On September 11, 2017 Advaxis, Inc. (NASDAQ:ADXS), a late-stage biotechnology company focused on the discovery, development and commercialization of immunotherapy products, reported a business update and announced its financial results for the third quarter (Q3) ended July 31, 2017 (Press release, Advaxis, SEP 11, 2017, View Source [SID1234520477]).

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"The board of directors selected Anthony Lombardo as interim chief executive officer in July, given his 30 years of leadership experience in the life sciences industry, including previous CEO and executive management positions in both public and private companies," said Dr. David Sidransky, chairman of the board at Advaxis. "We’re confident in his abilities and the value he’s already helping to deliver, and he will remain in this role for the foreseeable future. Over the past two months, Lombardo has been leading an effort to conduct a review of the current Advaxis business portfolio and our future strategic direction. We have a strong scientific and clinical asset base on which to build value, and the board and the management team are aligned on the path forward to commercialization. To further strengthen the management team, our top priority is conducting a search for a chief medical officer, to ensure the effective execution of our refined clinical strategy. The board and the management team are aligned on Advaxis’ path forward."

A Four Franchise Approach to Increasing Shareholder Value

This path forward is anchored in the company’s Lm Technology, a proven platform unique in its ability to safely and effectively target various cancers in multiple ways. As the field of immunotherapy continues to evolve, the flexibility of the Lm platform has allowed Advaxis to continue to adapt and introduce highly innovative programs.

"To fully leverage the technology’s potential and enhance the lives of more cancer patients, while also optimizing shareholder value, we’re reprioritizing programs for continued internal clinical development and implementing alternative strategies for others," said Anthony Lombardo, interim chief executive officer at Advaxis.

Advaxis’ sharpened growth strategy centers on four clear, distinct franchises that will drive significant value creation: HPV-associated cancers, prostate cancer, neoantigen therapy and hotspot mutation therapy.

1. Franchise One: HPV- Associated Cancers

Continue our commitment to commercializing axalimogene filolisbac:
Completion of the MAA submission for conditional approval in Europe is on track for year end.
Enrollment continues in eight countries for AIM2CERV to evaluate axalimogene filolisbac as an adjuvant therapy in patients with high-risk locally advanced cervical cancer.
Collaboration with AstraZeneca on the Phase 2 combination trial with durvalumab in cervical and head and neck cancers is ongoing and continues to enroll.
The combination trial with ADXS-DUAL and BMS’s nivolumab for the treatment of women with persistent, recurrent or metastatic cervical cancer will be initiated in 1H 2018. This program will provide a second registrational opportunity in cervical cancer.
Given the promising early data in head and neck and anal cancers, Advaxis is actively pursuing opportunities to continue development through investigator-sponsored trials (ISTs) or other third-party approaches.
2. Franchise Two: Prostate Cancer

Preliminary data presented at the 3rd International Cancer Immunotherapy Conference (CIMT) (Free CIMT Whitepaper) suggests that ADXS-PSA shows monotherapy activity in prostate cancer that is associated with a distinct immunologic and gene expression pattern. The ongoing trial, ADXS-PSA: Phase 1/2 Study (Keynote-046), evaluates ADXS-PSA as monotherapy and in combination with Merck’s pembrolizumab. The clinical benefit in prostate cancer could be a significant value creator to expand the Lm platform into the prostate cancer market.
In addition, the company is actively developing an additional product for prostate cancer, currently in preclinical testing, which could complement ADXS-PSA.
3. Franchise Three: Personalized Therapies Targeting Neoantigens

ADXS-NEO, in partnership with Amgen Inc., has the potential to be a major step forward in personalized medicine. First patient dosed is expected in 1H 2018.
The initial tumor types for ADXS-NEO are metastatic microsatellite stable colon, head and neck, and non-small cell lung cancers.
4. Franchise Four: Targeting Shared Hotpot Mutations and Tumor Associated Antigens

Advancement of the proprietary ADXS-HOT preclinical program will expand Lm Technology into multiple products targeting several of the most common cancers.
Advaxis expects to file INDs for the first HOT products in 2018.
As part of its portfolio refinement, the company has determined it will not pursue further clinical study of ADXS-HER2 at this time, but remains open to ISTs or licensing opportunities.

"We believe that focusing on these four franchises gives us the greatest opportunity to increase shareholder value and have a significant impact on patients and their families," said Lombardo. "Our excitement about the clinical potential of our Lm Technology is balanced by focus and fiscal discipline."

Financial Highlights for Q3

"The company had a productive third quarter while advancing the development of its core assets," said Sara Bonstein, chief financial officer at Advaxis. "There was increased spend in Q3 due to higher costs to support the regulatory filing of axalimogene filolisbac in Europe, and several one-time costs, which are not anticipated to recur. Our Q4 activities will focus on the execution of our core programs, and the disciplined identification and analysis of additional opportunities to leverage our Lm Technology platform."

Cash, cash equivalents and investments totaled $89.4 million, compared to $115.3 million as of April 30, 2017.
$34.2 million in disbursements include several one-time cash disbursements, among them technical operations costs associated with the European filing of axalimogene filolisbac (which is anticipated to be completed by the end of 2017) and increased clinical trial costs, together totaling approximately $7 million. Cash disbursements are anticipated to normalize in the fourth quarter.
Cash receivables totaled $8.2 million, primarily from partner reimbursements, specifically $4.5 million from Amgen in support of the ADXS-NEO program and $3 million from Stendhal in support of the AIM2CERV program.
Net loss was $70.1 million ($1.74 per share), compared to a net loss of $51.8 million ($1.52 per share) for the same period in 2016, largely due to increased research and development (R&D) expenses.
R&D expenses were $47.8 million, compared to $32.0 million in Q3 2016, related to an increase in clinical trial expense and technical operation support, primarily related to our HPV-franchise.
General and administrative expenses were $33.2 million, compared to $20.4 million in Q3 2016; the difference is primarily attributed to stock and cash compensation expense for past employees, of which approximately $9.5 million was a non-cash expense.
41 million common shares outstanding and 49.5 million shares outstanding on a fully diluted basis as of July 31, 2017.
"We continue to focus on building shareholder value and are committed to bringing clinically beneficial solutions to our patients and their families," said Lombardo.

To learn more about Advaxis and its immunotherapy clinical programs, visit www.advaxis.com.

On September 11, 2017 Kancera reported that it has launched the second part of the ongoing clinical Phase I study of KAND567 (Press release, Kancera, SEP 11, 2017, View Source [SID1234520475]). During this part of the study, KAND567 is administered to groups of healthy subjects in increasing doses, twice a day for seven days. The study is scheduled for completion in the fourth quarter of 2017.

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KAND567 works by blocking the Fractalkine system and has been demonstrated in preclinical disease models to effectively combat relapses in autoimmune disease as well as nerve inflammation and pain associated with chemotherapy against cancer.

In the clinical study KAND567 is administered orally to a total of 80 subjects, first in single doses and then in multiple doses. The purpose of the study is to evaluate KAND567 in healthy volunteers in terms of safety, tolerance and pharmacokinetics (drug absorption, exposure and excretion) as well as food interaction (how food affects the absorption of the drug in the body).

The study will be carried out at the QPS facility in Groningen. QPS is an internationally established contract research company that performs clinical studies, develops drug preparations and conducts laboratory analyses according to GLP and GCP quality standards (Good Laboratory Practice and Good Clinical Practice).

About the Fractalkine project
KAND567 is an orally available small molecule that blocks CX3CR1, the Fractalkine receptor. Fractalkine is an immune-modulating factor, a so-called chemokine, which transmits signals via the CX3CR1 receptor, thereby controlling the function of immune cells and cancer cells. The levels of Fractalkine molecules and CX3CR1 receptors have been shown to be elevated in several inflammatory diseases, in cancer and in chronic pain conditions.

Kancera’s drug candidate KAND567 is the most advanced drug candidate against CX3CR1 and has been shown to be effective against inflammation and pain in multiple preclinical disease models.

In the healthy individual, Fractalkine and its receptor, CX3CR1, regulate migration of immune cells from the blood capillary wall into areas where the immune system is needed. Cancer cells use the same system (CX3CR1 and Fractalkine) to invade healthy organs and form metastases. In addition, the presence of Fractalkine has been associated with a lack of effect of immuno-oncological drugs. Therefore, Kancera evaluates how well KAND567 can stop tumor growth.

Animal studies show that Fractalkine’s receptor is not essential for survival and that important immune functions remain intact despite the lack of receptor. The basis for successful development of KAND567 lies in effectively addressing local inflammation while maintaining a healthy immune system.

In clinical trials, blocking of the Fractalkine system has been shown to have the desired effect against auto-immune diseases such as Crohn’s disease and rheumatoid arthritis in refractory patients. These studies have been conducted by the pharmaceutical company Eisai using a monoclonal antibody. The results of these studies indicate that the probability increases for the Kancera AB drug candidate KAND567 to achieve clinical and commercial success as the first small-molecule drug that works through the Fractalkine system to combat many common diseases.

On September 11, 2017 Transgene (Paris:TNG), a biotech company that designs and develops viral-based immunotherapies, reported that the US Food and Drug Administration (FDA) has granted Transgene Investigational New Drug (IND) clearance to proceed with a Phase 2 clinical trial of TG4010 in combination with Opdivo (nivolumab) and chemotherapy as a first-line treatment for advanced non-squamous non-small cell lung cancer (NSCLC) in the USA (Press release, Transgene, SEP 11, 2017, View Source [SID1234520473]).

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The Phase 2 clinical trial will explore the potential of combining Transgene’s TG4010, an investigational therapeutic vaccine, in association with Bristol-Myers Squibb’s immune checkpoint inhibitor, nivolumab, which acts by overcoming immune suppression. Both therapies will be combined with standard chemotherapy in first-line NSCLC patients, whose tumors express low and undetectable levels of PD-L1.

Transgene is the sponsor of this international trial. Transgene has signed a clinical collaboration agreement with Bristol-Myers Squibb, which will provide nivolumab for the study (see press release dated April 25, 2017).

The Phase 2 trial will evaluate objective tumor responses and disease control. The study will also assess the safety and tolerability of the regimen together with other efficacy parameters. This multi-center single-arm trial will enroll patients both in the USA and Europe.

The first patient is expected to be included into this Phase 2 study at the end of 2017.

"We are very pleased that the FDA approval for the trial combining TG4010, nivolumab and chemotherapy as a first-line treatment of non-squamous NSCLC has been granted to Transgene" said Maud Brandely, Chief Medical Officer of Transgene. "Advanced lung cancer remains a high medical need, in particular for patients whose tumors express low or undetectable levels of PD-L1. We are looking forward to advancing this clinical trial and evaluate the potential of this triple combination regimen as a better treatment option for these patients."

About TG4010
TG4010 is an immunotherapy that has been designed to express the coding sequences of the MUC1 tumor-associated antigen and the cytokine, Interleukin-2 (IL2). It is based on a modified vaccinia virus (MVA), and has been shown to induce an immune response against MUC1 expressing tumors, such as non-small cell lung cancer (NSCLC).
The combination of TG4010 immunotherapy and chemotherapy has demonstrated significant efficacy in terms of progression-free survival and overall survival in patients with advanced stage NSCLC. The results from the Phase 2b TIME trial with TG4010 in conjunction with chemotherapy in NSCLC have been published in the peer-reviewed medical journal, The Lancet Oncology in December 2015.

About Non-Small Cell Lung Cancer
Lung cancer is one of the most common malignancies worldwide with an estimated 1.8 million new cases annually. It is also a leading cause of cancer-related deaths, accounting for an estimated nearly 1.6 million deaths in 2012 (Source: GLOBOCAN 2012). Advanced lung cancer remains one of the cancer types with the worst prognosis (five-year survival rate for advanced NSCLC of less than 5%), underlining the still unmet need in this disease.

On September 11, 2017 TESARO, Inc. (NASDAQ:TSRO), an oncology-focused biopharmaceutical company, reported a summary of ZEJULA and TSR-042, an anti-PD-1 antibody, data presented at the 2017 European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Annual Meeting in Madrid (Press release, TESARO, SEP 11, 2017, View Source [SID1234520472]).

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"ZEJULA is the market-leading PARP inhibitor, with unsurpassed efficacy in a broad patient population and convenient, once-daily dosing," said Mary Lynne Hedley, Ph.D., President and COO of TESARO. "‘Watchful waiting’ is no longer an acceptable option for women living with ovarian cancer. We believe combination approaches, including niraparib and anti-PD-1 antibodies, will become increasingly important and we are executing on our registration strategy for TSR-042, our anti-PD-1 antibody, in MSI-high cancers."

ZEJULA (niraparib) presentations:

Treatment with niraparib did not impact patient quality of life in the NOVA trial
Quality of life measures are important to understanding the benefit of niraparib in the maintenance treatment setting. Dr. Amit M. Oza, M.D., Senior Staff Physician, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, presented quality of life (QoL) data from the Phase 3 ENGOT-OV16/NOVA trial. Patient-reported outcomes (PROs) were evaluated along with individual patient-reported symptoms using the Functional Assessment of Cancer Therapy-Ovarian Symptoms Index (FOSI) and European Quality of Life Scale 5-Dimensions (EQ-5D-5L). The most common PRO symptoms at baseline were fatigue and pain, and 20% of patients experienced nausea at baseline. No significant difference in mean patient-reported outcomes (PRO) scores was observed between patients treated with niraparib versus placebo, regardless of germline BRCA mutation status. Hematologic adverse events (thrombocytopenia, neutropenia, anemia) decreased over time with dose modification and did not impact QoL. These results also suggest that patients with ovarian cancer often experience residual symptoms of their disease following the conclusion of chemotherapy.

Safety and efficacy of niraparib in elderly patients comparable to overall population in NOVA
In a poster discussion session, safety and efficacy results from the ENGOT-OV16/NOVA trial were highlighted for a sub-group of elderly patients, aged 70 years and older. In this post-hoc analysis, the efficacy of niraparib was similar for patients aged <70 years compared to patients aged ≥70 years in both the gBRCAmut and non-gBRCAmut cohorts. Grade ≥3 treatment-emergent adverse events (TEAEs) occurring in >10% of niraparib treated patients were also consistent between the two groups, and dose reductions, interruptions, and treatment discontinuations occurred with similar frequency, regardless of age. These results demonstrate that niraparib may provide clinical benefit to a broad population of patients with ovarian cancer irrespective of age.

Niraparib exposure — response findings support dosing patients at individually adjusted maximal tolerated dose
In a poster discussion session, the relationship between niraparib exposure and efficacy, as well as exposure and safety, was highlighted in patients enrolled in the ENGOT-OV16/NOVA trial. Efficacy as measured by PFS was compared in patients with high exposure (defined as greater than median exposure) versus low exposure (defined as less than or equal to median exposure). Patients experienced similar efficacy at their individual maximum tolerated dose regardless of the dose received. Reaching maximal exposure for individual patients, as was done in the ENGOT-OV16/NOVA trials via dose modifications, was likely an important factor in achieving maximal efficacy, especially for patients without a BRCA mutation. Limited exposure-efficacy association was observed among patients who were germline BRCA mutation carriers, while the exposure-efficacy association was more apparent for patients who were not germline BRCA mutation carriers. On a population level, the incidence of treatment-emergent adverse events (TEAEs) was higher with increased dose. These findings support that patients, especially those with BRCA wild-type tumors, should be treated at their individually adjusted maximal tolerated dose to provide the optimal chance of efficacy.

Model highlights niraparib pharmacokinetic properties, including high tissue distribution and slow elimination, and no need for dose adjustments in patients with mild-to-moderate renal or hepatic impairment
In a poster display session, data from the Phase 1 dose-escalation and expansion studies (n=104) and the Phase 3 ENGOT-OV16/NOVA study (n=408) of niraparib were used to model the impact of patient variables (age, race, ethnicity, body weight), renal impairment (normal, mild, or moderate), and hepatic function (baseline serum alanine and aspartate aminotransferase, albumin, total bilirubin) on niraparib pharmacokinetic parameters. In the base model, the typical value for niraparib apparent clearance was 16.2 L/h, with inter-individual variability of 52.6%. The estimated volume of distribution was 1074 L (290 L central and 784 L peripheral compartment). None of the patient variables impacted niraparib pharmacokinetics, including mild-to-moderate renal impairment and mild hepatic impairment, and model diagnostics showed good agreement between predicted and observed individual niraparib plasma concentrations. These results demonstrate that no dose adjustments are needed for patients treated with niraparib with mild-to-moderate renal or hepatic impairment.

Bevacizumab-niraparib combination demonstrated preliminary evidence of activity and a predictable adverse event profile
Updated data from the ongoing Phase 2 AVANOVA study of bevacizumab plus niraparib, an Investigator Supported Trial (IST), in patients with platinum sensitive recurrent ovarian cancer (n=12) demonstrated activity and a predictable adverse event profile. In the first cycle (21 days) of the study, patients experienced expected and manageable adverse events including anemia, constipation, fatigue, hypertension, nausea and thrombocytopenia. One dose-limiting toxicity (grade 3 thrombocytopenia) was observed at the highest dose level. Three patients were dose reduced and two patients terminated bevacizumab. Preliminary evidence of activity was demonstrated, with a disease control rate of 92% and response rate of 50%, including 1 CR and 5 PRs. There were five additional patients with stable disease. The median progression-free survival (PFS) was 49 weeks. These data support the potential to combine niraparib plus bevacizumab. Part 2 of the AVANOVA trial continues to enroll patients.

Frequent hospitalizations and ER visits during "watchful waiting" period support a change in clinical practice to maintenance therapy options for ovarian cancer patients
A retrospective study was conducted in the U.S. to characterize the treatment-free interval (or "watchful waiting") for patients newly diagnosed with ovarian cancer following completion of treatment with platinum-based chemotherapy. The analysis found that during the "watchful waiting" period, 30.1% of patients were admitted to the hospital as an in-patient, and 27.4% of patients visited the emergency room. These results suggest that patients with ovarian cancer often experience residual symptoms of their disease following the conclusion of chemotherapy.

Preliminary Phase 2 niraparib/pembrolizumab combination (TOPACIO) data shows activity in patients with platinum-resistant ovarian and triple-negative breast cancer
Data from a Phase 1 dose-escalation study of niraparib in combination with pembrolizumab in patients with platinum-resistant ovarian cancer (OC) or triple negative breast cancer (TNBC) was presented, along with preliminary response data from patients thus far treated in the Phase 2 TOPACIO study. In Phase 1, among the nine evaluable OC patients, five responded (partial or complete response) and four achieved stable disease. Three of the five responders had tumors that tested as wildtype BRCA 1/2 and three as PD-L1 negative (<1%). Of the four evaluable TNBC patients, three had stable disease and one patient came off study prior to her first assessment. The most common treatment related grade ≥3 adverse events occurring in ≥2 patients included anemia (35.7%), thrombocytopenia (35.7%), neutropenia (14.3%) and decreased platelet counts (14.3%). The recommended Phase 2 dose of niraparib was established as 200 mg oral niraparib once daily (increasing to 300 mg after cycle 2 in patients with no significant hematologic toxicities) in combination with 200 mg IV pembrolizumab on day 1 of each 21-day cycle.

The Phase 2 portion of the TOPACIO study is ongoing, and, as of the data cutoff, 36 OC patients and 47 TNBC patients were enrolled out of a planned 48 patients for each tumor cohort. Twenty-nine OC and 27 TNBC patients have been assessed by at least one scan with responses observed in both BRCA wild-type and PD-L1 negative tumors. Among the patients who had received at least one on-study scan, 6 OC patients and 5 TNBC patients had a ≥30% decrease in tumor lesion size and 10 of these 11 patients continue on therapy. Overall 52% OC and 63% TNBC patients who did not have progressive disease continue on therapy. No new safety signals were identified, and less than 7% of Phase 2 patients had experienced grade ≥3 thrombocytopenia during the first treatment cycle. Thirty patients (36.1%) enrolled in Phase 2 reported treatment-related grade ≥3 adverse events including anemia (8.4%), fatigue (6.0%), platelet count decrease (6.0%) and thrombocytopenia (6.0%).

TSR-042 (anti-PD-1 antibody)

TSR-042 safety profile and clinical activity demonstrated in heavily pre-treated patients
In a poster display session, preliminary safety, efficacy, receptor occupancy, and pharmacokinetic data for TSR-042, an anti-PD-1 antibody, were presented from a two-part Phase 1 study. No dose limiting toxicities were observed. Adverse events included fatigue, nausea, arthralgia, decreased appetite, and pruritus, which occurred in ≥10% of patients. In Part 1 (n=21), two patients with ovarian cancer and small cell lung cancer who were treated with TSR-042 experienced a partial response and five patients with fallopian tube or ovarian cancer had stable disease, two of whom are continuing treatment. Consistent with data reported for other anti-PD-1 antibodies, maximum direct and functional receptor occupancy was observed with both CD3+ binding and IL-2 stimulation assays at all three dose levels evaluated. In Part 2A (n=13), full receptor occupancy, as assessed by the assays used in Part 1, was maintained over 3 and 6 weeks at doses of 500 mg and 1,000 mg, respectively.

These preliminary findings indicate that TSR-042 is safe and well tolerated, with a safety and efficacy profile expected for an agent targeting the PD-1 pathway, evidence of linear PK, and sustained target engagement at administration intervals up to 6 weeks. The recommended Phase 2 dose was established at 500 mg Q3W for the first four cycles and 1000 mg Q6W thereafter. Serum concentrations of TSR-042 observed 3 weeks after the 500 mg dose were comparable to those observed 6 weeks after the 1000 mg dose. Patients with microsatellite instability high (MSI-H) and microsatellite stable endometrial cancer and non-small cell lung cancer are currently enrolling in the expansion phase of this study, and additional tumor types are planned for evaluation.

About ZEJULA (Niraparib)
Niraparib is marketed in the United States under trade name ZEJULA. ZEJULA (niraparib) is a poly(ADP-ribose) polymerase (PARP) inhibitor indicated 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 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.