NOVA trial of niraparib were presented today during the ASCO (Free ASCO Whitepaper) Annual Meeting.

An analysis was performed to assess PFS and safety in patients who enrolled in the NOVA trial after a PR to their last platinum-based chemotherapy. Approximately 50% of all patients who enrolled in this trial entered with a PR, and results demonstrated that niraparib treatment provided significant benefit to these patients, with a treatment effect similar to that observed in the overall study population in both the gBRCAmut cohort (HR=0.24 for patients with a PR vs. HR=0.27 for all patients) and non-gBRCAmut cohort (HR=0.35 for patients with a PR and HR=0.45 for all patients). The safety profile of niraparib-treated patients with a PR was similar to that of the overall study population.

An assessment of platinum resistance status of patients in the NOVA trial was performed to better understand the population of patients that could benefit from treatment with niraparib. Approximately 50% of the patients in the placebo arm of this trial were found to have platinum-resistant disease following their last platinum-based therapy, as defined by progressive disease occurring less than six months following the last dose of chemotherapy. These findings suggest that approximately half of the total NOVA study population had disease that would have been considered platinum-resistant when they began maintenance treatment during the trial. The results of NOVA demonstrate that patients who had developed platinum-resistant disease after their last round of chemotherapy experienced benefit from niraparib maintenance.

Additional analyses of NOVA assessed the longer-term efficacy of niraparib. Across both the gBRCAmut and non-gBRCAmut cohorts, treatment with niraparib increased the probability of PFS at 12, 18 and 24 months from randomization vs. placebo, as demonstrated by Kaplan-Meier estimates. The similarity in results for PFS2 minus PFS1 between niraparib and placebo suggests that niraparib had no decremental effect on the benefit of subsequent therapy.
Robust Demand for ZEJULA Continues
The U.S. launch of ZEJULA is off to a strong start, with more than 800 new patient starts since approval and prescriptions written by over 600 physicians. TESARO introduced ZEJULA in late April, following U.S. FDA approval for use as a maintenance treatment for women with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response (CR or PR) to platinum-based chemotherapy. ZEJULA is the only PARP inhibitor to have demonstrated efficacy in patients without BRCA mutations in a randomized, Phase 3 trial and is the only PARP inhibitor to be approved by the FDA that does not require patient selection with a biomarker test. Pre-launch preparations continue in support of a European launch of ZEJULA by year-end 2017, pending European Commission approval. The niraparib early access program, or EAP, has already enrolled a number of patients in Europe, and more patients are anticipated to enter the program.

VARUBY Launches Ongoing in Europe; VARUBI IV PDUFA Date Established in the U.S.
Following the approval of VARUBY (oral formulation) by the European Commission for the prevention of delayed nausea and vomiting associated with highly and moderately emetogenic cancer chemotherapy in adults, VARUBY is now available in Germany. In the U.S., the FDA has accepted the Company’s NDA re-submission for rolapitant IV and classified it as a Class 2 resubmission with a Prescription Drug User Fee Act (PDUFA) action date of October 25, 2017. TESARO is committed to bringing the intravenous formulation of VARUBI to physicians and patients to enable additional flexibility and choice of antiemetic regimens.

About ZEJULA (niraparib)
ZEJULA (niraparib) is an oral, once-daily poly(ADP-ribose) polymerase (PARP) 1/2 inhibitor that is indicated in the U.S. for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. In preclinical studies, ZEJULA concentrates in the tumor relative to plasma, delivering greater than 90% durable inhibition of PARP 1/2 and a persistent antitumor effect.

ZEJULA (niraparib) Select Important Safety Information
Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) was reported in patients treated with ZEJULA in all clinical studies. Discontinue ZEJULA if MDS/AML is confirmed. Hematologic adverse reactions (thrombocytopenia, anemia and neutropenia) have been reported in patients treated with ZEJULA. Do not start ZEJULA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1). Monitor complete blood counts weekly for the first month, monthly for the next 11 months of treatment, and periodically after this time.

Hypertension and hypertensive crisis have been reported in patients treated with ZEJULA. Monitor blood pressure and heart rate monthly for the first year and periodically thereafter during treatment with ZEJULA. Closely monitor patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Based on its mechanism of action, ZEJULA can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for six months after receiving the final dose. Because of the potential for serious adverse reactions in breastfed infants from ZEJULA, advise a lactating woman not to breastfeed during treatment with ZEJULA and for one month after receiving the final dose.

In clinical studies, the most common adverse reactions included: thrombocytopenia, anemia, neutropenia, nausea, constipation, vomiting, abdominal pain/distension, mucositis/stomatitis, diarrhea, fatigue/asthenia, decreased appetite, headache, insomnia, nasopharyngitis, dyspnea, rash and hypertension.

Please see full Prescribing Information for additional Safety Information at www.zejula.com.

About VARUBI (rolapitant)
VARUBI is a substance P/neurokinin-1 (NK-1) receptor antagonist indicated in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. NK-1 receptors are highly concentrated in the brain and bind neurokinin substance P. Activation of NK-1 receptors plays a central role in nausea and vomiting induced by emetogenic stimuli, including certain cancer chemotherapies. A Positron Emission Tomography (PET) study with rolapitant in normal, healthy volunteers demonstrated that rolapitant crosses the blood brain barrier and occupies brain NK-1 receptors at high levels for up to 120 hours. VARUBI has a half-life of approximately seven days, which may contribute to the ability of a single dose of VARUBI to cover the entire delayed CINV Phase (25-120 hours). VARUBI is contraindicated in patients receiving thioridazine, a CYP2D6 substrate. The inhibitory effect of a single dose of VARUBI on CYP2D6 lasts at least seven days and may last longer. Avoid use of pimozide; monitor for adverse events if concomitant use with other CYP2D6 substrates with a narrow therapeutic index cannot be avoided. Please see full prescribing information, including additional important safety information, available at View Source

About TSR-042
TSR-042 is a monoclonal antibody targeting PD-1 and was developed as part of the collaboration between TESARO and AnaptysBio, Inc. This collaboration was initiated in March of 2014, and is focused on the development of monospecific antibody drugs targeting PD-1, TIM-3 (TSR-022), and LAG-3 (TSR-033), in addition to a bi-specific antibody drug candidate targeting PD-1/LAG-3.

About Endometrial Cancer
Endometrial cancer is the most common type of uterine cancer, accounting for more than 95 percent of cases. Endometrial cancer develops in the lining of the uterus, called the endometrium. The annual number of new cases of endometrial cancer is estimated at 325,000 worldwide. The most common histologic form is endometrioid adenocarcinoma originating in the glandular tissue, which represents about 75-80% of diagnosed cases. In 2017, SEER1 estimates 61,380 patients will be diagnosed with endometrial cancer, with approximately 30% or 18,414 being stage III/IV patients. Based on genomic characterization studies of endometrial cancer, 20-25% of patients have tumors with a microsatellite instability phenotype (MSI-H)2. Microsatellite instability arises from a failure to repair replication-associated errors due to a defective DNA mismatch repair system. This failure allows persistence of mismatch mutations all over the genome, but especially in regions of repetitive DNA known as microsatellites, leading to increased mutational load that has been demonstrated to improve responses to anti-PD-1 therapies.3,4

On June 5, 2017 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that new data for TECENTRIQ and updates from across its extensive cancer immunotherapy clinical development programme will be presented during the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting on 2 June – 6 June in Chicago, Illinois, United States (Press release, Hoffmann-La Roche, JUN 3, 2017, View Source [SID1234519439]). Data from phase I, II and Phase III studies presented at ASCO (Free ASCO Whitepaper) 2017 suggest that TECENTRIQ has the potential to be used as a foundational combination partner with cancer immunotherapies, targeted medicines and various chemotherapies across a broad range of cancers.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Data from a study of TECENTRIQ plus Avastin in metastatic Renal Cell Carcinoma (mRCC) supports a scientific rationale for combining TECENTRIQ with Avastin including its potential to increase infiltration (trafficking) of T-cells into tumours and other immune-modulatory properties. New data will also be presented for TECENTRIQ as a monotherapy from the OAK trial, which represent the first treatment-beyond-progression data from a Phase III study of cancer immunotherapy in advanced lung cancer (NSCLC). Updated data will also be presented from the Phase Ib study of TECENTRIQ in combination with chemotherapy for people with advanced NSCLC. Two Phase Ib studies in melanoma combining TECENTRIQ plus Cotellic (cobimetinib) and TECENTRIQ plus Cotellic plus Zelboraf (vemurafenib) showed that the addition of Zelboraf and/or Cotellic may alter the tumour micro environment, enhancing the anti-tumour activity of TECENTRIQ.

"By applying our seminal research in immune tumour profiling within the framework of the Roche-devised cancer immunity cycle, we are accelerating and expanding the transformative benefits with TECENTRIQ to a greater number of people living with cancer," said Sandra Horning, MD, Chief Medical Officer and Head of Global Product Development. "Our cancer immunotherapy development programme takes a comprehensive approach in pursuing the goal of restoring cancer immunity to improve outcomes for patients, and at ASCO (Free ASCO Whitepaper) 2017 we are presenting data from a range of medicines and combinations that we believe have this potential."
Kidney cancer (Renal Cell Carcinoma RCC)

IMmotion150 is a global, multicentre Phase II study that was designed to evaluate the efficacy and safety of TECENTRIQ plus Avastin, TECENTRIQ alone or sunitinib alone in 305 patients with previously untreated, locally advanced or mRCC. After progression on the sunitinib or TECENTRIQ arms of the study, 77% and 75% of patients crossed over to TECENTRIQ plus Avastin treatment, respectively.

Clinical activity of TECENTRIQ plus Avastin was seen in crossover patients regardless of first line TECENTRIQ or sunitinib therapy or response to first line therapy, further supporting this combination as a potential treatment option. Specifically, TECENTRIQ plus Avastin resulted in an Overall Response Rate (ORR) of 26% in all-crossover patients (28% in crossover post-sunitinib; 24% in crossover post-TECENTRIQ patients) with a median Progression Free Survival (PFS) of 8.8 months in all-crossover patients. There were no new safety signals observed in the crossover treated patients.

A Phase III study, IMmotion151, in a similar population is expected to provide initial results in early 2018.
IMmotion150: A Phase II trial in untreated metastatic renal cell carcinoma (mRCC) patients (pts) of atezolizumab (atezo) and bevacizumab (bev) vs and following atezo or sunitinib (sun). Oral abstract 4505 Monday 5 June, 08:00 – 11:00 CDT

Lung cancer
In the Phase III OAK trial, which studied the impact of TECENTRIQ treatment beyond radiologic disease progression (PD), showed that a continuation of TECENTRIQ treatment after PD resulted in promising clinical benefit. The study design allowed patients randomised to TECENTRIQ to continue treatment beyond PD, as assessed by Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, if the patient was considered to be deriving clinical benefit from treatment. TECENTRIQ could be continued until there was loss of clinical benefit according to the investigator’s clinical judgement.

Patients in the TECENTRIQ arm who continued TECENTRIQ therapy beyond PD had a prolonged clinical benefit, 12.7 months Overall Survival (OS) (95% CI 9.3–14.9) compared with 8.8 months OS (6.0 – 12.1) for those treated with other anti-cancer treatments post PD. Tumour target lesion responses and stabilisation post-PD were seen across all subgroups of programmed death-ligand 1 (PD-L1) expression. These data support the treatment strategy of continuing TECENTRIQ beyond PD until loss of clinical benefit in patients, regardless of the level of PD-L1 expression.
Impact of atezolizumab (atezo) treatment beyond disease progression (TBP) in advanced NSCLC: Results from the randomised phase III OAK study. Oral abstract TPS5090
Tuesday 6 June, 09:45 – 12:45 CDT

The updated efficacy and safety data for Arms C–E of our phase Ib GP28328 study are encouraging for TECENTRIQ in combination with various chemotherapies. The primary endpoint of the study was safety and TECENTRIQ was well tolerated when combined with various chemotherapies.
Updated efficacy and safety data table for TECENTRIQ in combination Arms C–E

The confirmed ORRs and mature OS data provide further evidence for a synergy between the anti-tumour activity of TECENTRIQ and chemotherapy.
Abstract 9092, Poster Board: #418. Lung Cancer—Non-Small Cell Metastatic
Saturday 6 June, 08:00 – 11:30 CDT

Melanoma
Updated study results from two Phase Ib studies combining TECENTRIQ plus Cotellic (cobimetinib) and, TECENTRIQ plus Cotellic plus Zelboraf (vemurafenib) showed improved ORR and PFS after a longer follow up. Both combination studies demonstrated a manageable safety profile.

Based on the results of the Phase 1b studies both combinations are now in Phase III clinical trials. The TECENTRIQ plus Cotellic plus Zelboraf combination will be investigated in people with untreated BRAFV600‑mutant unresectable metastatic melanoma while the TECENTRIQ plus Cotellic combination will be studied in people with untreated, unresectable metastatic BRAF wild-type melanoma.
Atezolizumab (A) + cobimetinib (C) + vemurafenib (V) in BRAFV600-mutant metastatic melanoma (mel): Updated safety and clinical activity. Abstract 3063
Monday 5 June, 08:00 – 11:30 CDT
Atezolizumab (A) + cobimetinib (C) in metastatic melanoma (mel): Updated safety and clinical activity.
Abstract 3057
Monday 5 June, 8:00 – 11:30CDT
Pipeline
Data from two studies will be presented that demonstrate the potential of TECENTRIQ in combination with novel cancer immunotherapies. These studies include a Phase I dose escalation study evaluating the T-cell bispecific (CEA- TCB) antibody as a single agent or in combination with TECENTRIQ in patients with metastatic colorectal cancer and a Phase Ib dose-escalation study evaluating the combined inhibition of TECENTRIQ plus IDO1 (GDC-0919) in patients with locally advanced or metastatic solid tumours and
Monotherapy data will also be presented from a Phase Ia study of TECENTRIQ in advanced/recurrent endometrial cancer (rEC), a patient population for whom the prognosis remains poor. The study is evaluating clinical activity and safety. Results show that TECENTRIQ has a favourable safety profile in rEC, with durable clinical benefit seen in some patients. Clinical benefit appeared to increase with higher PD-L1 expression, suggesting a link between PD-L1 status and response.

Further information on Roche’s contribution to the ASCO (Free ASCO Whitepaper) 2017 scientific programme, the company’s wider progress in cancer care and key data being presented at the conference will be featured at a Roche investor briefing on Monday, 5 June 2017 at 17:15 CDT. This event is independently organised by Roche and is open to analysts attending the ASCO (Free ASCO Whitepaper) 2017 Annual Meeting. To register for the Roche investor briefing, please use the following link: http://roche.cvent.com/d/85qzfy.

To learn more about Roche’s personalised cancer immunotherapy programme and Roche’s contribution to ASCO (Free ASCO Whitepaper) 2017, please follow Roche on Twitter via @Roche. You can keep up to date with ASCO (Free ASCO Whitepaper) 2017 Annual Meeting news and updates by using the hashtag #ASCO17.
Overview of Roche cancer immunotherapy data being presented at ASCO (Free ASCO Whitepaper) 2017

On June 3, 2017 Incyte Corporation (NASDAQ:INCY) reported updated data from the advanced non-small cell lung cancer (NSCLC) patient cohort of the ongoing Phase 1/2 ECHO-202 trial, evaluating epacadostat, Incyte’s selective IDO1 enzyme inhibitor, in combination with pembrolizumab (Keytruda), an anti-PD-1 therapy marketed by Merck & Co., Inc., Kenilworth, NJ USA (known as MSD outside the United States and Canada) (Press release, Incyte, JUN 3, 2017, View Source;p=RssLanding&cat=news&id=2278620 [SID1234519423]). Data showed an overall response rate (ORR) of 35 percent (n=14/40) among all patients with advanced squamous and non-squamous NSCLC treated with the combination of epacadostat and pembrolizumab, irrespective of PD-L1 status. Findings will be highlighted in a poster discussion at the 2017 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago on Saturday, June 3, from 3:00 pm to 4:15 p.m. CDT (Location: Hall D2) (Abstracts #9014).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"These updated data suggest that the combination of epacadostat and pembrolizumab has promise for patients with advanced NSCLC, irrespective of PD-L1 status," said ECHO-202 study investigator Tara Gangadhar, M.D., Assistant Professor of Medicine, Perelman School of Medicine at the Hospital of the University of Pennsylvania. "The results show a clinical benefit for patients with advanced lung cancer and establish a strong basis for progressing this novel, investigational immunotherapy combination into pivotal studies for the first-line treatment of these patients."

Key Findings from the ECHO-202 NSCLC Cohort
Data at ASCO (Free ASCO Whitepaper) (as of February 27, 2017) show an ORR of 35 percent (n=14/40) among all patients with advanced NSCLC treated with the combination of epacadostat and pembrolizumab, with a complete response (CR) in two patients (5%) and partial response (PR) in 12 patients (30%). The data show a disease control rate (DCR) of 63 percent (n=25/40), with 71 percent (n=10/14) of responses ongoing at the time of the data cut-off (duration of response, range: 8.9 to 76.6+ weeks). Responses were observed in patients with high levels of PD-L1 expression [tumor proportion score (TPS) ≥50%], as well as in those patients with lower levels of PD-L1 expression (TPS of less than 50%). All responses were observed in the subgroup of patients with zero to two prior lines of therapy for advanced disease.

ECHO-202 Overall Response Rates (ORR), Disease Control Rates (DCR) and Durability of Response (DoR) in Advanced NSCLC
n/N
(%)
All pts

0-2 prior lines of therapy for advanced disease
Total Total TPS ≥50%* TPS <50%*
ORR n=14/40
(35)
n=14/36
(39)
n=3/7
(43) n=6/18
(33)
2 CR (5)
12 PR (30)
2 CR (6)
12 PR (33)
all PR 1 CR (6)
5 PR (28)
DCR n=25/40
(63) n=23/36
(64)
n=4/7
(57) n=10/18
(56)
DoR 10/14 responses ongoing
Median (range) duration of response: 26.9+ (8.9 to 76.6+) weeks
*Note: PD-L1 status was not available for 11 of the 36 patients.

Among patients treated with pembrolizumab in combination with epacadostat ≥100 mg twice daily, the ORR was 40 percent (n=14/35).

The most common treatment-related adverse events (TRAEs) for epacadostat plus pembrolizumab included fatigue (28%), arthralgia (17%), nausea (14%), decreased appetite (10%), pruritus (10%), and rash (10%). Grade ≥3 TRAEs that occurred in >1 patient were limited to lipase increased (n=3), fatigue (n=2), and rash (n=2). TRAEs led to discontinuation of treatment in 5 percent of study patients. The safety profile was consistent with previously reported Phase 1 findings, as well as the Phase 1/2 safety results in other tumor cohorts and pooled safety data from this study. In general, the safety profile of the combination was also consistent with pembrolizumab monotherapy.

About ECHO-202 (KEYNOTE-037)
The ECHO-202 study (NCT02178722) is evaluating the safety and efficacy of epacadostat, Incyte’s selective IDO1 inhibitor, in combination with pembrolizumab (Keytruda). Patients previously treated with anti-PD-1 or anti-CTLA-4 therapies were excluded from this trial. Enrollment is complete for the Phase 1 dose escalation (epacadostat 25, 50, 100 mg BID + pembrolizumab 2 mg/kg IV Q3W and epacadostat 300 mg BID + pembrolizumab 200 mg IV Q3W) and Phase 1 dose expansion (epacadostat 50, 100, and 300 mg BID + pembrolizumab 200 mg IV Q3W) portions of the trial. For more information about ECHO-202, visit View Source

About ECHO
The ECHO clinical trial program was established to investigate the efficacy and safety of epacadostat as a core component of combination therapy in oncology. Ongoing Phase 1 and Phase 2 studies evaluating epacadostat in combination with PD-1 and PD-L1 inhibitors collectively plan to enroll over 900 patients in a broad range of solid tumor types as well as hematological malignancies. ECHO-301 (NCT02752074), a Phase 3 randomized, double-blind, placebo-controlled study investigating pembrolizumab (Keytruda) in combination with epacadostat or placebo for the treatment of patients with unresectable or metastatic melanoma, is also underway. For more information about the ECHO clinical trial program, visit www.ECHOClinicalTrials.com.

About Epacadostat (INCB024360)
Indoleamine 2,3-dioxygenase 1 (IDO1) is a key immunosuppressive enzyme that modulates the anti-tumor immune response by promoting regulatory T cell generation and blocking effector T cell activation, thereby facilitating tumor growth by allowing cancer cells to avoid immune surveillance. Epacadostat is an investigational, highly potent and selective oral inhibitor of the IDO1 enzyme that regulates the tumor immune microenvironment, thereby restoring effective anti-tumor immune responses. In single-arm studies, the combination of epacadostat and immune checkpoint inhibitors has shown proof-of-concept in patients with unresectable or metastatic melanoma. In these studies, epacadostat combined with the CTLA-4 inhibitor ipilimumab or the PD-1 inhibitor KEYTRUDA improved response rates compared with studies of the immune checkpoint inhibitors alone.

On June 3, 2017 Incyte Corporation (Nasdaq:INCY) and Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported updated data from the advanced non-small cell lung cancer (NSCLC) patient cohort of the ongoing Phase 1/2 ECHO-202 trial, evaluating epacadostat, Incyte’s selective IDO1 enzyme inhibitor, in combination with KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 therapy (Press release, Incyte, JUN 3, 2017, View Source;p=RssLanding&cat=news&id=2278619 [SID1234519418]). Data showed an overall response rate (ORR) of 35 percent (n=14/40) among all patients with advanced squamous and non-squamous NSCLC treated with the combination of epacadostat and KEYTRUDA, irrespective of PD-L1 status. Findings will be highlighted in a poster discussion at the 2017 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago on Saturday, June 3, from 3:00 pm to 4:15 p.m. CDT (Location: Hall D2) (Abstracts #9014). This

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"These updated data suggest that the combination of epacadostat and pembrolizumab has promise for patients with advanced NSCLC, irrespective of PD-L1 status," said ECHO-202 study investigator Tara Gangadhar, M.D., Assistant Professor of Medicine, Perelman School of Medicine at the Hospital of the University of Pennsylvania. "The results show a clinical benefit for patients with advanced lung cancer and establish a strong basis for progressing this novel, investigational immunotherapy combination into pivotal studies for the first-line treatment of these patients." Key Findings from the ECHO-202 NSCLC Cohort Data at ASCO (Free ASCO Whitepaper) (as of February 27, 2017) show an ORR of 35 percent (n=14/40) among all patients with advanced NSCLC treated with the combination of epacadostat and KEYTRUDA, with a complete response (CR) in two patients (5%) and partial response (PR) in 12 patients (30%). The data show a disease control rate (DCR) of 63 percent (n=25/40), with 71 percent (n=10/14) of responses ongoing at the time of the data cut-off (duration of response, range: 8.9 to 76.6+ weeks). Responses were observed in patients with high levels of PD-L1 expression [tumor proportion score (TPS) ≥50%], as well as in those patients with lower levels of PD-L1 expression (TPS of less than 50%). All responses were observed in the subgroup of patients with zero to two prior lines of therapy for advanced disease. ECHO-202 Overall Response Rates (ORR), Disease Control Rates (DCR) and Durability of Response (DoR) in Advanced NSCLC n/N (%) All pts 0-2 prior lines of therapy for advanced disease Total Total TPS ≥50%* TPS <50%* ORR n=14/40 (35) n=14/36 (39) n=3/7 (43) n=6/18 (33) 2 CR (5) 12 PR (30) 2 CR (6) 12 PR (33) all PR 1 CR (6) 5 PR (28) DCR n=25/40 n=23/36 n=4/7 n=10/18 (63) (64) (57) (56) DoR 10/14 responses ongoing Median (range) duration of response: 26.9+ (8.9 to 76.6+) weeks *Note: PD-L1 status was not available for 11 of the 36 patients. Among patients treated with KEYTRUDA in combination with epacadostat ≥100 mg twice daily, the ORR was 40 percent (n=14/35). The most common treatment-related adverse events (TRAEs) for epacadostat plus KEYTRUDA included fatigue (28%), arthralgia (17%), nausea (14%), decreased appetite (10%), pruritus (10 %), and rash (10%). Grade ≥3 TRAEs that occurred in >1 patient were limited to lipase increased (n=3), fatigue (n=2), and rash (n=2). TRAEs led to discontinuation of treatment in 5 percent of study patients. The safety profile was consistent with previously reported Phase 1 findings, as well as the Phase 1/2 safety results in other tumor cohorts and pooled safety data from this study. In general, the safety profile of the combination was also consistent with KEYTRUDA monotherapy. About ECHO-202 (KEYNOTE-037) The ECHO-202 study (NCT02178722) is evaluating the safety and efficacy of epacadostat, Incyte’s selective IDO1 inhibitor, in combination with KEYTRUDA. Patients previously treated with anti-PD-1 or anti-CTLA-4 therapies were excluded from this trial. Enrollment is complete for the Phase 1 dose escalation (epacadostat 25, 50, 100 mg BID + KEYTRUDA 2 mg/kg IV Q3W and epacadostat 300 mg BID + KEYTRUDA 200 mg IV Q3W) and Phase 1 dose expansion (epacadostat 50, 100, and 300 mg BID + KEYTRUDA 200 mg IV Q3W) portions of the trial. For more information about ECHO-202, visit View Source About ECHO The ECHO clinical trial program was established to investigate the efficacy and safety of epacadostat as a core component of combination therapy in oncology. Ongoing Phase 1 and Phase 2 studies evaluating epacadostat in combination with PD-1 and PD-L1 inhibitors collectively plan to enroll over 900 patients in a broad range of solid tumor types as well as hematological malignancies. ECHO-301 (NCT02752074), a Phase 3 randomized, double-blind, placebo-controlled study investigating KEYTRUDA (pembrolizumab) in combination with epacadostat or placebo for the treatment of patients with unresectable or metastatic melanoma, is also underway. For more information about the ECHO clinical trial program, visit www.ECHOClinicalTrials.com. About Epacadostat (INCB024360) Indoleamine 2,3-dioxygenase 1 (IDO1) is a key immunosuppressive enzyme that modulates the anti-tumor immune response by promoting regulatory T cell generation and blocking effector T cell activation, thereby facilitating tumor growth by allowing cancer cells to avoid immune surveillance. Epacadostat is an investigational, highly potent and selective oral inhibitor of the IDO1 enzyme that regulates the tumor immune microenvironment, thereby restoring effective anti-tumor immune responses. In single-arm studies, the combination of epacadostat and immune checkpoint inhibitors has shown proof-of-concept in patients with unresectable or metastatic melanoma. In these studies, epacadostat combined with the CTLA-4 inhibitor ipilimumab or the PD-1 inhibitor KEYTRUDA improved response rates compared with studies of the immune checkpoint inhibitors alone.

About KEYTRUDA (pembrolizumab) Injection KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells. Studies of KEYTRUDA – from the largest immuno-oncology program in the industry with more than 500 trials – include a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand factors that predict a patient’s likelihood of benefiting from treatment with KEYTRUDA, including the exploration of several different biomarkers across a broad range of tumors. KEYTRUDA is administered as an intravenous infusion over 30 minutes every three weeks for the approved indications. KEYTRUDA for injection is supplied in a 100 mg single-dose vial. KEYTRUDA (pembrolizumab) Indications and Dosing Melanoma KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity. Lung Cancer KEYTRUDA (pembrolizumab), as a single agent, is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [tumor proportion score (TPS) ≥50%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations. KEYTRUDA, as a single agent, is also indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA. KEYTRUDA, in combination with pemetrexed and carboplatin, is indicated for the first-line treatment of patients with metastatic nonsquamous NSCLC. This indication is approved under accelerated approval based on tumor response rate and progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. When administering KEYTRUDA in combination with chemotherapy, KEYTRUDA should be administered prior to chemotherapy when given on the same day. See also the Prescribing Information for pemetrexed and carboplatin. Head and Neck Cancer KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In HNSCC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. Classical Hodgkin Lymphoma KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after three or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In adults with cHL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with cHL, KEYTRUDA (pembrolizumab) is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression. Urothelial Carcinoma KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. KEYTRUDA is also indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. In locally advanced or metastatic urothelial carcinoma, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression. Microsatellite Instability-High (MSI-H) Cancer KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established. In adult patients with MSI-H cancer, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with MSI-H cancer, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression. Selected Important Safety Information for KEYTRUDA (pembrolizumab) KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%) pneumonitis, and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis. KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 48 (1.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%) colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis. KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 19 (0.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%) hepatitis. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA. KEYTRUDA can cause hypophysitis. Hypophysitis occurred in 17 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%) hypophysitis. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis. KEYTRUDA can cause thyroid disorders, including hyperthyroidism, hypothyroidism, and thyroiditis. Hyperthyroidism occurred in 96 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.8%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 237 (8.5%) of 2799 patients receiving KEYTRUDA, including Grade 2 (6.2%) and 3 (0.1%) hypothyroidism. Thyroiditis occurred in 16 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.3%) thyroiditis. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. KEYTRUDA can cause type 1 diabetes mellitus, including diabetic ketoacidosis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia. KEYTRUDA (pembrolizumab) can cause immune-mediated nephritis. Nephritis occurred in 9 (0.3%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis. KEYTRUDA can cause other clinically important immune-mediated adverse reactions. These immune-mediated reactions may occur in any organ system. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction. The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), exfoliative dermatitis, bullous pemphigoid, rash (1.4%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and postmarketing use. Solid organ transplant rejection has been reported in postmarketing use of KEYTRUDA. Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment with KEYTRUDA vs the risk of possible organ rejection in these patients. KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for signs and symptoms of infusion-related reactions, including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA. Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) after being treated with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after treatment with KEYTRUDA on any trial, 6 patients (26%) developed graft-versus-host-disease (GVHD), one of which was fatal, and 2 patients (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning, one of which was fatal. Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor–blocking antibody before transplantation. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT. Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune-mediated adverse reactions, and intervene promptly. Based on its mechanism of action, KEYTRUDA (pembrolizumab) can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA. KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC. The most common adverse event resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). Adverse reactions leading to interruption of KEYTRUDA occurred in 23% of patients; the most common (≥1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis (1%). The most common adverse reactions (occurring in at least 20% of patients and at a higher incidence than with docetaxel) were decreased appetite (25% vs 23%), dyspnea (23% vs 20%), and nausea (20% vs 18%). When KEYTRUDA was administered in combination with carboplatin and pemetrexed (carbo/pem), KEYTRUDA was discontinued in 10% of 59 patients. The most common adverse reaction resulting in discontinuation of KEYTRUDA (≥2%) was acute kidney injury (3.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 39% of patients; the most common (≥2%) were fatigue (8%), neutrophil count decreased (8%), anemia (5%), dyspnea (3.4%), and pneumonitis (3.4%). The most common adverse reactions (≥20%) with KEYTRUDA compared to carbo/pem alone were fatigue (71% vs 50%), nausea (68% vs 56%), constipation (51% vs 37%), rash (42% vs 21%), vomiting (39% vs 27%), dyspnea (39% vs 21%), diarrhea (37% vs 23%), decreased appetite (31% vs 23%), headache (31% vs 16%), cough (24% vs 18%), dizziness (24% vs 16%), insomnia (24% vs 15%), pruritus (24% vs 4.8%), peripheral edema (22% vs 18%), dysgeusia (20% vs 11%), alopecia (20% vs 3.2%), upper respiratory tract infection (20% vs 3.2%), and arthralgia (15% vs 24%). This study was not designed to demonstrate a statistically significant difference in adverse reaction rates for KEYTRUDA as compared to carbo/pem alone for any specified adverse reaction. It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.

On June 3, 2017 Loxo Oncology, Inc. (Nasdaq: LOXO), a biopharmaceutical company innovating the development of highly selective medicines for patients with genetically defined cancers, reported interim clinical data from all three ongoing larotrectinib (LOXO-101) clinical trials in patients whose tumors harbor tropomyosin receptor kinase (TRK) fusions (Press release, Loxo Oncology, JUN 3, 2017, https://ir.loxooncology.com/press-releases/loxo-oncology-breakthrough-therapy-larotrectinib-demonstrates-76-percent-confirmed-objective-response-rate-in-trk-fusion-adult-and-pediatric-cancers-as-presented-at-the-american-society-of-clinical-on [SID1234519411]). These data, demonstrating a 76 percent confirmed objective response rate (ORR) across tumor types, are being presented today at the 2017 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (abstract LBA2501). The larotrectinib pediatric data, included in this presentation, are also being presented in a separate oral presentation on Monday, June 5th (abstract 10510).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"Larotrectinib delivers consistent and durable responses in TRK fusion patients across all ages, regardless of tumor context, and does so with few side effects," said David Hyman, M.D., the NAVIGATE global principal investigator and chief of the early drug development service at Memorial Sloan Kettering Cancer Center who will present the data at ASCO (Free ASCO Whitepaper). "In this way, the larotrectinib TRK fusion story fulfills the promise of precision medicine, where tumor genetics rather than tumor site of origin define the treatment approach. It is now incumbent upon the clinical oncology and pathology communities to examine our testing paradigms, so that TRK fusions and other actionable biomarkers become part of the standard patient workup."

The ASCO (Free ASCO Whitepaper) presentation includes adult and pediatric patients with RECIST-evaluable TRK fusion cancers enrolled across all three larotrectinib clinical trials, and employs an April 14, 2017 data cut-off. These patients will serve as the basis for the larotrectinib New Drug Application (NDA), which the company expects to submit in late 2017 or early 2018 for evaluation by the U.S. Food and Drug Administration (FDA). The primary analysis for the NDA will rely upon central, independent radiology review, which will be performed in the second half of 2017. The company plans to announce these data, which will also include additional patient follow-up, before the end of 2017.

Larotrectinib received Breakthrough Therapy Designation from the FDA in July 2016, "for the treatment of unresectable or metastatic solid tumors with NTRK-fusion proteins in adult and pediatric patients who require systemic therapy and who have either progressed following prior treatment or who have no acceptable alternative treatments."

"The Loxo Oncology team is proud to have contributed to these important data presentations at ASCO (Free ASCO Whitepaper)," said Josh Bilenker, M.D., chief executive officer of Loxo Oncology. "We are grateful to the patients, families, and clinical trial teams who help push the boundaries of available care through their participation in clinical trials. We hope that larotrectinib is the first of many new medicines we develop together."

Key Data Presented at ASCO (Free ASCO Whitepaper)
The primary efficacy outcome measure for the analysis presented at ASCO (Free ASCO Whitepaper) is objective response rate (ORR) as measured by RECIST v 1.1. Key secondary endpoints include duration of response (DOR), progression-free survival (PFS) and safety. The data presented at ASCO (Free ASCO Whitepaper), summarized below, are based on response assessments as performed by each respective clinical trial site (local, investigator-assessed radiology). A separate response assessment performed by independent radiologists, not yet conducted, will be required to support global regulatory filings.

Consistent with written FDA correspondence, TRK fusion patients enrolled in Loxo Oncology’s Phase 1 adult trial, Phase 2 trial (NAVIGATE), and Phase 1/2 pediatric trial (SCOUT) contributed to the primary efficacy analysis. The data presented are based on the intent to treat (ITT) principle, using the first 55 TRK fusion patients with RECIST-evaluable disease enrolled to the three clinical trials, regardless of prior therapy or tumor tissue diagnostic method.

Forty-three adult and 12 pediatric patients were enrolled, identified by 15 different lab tests. TRK fusion patients carried primary diagnoses of appendiceal cancer, breast cancer, cholangiocarcinoma, colorectal cancer, gastrointestinal stromal tumor (GIST), infantile fibrosarcoma, lung cancer, mammary analogue secretory carcinoma of the salivary gland, melanoma, pancreatic cancer, thyroid cancer, and various sarcomas. One patient had central nervous system (CNS) metastases at study entry.

Enrolled Patients with Confirmatory Response Data Available (n=50) All Enrolled Patients (n=55)*
Objective Response Rate
(ORR = PR+CR) 76%
(95% CI: 62% – 87%) 78%
(95% CI: 65% – 88%)
Partial Response (PR) 64% 65%*
Complete Response (CR) 12% 13%*
Stable Disease 12% 11%
Progressive Disease 12% 11%
* Includes unconfirmed responses with confirmatory scans pending (4 PR, 1 CR). All patients with unconfirmed responses remain in response and ongoing on study.

As shown in the above table, the confirmed ORR is 76 percent in 50 patients for whom follow-up was sufficiently long to include a confirmatory scan. The ORR is 78 percent when an additional 5 patients, recently enrolled, with unconfirmed PR (n=4) and CR (n=1), are included. ORR was generally consistent across tumor types, TRK gene fusions, and various diagnostic tests. In the pediatric setting, larotrectinib showed promising activity in the pre-surgical management of patients with infantile fibrosarcoma, with 3 patients treated to best response, which allowed for subsequent referral to surgery with curative intent.

Median DOR and PFS have not been reached. Ninety-three percent of all responding patients either remain on drug or received surgery with curative intent. Seventy-five percent of all patients enrolled either remain on drug or received surgery with curative intent.

The safety data presented at ASCO (Free ASCO Whitepaper) encompass the entire larotrectinib safety database in cancer patients (n=125) intended to support an NDA. The most common treatment-emergent adverse events, regardless of relationship to larotrectinib, included fatigue (15% Grade 1, 18% Grade 2, 5% Grade 3), dizziness (22% Grade 1, 4% Grade 2, 2% Grade 3), nausea (20% Grade 1, 5% Grade 2, 2% Grade 3), and anemia (8% Grade 1, 9% Grade 2, 9% Grade 3). Seven (13%) of patients required a dose reduction due to an adverse event. Of note, all patients requiring dose reduction experienced tumor regression (1 CR, 5 PR, 1 SD), which has continued on the reduced dose. Nearly all of the dose reductions were due to infrequent neurocognitive adverse events, likely a result of on-target TRK inhibition in the CNS. No patients discontinued larotrectinib due to an adverse event.

Six patients responded to larotrectinib but subsequently progressed, a pattern referred to as "acquired resistance." Progression biopsies from five of six patients indicate a consistent mechanism of acquired resistance, namely a solvent front mutation. A solvent front mutation is an amino acid substitution in a kinase that reduces the binding potency of a targeted drug. In the case of NTRK1 and NTRK3, these solvent front amino acid substitutions are denoted as G595R and G623R, respectively. The presence of an acquired resistance mutation in a primary activating oncogene suggests that the involved cancer cell remains dependent on the aberrant signaling pathway that had been successfully drugged previously. LOXO-195, Loxo Oncology’s next-generation selective TRK inhibitor, was designed to address solvent front and other acquired resistance mutations to potentially induce new responses in TRK fusion dependent cancers with acquired resistance mutations.

About the ASCO (Free ASCO Whitepaper) Presentations
These data are being presented in two oral presentations at ASCO (Free ASCO Whitepaper).

"The efficacy of larotrectinib (LOXO-101), a selective tropomyosin receptor kinase (TRK) inhibitor, in adult and pediatric TRK fusion cancers." This includes the integrated database across the three larotrectinib clinical trials and is being presented by Dr. David Hyman, Memorial Sloan Kettering Cancer Center, during the Session entitled, "Developmental Therapeutics – Clinical Pharmacology and Experimental Therapeutics," from 1:15 – 4:15PM CT on Saturday, June, 3, 2017 (Abstract LBA2501).
"A pediatric phase 1 study of larotrectinib, a highly selective inhibitor of the tropomyosin receptor kinase (TRK) family." This focuses specifically on the pediatric Phase 1 clinical trial data, included in the aforementioned data set, and is being presented by Dr. Theodore Laetsch, University of Texas Southwestern Medical Center, during the Session entitled, "Pediatric Oncology II," from 8:00 – 11:00AM CT on Monday, June, 5, 2017 (Abstract 10510).
The presentations will be available online at View Source at the time of their scheduled presentation at ASCO (Free ASCO Whitepaper).

Conference Call and Webcast Information
Loxo Oncology will host a conference call and live webcast with slides and Q&A on Sunday, June 4, 2017 at 5:30 p.m. CT to discuss the larotrectinib data. Loxo Oncology management will be joined by the primary investigators of the larotrectinib clinical development program, Dr. David Hyman and Dr. Alex Drilon of Memorial Sloan Kettering Cancer Center, and Dr. Theodore Laetsch of University of Texas Southwestern Medical Center. To participate in the conference call, please dial (877) 930-8065 (domestic) or (253) 336-8041 (international) and refer to conference ID 14447513. A live webcast of the presentation will be available at View Source A replay of the webcast will be available shortly after the conclusion of the call and archived on the company’s website for 90 days following the call.

About Larotrectinib (LOXO-101)
Larotrectinib is a potent, oral and selective investigational new drug in clinical development for the treatment of patients with cancers that harbor abnormalities involving the tropomyosin receptor kinases (TRKs). Growing research suggests that the NTRK genes, which encode for TRKs, can become abnormally fused to other genes, resulting in growth signals that can lead to cancer in many sites of the body. In an analysis of 55 RECIST-evaluable TRK fusion adult and pediatric patients, larotrectinib demonstrated a 76 percent confirmed objective response rate (ORR), across many different types of solid tumors. Larotrectinib has been granted Breakthrough Therapy Designation Rare Pediatric Disease Designation and Orphan Drug Designation by the U.S. FDA. For additional information about the larotrectinib clinical trials, please refer to www.clinicaltrials.gov. Interested patients and physicians can contact the Loxo Oncology Physician and Patient Clinical Trial Hotline at 1-855-NTRK-123 or visit www.loxooncologytrials.com.