On June 5, 2017 Celldex Therapeutics, Inc. (NASDAQ:CLDX) reported positive, mature results from the Company’s Phase 2 study of glembatumumab vedotin in patients with stage III/IV checkpoint inhibitor-refractory, and, if applicable, BRAF/MEK inhibitor-refractory metastatic melanoma (n=62) (Press release, Celldex Therapeutics, JUN 5, 2017, View Source [SID1234519397]). Glembatumumab vedotin is a fully human monoclonal antibody-drug conjugate (ADC) that targets glycoprotein NMB (gpNMB), a protein overexpressed by multiple tumor types, including metastatic melanoma, where more than 80% of patients overexpress the marker. High tumor expression of gpNMB is associated with shorter metastasis-free survival and reduced overall survival.1 Study results were presented today in an oral presentation by Patrick A. Ott, M.D., Ph.D., Clinical Director of Dana-Farber Cancer Institute’s Melanoma Center and its Center for Immuno-Oncology, Assistant Professor of Medicine at Harvard Medical School and an investigator in the study, at the 2017 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago.

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Study Highlights

Median overall survival (OS) for all patients was 9.0 months (95% CI: 6.1, 13.0).
As previously reported in October 2016, 7 of 62 (11%) patients experienced a confirmed response, and an additional three patients also experienced single timepoint partial responses. Since data were reported in October, one patient converted from a confirmed partial response to a confirmed complete response.
Patients who experienced rash in Cycle 1 experienced a more prolonged OS with a median of 15.8 months (p=0.026, HR=0.44) as compared to those who did not experience rash.
"It’s exciting to see clinical activity in this study as very few treatment options exist for melanoma patients who progress after immune checkpoint inhibitors and BRAF targeted therapy," said Dr. Ott. "The single-agent response rate observed in this study, including a complete response, and the duration of the objective responses continue to suggest that glembatumumab vedotin is an active agent in this disease. I am hopeful that leveraging the immune system with checkpoint inhibition in combination with the cytotoxic and immunologic cell death induced by glembatumumab vedotin could bring benefit to an even larger number of patients with melanoma, and I look forward to the outcome of these additional cohorts."

Phase 2 Study Single-agent Cohort Overview and Previously Presented Results

Patients enrolled in this single-agent, open-label cohort of glembatumumab vedotin presented with unresectable stage IV (n=62) melanoma. The median number of prior therapies was three (range of 1 to 8). All patients had been heavily pre-treated and had progressed during or after checkpoint inhibitor therapy, and almost all patients had received both ipilimumab (n=58; 94%) and anti-PD-1/anti-PD-L1 (n=58; 94%) therapy. Twelve patients presented with BRAF mutation, and fifteen had prior treatment with BRAF or BRAF/MEK targeted agents. Patients received glembatumumab vedotin every three weeks until disease progression or intolerance. The safety profile was consistent with prior studies of glembatumumab vedotin with rash, neutropenia and neuropathy experienced as the most significant adverse events.

As previously reported, the primary endpoint of the cohort (6 or more objective responses in the first 52 patients enrolled) was exceeded. Seven of 62 (11%) patients experienced a confirmed response, and an additional three patients also experienced single timepoint responses. The median duration of response was 6.0 months. A 52% disease control rate (patients without progression for greater than three months) was demonstrated, and median PFS for all patients was 4.4 months. Consistent with previous studies in melanoma and breast cancer, rash was associated with greater clinical benefit. Patients who experienced rash in Cycle 1 experienced a 21% confirmed response rate, a more prolonged PFS with a median of 5.5 months (p=0.006; HR=0.39) and a more prolonged OS with a median of 15.8 months (p=0.026, HR=0.44).

Pre-treatment tumor tissue was available for 59 patients. All samples were gpNMB positive, and 78% of patients had tumors with 100% of their epithelial cells expressing gpNMB. Given both the high level of expression and the intensity of expression across this patient population, identifying a potential population for gpNMB enrichment is not feasible; therefore, all patients with metastatic melanoma could be evaluated as potential candidates for treatment with glembatumumab vedotin in future studies.

Ongoing Cohorts Combining Glembatumumab Vedotin with Varlilumab or Checkpoint Inhibitor

In August 2016, the Company announced that the study protocol was amended to add a second cohort of patients to a glembatumumab vedotin and varlilumab combination. Varlilumab is Celldex’s fully human monoclonal agonist antibody that binds and activates CD27, a critical co-stimulatory molecule in the immune activation cascade. This additional cohort has completed enrollment with data presentation expected in the fall of 2017. Celldex is now enrolling patients to a third arm in the study to assess a glembatumumab vedotin and checkpoint combination in patients who have previously progressed on checkpoint inhibitor. This rationale is strongly supported by preclinical data that suggest that the anti-tumor activity may be enhanced with the combination. In addition, due to their direct cytotoxic properties, microtubule-depolymerizing agents like MMAE also appear to convert tumor-resident tolerogenic dendritic cells into active antigen-presenting cells.2

The Company also intends to conduct exploratory analyses of pre-entry skin biopsies in future patients to investigate potential predictors of response to glembatumumab vedotin, given the association of rash and outcome.

About Glembatumumab Vedotin

Glembatumumab vedotin is a fully human monoclonal antibody-drug conjugate (ADC) that targets glycoprotein NMB (gpNMB). gpNMB is a protein overexpressed by multiple tumor types, including breast cancer, melanoma, lung cancer, uveal melanoma and osteosarcoma. gpNMB has been shown to be associated with the ability of the cancer cell to invade and metastasize and to correlate with reduced time to progression and survival in breast cancer. The gpNMB-targeting antibody, CR011, is linked to a potent cytotoxic, monomethyl auristatin E (MMAE), using Seattle Genetics’ proprietary technology. Glembatumumab vedotin is designed to be stable in the bloodstream but to release MMAE upon internalization into gpNMB-expressing tumor cells, resulting in a targeted cell-killing effect. Glembatumumab vedotin is in development for the treatment of locally advanced or metastatic breast cancer with an initial focus in triple negative disease, stage III and IV melanoma, squamous cell lung cancer and uveal melanoma.

On June 5, 2017 Celldex Therapeutics, Inc. (Nasdaq:CLDX) reported data from the Phase 1 portion of a Phase 1/2 dose escalation and cohort expansion study examining the combination of varlilumab, Celldex’s CD27 targeting investigational immune-activating antibody, and Bristol-Myers Squibb’s anti-PD-1 immunotherapy Opdivo (nivolumab) (Press release, Celldex Therapeutics, JUN 5, 2017, View Source [SID1234519395]). Rachel E. Sanborn, M.D., Co-director of the Providence Thoracic Oncology Program; and Phase I Clinical Trials Program, at the Earle A. Chiles Research Institute, Providence Cancer Center, in Portland, Ore. presented results from the study in an oral presentation entitled, "Clinical Results with Combination of Anti-CD27 Agonist Antibody, Varlilumab, with Anti-PD1 Antibody Nivolumab in Advanced Cancer Patients" at the 2017 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago. The primary objective of the Phase 1 portion (n=36) of the study was to evaluate the safety and tolerability of the combination. The Phase 2 portion of the study is expected to complete enrollment in early 2018.

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"Combining PD-1 inhibition with a potent T cell activating agent provides the opportunity to broaden the number of patients that benefit from checkpoint blockade," said Dr. Sanborn. "While early, we have evidence that this combination does not add toxicity, can turn some ‘immune-cold’ tumors hot, and may have clinical benefit, including in some patients who are not likely to respond to monotherapy. Further elucidating the role of intermittent versus chronic T cell activation through the comparison of alternate varlilumab dosing regimens is an essential component of the ongoing Phase 2 study and could be important in optimizing the potential of this combination."

Key Highlights

• The majority of patients enrolled in the study had PD-L1 negative tumor at baseline and presented with Stage IV, heavily-pretreated disease. 80% of patients enrolled presented with refractory or recurrent colorectal (n=21) or ovarian cancer (n=8), a population expected to have minimal response to checkpoint blockade.

• Combining the potent immune activator, varlilumab, with the PD-1 inhibitor, Opdivo, was well tolerated at all varlilumab dose levels tested without any evidence of increased autoimmunity or inappropriate immune activation.

• Notable disease control observed (stable disease or better for at least 3 months), considering the Stage IV patient population, contained mostly colorectal and ovarian cases (80%).

0.1 mg/kg varlilumab + 240 mg Opdivo: 1/5 (20%)
1 mg/kg varlilumab + 240 mg Opdivo: 5/15 (33%)
10 mg/kg varlilumab + 240 mg Opdivo: 6/15 (40%)
• Three partial responses (PR) observed.

A patient with PD-L1 negative, MMR proficient colorectal cancer, typically unlikely to respond to checkpoint blockade monotherapy, achieved a confirmed PR (presented with metastatic disease to the liver, adrenal gland, abdomen and mesenteric nodule and on study experienced a 95% decrease in target lesions, including resolution of 4/5 target lesions, one 6 mm mesenteric nodule remains). Following completion of combination treatment, the patient continues to receive treatment with Opdivo monotherapy at 22 months. The patients previously received two prior chemotherapy-based regimens, one of which also included EGFR-targeted therapy.
A patient with low PD-L1 (5% expression) squamous cell head and neck cancer achieved a confirmed PR (59% shrinkage) and experienced progression free survival of 6.7 months.
A patient with PD-L1 negative ovarian cancer experienced a single timepoint PR (49% shrinkage) but discontinued treatment to a dose-limiting toxicity (immune hepatitis, an event known to be associated with checkpoint inhibition therapy).
• Migration of immune cells to tumor observed.

Peripheral blood analysis consistent with varlilumab monotherapy, transient increase in inflammatory chemokines (CXCL10, MCP-1, MIP-1β and MIG) and prominent decreases in CD4 and Treg cells without clear association with dose observed.
Tumor biopsy analysis revealed the majority of patients had "cold" tumors at baseline (negative or low PD-L1 and low T cell infiltrate).
A subgroup analysis was conducted in patients with ovarian cancer based on an observed increase of PD-L1 and tumor-infiltrating lymphocytes in this patient population.
• In patients with paired baseline and on-treatment biopsies (n=13), only 15% were PD-L1 positive (≥ 1% tumor cells) at baseline compared to 77% during treatment (p=0.015).
• Patients with increased tumor PD-L1 expression and tumor CD8 T cells correlated with better clinical outcome with treatment (stable disease or better).
• Continuous activation by immune agonists may not be optimal as it could lead to immune exhaustion and dampen the effect of combination therapy. The Phase 2 portion of this study includes alternate varlilumab dosing regimens to evaluate continuous versus intermittent immune activation at higher and lower dose levels and varied frequency.

In April 2016, the trial advanced to the Phase 2 portion of the study and includes cohorts in colorectal cancer, ovarian cancer, head and neck squamous cell carcinoma, renal cell carcinoma and glioblastoma. Varied dosing schedules are being explored in the ovarian and head and neck cohorts. Celldex plans to complete enrollment across all cohorts in the first quarter of 2018 and will work with Bristol-Myers Squibb to present data from the Phase 2 study at a future medical meeting. The primary objective of the Phase 2 study is overall response rate for all cohorts except glioblastoma, where the primary objective is the rate of 12-month overall survival. Secondary objectives include pharmacokinetics assessments, determining the immunogenicity of varlilumab when given in combination with Opdivo and further assessing the antitumor activity of combination treatment, including duration of response, time to response, progression-free survival and overall survival. The study is being conducted by Celldex under a clinical trial collaboration with Bristol-Myers Squibb Company. The companies are sharing development costs.

About Varlilumab

Varlilumab is a fully human monoclonal agonist antibody that binds and activates CD27, a critical co-stimulatory molecule in the immune activation cascade. CD27 can be effectively manipulated with activating antibodies to induce potent anti-tumor responses and may result in fewer toxicities due to its restricted expression and regulation. Varlilumab is a potent anti-CD27 agonist that induces activation and proliferation of human T cells when combined with T cell receptor stimulation. In lymphoid malignancies that express CD27 at high levels, varlilumab may have an additional mechanism of action through a direct anti-tumor effect. Varlilumab has completed a single-agent Phase 1 dose-escalation study, demonstrating potent immunologic activity consistent with its mechanism of action and antitumor activity in patients with advanced, refractory disease. No maximum tolerated dose was reached, and minimal toxicities were observed.

Opdivo is a registered trademark of Bristol-Myers Squibb.

On June 5, 2017 Bristol-Myers Squibb Company (NYSE:BMY) reported it has entered into a clinical research collaboration with Novartis to investigate the safety, tolerability and efficacy of Opdivo (nivolumab) and Opdivo + Yervoy (ipilimumab) regimen in combination with Mekinist (trametinib), as a potential treatment option for metastatic colorectal cancer in patients with microsatellite stable tumors where the tumors are proficient in mismatch repair (MSS mCRC pMMR) (Press release, Bristol-Myers Squibb, JUN 5, 2017, View Source [SID1234519393]).

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The Phase 1/2 study is expected to establish recommended dose regimens and explore the preliminary anti-tumor activity of combining trametinib with Opdivo, as well as trametinib in combination with the Opdivo + Yervoy regimen. Results will be used to determine optimal approaches to further potential clinical development of these combinations.

"We continue to investigate novel combinations of therapy that may hold the potential to expand the therapeutic benefits of immunotherapy to patients with difficult to treat cancer or those who don’t respond, and look forward to evaluating the combination of Novartis’ MEK inhibitor with our immunotherapies," said Fouad Namouni, M.D., head of Oncology Development, Bristol-Myers Squibb.

Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world in July 2014, and currently has regulatory approval in more than 60 countries including the United States, Japan, and in the European Union.

About Colorectal Cancer

Worldwide, colorectal cancer is the third most common type of cancer in men and the second most common in women, with approximately 1.4 million new diagnoses in 2012. Of these, nearly 750,000 were diagnosed in men, and 614,000 in women. Globally in 2012, approximately 694,000 deaths were attributed to colorectal cancer. In the U.S. alone, an estimated 135,430 patients will be diagnosed with cancer of the colon or rectum in 2017, and approximately 50,000 are estimated to die of their disease. There is wide variation in 5-year survival rates across the globe, with 5-year survival expected to be around 65% in the developed world and dropping to around 20% in some developing countries. The incidence of microsatellite stability in colorectal tumors varies by stage, with nearly 80% of early stage, resectable tumors and approximately 67% of advanced, metastatic tumors exhibiting MSS.

Bristol-Myers Squibb & Immuno-Oncology: Advancing Oncology Research

At Bristol-Myers Squibb, patients are at the center of everything we do. Our vision for the future of cancer care is focused on researching and developing transformational Immuno-Oncology (I-O) medicines for hard-to-treat cancers that could potentially improve outcomes for these patients.

We are leading the scientific understanding of I-O through our extensive portfolio of investigational compounds and approved agents. Our differentiated clinical development program is studying broad patient populations across more than 50 types of cancers with 14 clinical-stage molecules designed to target different immune system pathways. Our deep expertise and innovative clinical trial designs position us to advance I-O/I-O, I-O/chemotherapy, I-O/targeted therapies and I-O/radiation therapies across multiple tumors and potentially deliver the next wave of therapies with a sense of urgency. We also continue to pioneer research that will help facilitate a deeper understanding of the role of immune biomarkers and how patients’ individual tumor biology can be used as a guide for treatment decisions throughout their journey.

We understand making the promise of I-O a reality for the many patients who may benefit from these therapies requires not only innovation on our part but also close collaboration with leading experts in the field. Our partnerships with academia, government, advocacy and biotech companies support our collective goal of providing new treatment options to advance the standards of clinical practice.

About Opdivo

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the body’s own immune system to help restore anti-tumor immune response. By harnessing the body’s own immune system to fight cancer, Opdivo has become an important treatment option across multiple cancers.

Opdivo’s leading global development program is based on Bristol-Myers Squibb’s scientific expertise in the field of Immuno-Oncology and includes a broad range of clinical trials across all phases, including Phase 3, in a variety of tumor types. To date, the Opdivo clinical development program has enrolled more than 25,000 patients. The Opdivo trials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from Opdivo across the continuum of PD-L1 expression.In July 2014, Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Opdivo is currently approved in more than 60 countries, including the United States, the European Union and Japan. In October 2015, the company’s Opdivo and Yervoy combination regimen was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 50 countries, including the United States and the European Union.

About Yervoy

Yervoy, which is a recombinant, human monoclonal antibody, blocks the cytotoxic T- lymphocyte-associated antigen-4 (CTLA-4). CTLA-4 is a negative regulator of T-cell activation. Yervoy binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation. The mechanism of action of Yervoy effect in patients with melanoma is indirect, possibly through T-cell mediated anti-tumor immune responses. On March 25, 2011, the FDA approved Yervoy 3 mg/kg monotherapy for patients with unresectable or metastatic melanoma. Yervoy is now approved in more than 40 countries. There is a broad, ongoing development program in place for Yervoy spanning multiple tumor types. This includes Phase 3 trials in prostate and lung cancers.

U. S. FDA APPROVED INDICATIONS FOR OPDIVO

OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials

OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

OPDIVO (nivolumab) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

OPDIVO (nivolumab) is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin or after 3 or more lines of systemic therapy that includes autologous HSCT. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

OPDIVO (nivolumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-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 confirmatory trials.

IMPORTANT SAFETY INFORMATION

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

YERVOY can result in severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.

Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs), adrenocorticotropic hormone (ACTH) level, and thyroid function tests at baseline and before each dose.

Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

Immune-Mediated Pneumonitis

OPDIVO can cause immune-mediated pneumonitis. Fatal cases have been reported. Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer corticosteroids for Grade 2 or more severe pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In patients receiving OPDIVO monotherapy, fatal cases of immune-mediated pneumonitis have occurred. Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated pneumonitis occurred in 6% (25/407) of patients.

In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 6.0% (16/266) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=12).

Immune-Mediated Colitis

OPDIVO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO monotherapy for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon re-initiation of OPDIVO. When administered with YERVOY, withhold OPDIVO and YERVOY for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated colitis occurred in 26% (107/407) of patients including three fatal cases.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) patients. Across all YERVOY-treated patients in that study (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis.

Immune-Mediated Hepatitis

OPDIVO can cause immune-mediated hepatitis. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated hepatitis occurred in 13% (51/407) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or total bilirubin elevations >3x the ULN; Grade 3-5) occurred in 8 (2%) patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4%.

Immune-Mediated Neuropathies

In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported.

Immune-Mediated Endocrinopathies

OPDIVO can cause immune-mediated hypophysitis, immune-mediated adrenal insufficiency, autoimmune thyroid disorders, and Type 1 diabetes mellitus. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer hormone replacement as clinically indicated and corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients. In patients receiving OPDIVO with YERVOY, hypophysitis occurred in 9% (36/407) of patients. In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994) of patients. In patients receiving OPDIVO with YERVOY, adrenal insufficiency occurred in 5% (21/407) of patients. In patients receiving OPDIVO monotherapy, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 9% (171/1994) of patients. Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO monotherapy. In patients receiving OPDIVO with YERVOY, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (89/407) of patients. Hyperthyroidism occurred in 8% (34/407) of patients receiving OPDIVO with YERVOY. In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients. In patients receiving OPDIVO with YERVOY, diabetes occurred in 1.5% (6/407) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. 6 of the 9 patients were hospitalized for severe endocrinopathies.

Immune-Mediated Nephritis and Renal Dysfunction

OPDIVO can cause immune-mediated nephritis. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grades 2-4 increased serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 increased serum creatinine. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients.

Immune-Mediated Skin Adverse Reactions and Dermatitis

OPDIVO can cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with fatal outcome. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4 rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient for specialized care for assessment and treatment; if confirmed, permanently discontinue. In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated rash occurred in 22.6% (92/407) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13 (2.5%) patients. 1 (0.2%) patient died as a result of toxic epidermal necrolysis. 1 additional patient required hospitalization for severe dermatitis.

Immune-Mediated Encephalitis

OPDIVO can cause immune-mediated encephalitis. Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. In patients receiving OPDIVO monotherapy, encephalitis occurred in 0.2% (3/1994) of patients. Fatal limbic encephalitis occurred in one patient after 7.2 months of exposure despite discontinuation of OPDIVO and administration of corticosteroids. Encephalitis occurred in one patient receiving OPDIVO with YERVOY (0.2%) after 1.7 months of exposure.

Other Immune-Mediated Adverse Reactions

Based on the severity of adverse reaction, permanently discontinue or withhold treatment, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. Across clinical trials of OPDIVO the following clinically significant immune-mediated adverse reactions occurred in <1.0% of patients receiving OPDIVO: uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), myositis, myocarditis, rhabdomyolysis, motor dysfunction, vasculitis, and myasthenic syndrome.

Infusion Reactions

OPDIVO can cause severe infusion reactions, which have been reported in <1.0% of patients in clinical trials. Discontinue OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt or slow the rate of infusion in patients with Grade 1 or 2. In patients receiving OPDIVO monotherapy, infusion-related reactions occurred in 6.4% (127/1994) of patients. In patients receiving OPDIVO with YERVOY, infusion-related reactions occurred in 2.5% (10/407) of patients.

Complications of Allogeneic HSCT after OPDIVO

Complications, including fatal events, occurred in patients who received allogeneic HSCT after OPDIVO. Outcomes were evaluated in 17 patients from Checkmate 205 and 039, who underwent allogeneic HSCT after discontinuing OPDIVO (15 with reduced-intensity conditioning, 2 with myeloablative conditioning). Thirty-five percent (6/17) of patients died from complications of allogeneic HSCT after OPDIVO. Five deaths occurred in the setting of severe or refractory GVHD. Grade 3 or higher acute GVHD was reported in 29% (5/17) of patients. Hyperacute GVHD was reported in 20% (n=2) of patients. A steroid-requiring febrile syndrome, without an identified infectious cause, was reported in 35% (n=6) of patients. Two cases of encephalitis were reported: Grade 3 (n=1) lymphocytic encephalitis without an identified infectious cause, and Grade 3 (n=1) suspected viral encephalitis. Hepatic veno-occlusive disease (VOD) occurred in one patient, who received reduced-intensity conditioned allogeneic HSCT and died of GVHD and multi-organ failure. Other cases of hepatic VOD after reduced-intensity conditioned allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor blocking antibody before transplantation. Cases of fatal hyperacute GVHD have also been reported. 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.

Embryo-Fetal Toxicity

Based on their mechanisms of action, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with an OPDIVO- or YERVOY- containing regimen and for at least 5 months after the last dose of OPDIVO.

Lactation

It is not known whether OPDIVO or YERVOY is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from an OPDIVO-containing regimen, advise women to discontinue breastfeeding during treatment. Advise women to discontinue nursing during treatment with YERVOY and for 3 months following the final dose.

Serious Adverse Reactions

In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO (n=268). Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO . The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In Checkmate 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO (n=206). Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In Checkmate 067, serious adverse reactions (73% and 37%), adverse reactions leading to permanent discontinuation (43% and 14%) or to dosing delays (55% and 28%), and Grade 3 or 4 adverse reactions (72% and 44%) all occurred more frequently in the OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313). The most frequent (≥10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.6%), colitis (10% and 1.6%), and pyrexia (10% and 0.6%). In Checkmate 017 and 057, serious adverse reactions occurred in 46% of patients receiving OPDIVO (n=418). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO (n=406). The most frequent serious adverse reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 205 and 039, adverse reactions leading to discontinuation occurred in 7% and dose delays due to adverse reactions occurred in 34% of patients (n=266). Serious adverse reactions occurred in 26% of patients. The most frequent serious adverse reactions reported in ≥1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last OPDIVO dose, 2 from infection 8 to 9 months after completing OPDIVO, and 6 from complications of allogeneic HSCT. In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. In Checkmate 275, serious adverse reactions occurred in 54% of patients receiving OPDIVO (n=270). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration.

Common Adverse Reactions

In Checkmate 037, the most common adverse reaction (≥20%) reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse reactions (≥20%) reported with OPDIVO (n=206) vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) were fatigue (59%), rash (53%), diarrhea (52%), nausea (40%), pyrexia (37%), vomiting (28%), and dyspnea (20%). The most common (≥20%) adverse reactions in the OPDIVO (n=313) arm were fatigue (53%), rash (40%), diarrhea (31%), and nausea (28%). In Checkmate 017 and 057, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) were asthenic conditions (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate 205 and 039, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=266) were upper respiratory tract infection (44%), fatigue (39%), cough (36%), diarrhea (33%), pyrexia (29%), musculoskeletal pain (26%), rash (24%), nausea (20%) and pruritus (20%). In Checkmate 141, the most common adverse reactions (≥10%) in patients receiving OPDIVO were cough and dyspnea at a higher incidence than investigator’s choice. In Checkmate 275, the most common adverse reactions (≥ 20%) reported in patients receiving OPDIVO (n=270) were fatigue (46%), musculoskeletal pain (30%), nausea (22%), and decreased appetite (22%).

In a separate Phase 3 study of YERVOY 3 mg/kg, the most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).

Please see U.S. Full Prescribing Information for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY.

About the Bristol-Myers Squibb and Ono Pharmaceutical Co., Ltd. Collaboration

In 2011, through a collaboration agreement with Ono Pharmaceutical Co., Ltd (Ono), Bristol-Myers Squibb expanded its territorial rights to develop and commercialize Opdivo globally except in Japan, South Korea and Taiwan, where Ono had retained all rights to the compound at the time. On July 23, 2014, Bristol-Myers Squibb and Ono further expanded the companies’ strategic collaboration agreement to jointly develop and commercialize multiple immunotherapies – as single agents and combination regimens – for patients with cancer in Japan, South Korea and Taiwan.

On June 5, 2017 AVEO Oncology (NASDAQ: AVEO) and Biodesix, Inc., co-development partners, reported the presentation of results from two investigator-sponsored Phase 1 studies of ficlatuzumab at the 2017 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting taking place in Chicago, Illinois (Press release, AVEO, JUN 5, 2017, View Source [SID1234519391]). The first is a study of ficlatuzumab in combination with the EGFR inhibitor cetuximab in patients with cetuximab-resistant, metastatic head and neck squamous cell carcinoma (HNSCC), and the second is a study of ficlatuzumab in combination with high-dose cytarabine in patients with high risk relapsed or refractory acute myeloid leukemia (AML). Ficlatuzumab is a humanized IgG1 antibody that binds to the HGF ligand with high affinity and specificity to inhibit the biological activities of the HGF/c-Met pathway.

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"HGF is an important pathway for resistance and proliferation in a number of cancer models, serving as a means to overcome EGFR inhibition in HNSCC, and as an adverse prognostic factor in AML," said Michael Needle, chief medical officer of AVEO. "In a Phase 1 study in patients with cetuximab-resistant recurrent/metastatic HNSCC, the addition of ficlatuzumab to the EGFR-targeted antibody cetuximab resulted in a disease control rate of 67%, and prolonged progression free and overall survival compared to historical controls, in addition to being well tolerated. With continued, strong investigator support, we look forward to the expected initiation, in the second half of 2017, of a randomized, Phase 2, multicenter, investigator-initiated trial to confirm these findings. We also look forward to the completion of the ongoing investigator-sponsored study in AML, which has demonstrated early signs of tolerability and activity, including a 50% complete response rate in the relapsed/refractory setting."

"Median PFS for cetuximab monotherapy in the naïve setting is only two months, as with the median PFS for nivolumab or single-agent chemotherapy in the platinum-refractory setting, suggesting an urgent need for new therapies," said Julie E. Bauman, MD, MPH, Professor of Medicine, Chief, Division of Hematology/Oncology, Associate Director of Translational Research, University of Arizona Cancer Center. "Although a small cohort, the fact that we observed significant responses and PFS of 6 months in a refractory population in this study suggests important biologic activity."

AVEO also announced that a Trials in Progress presentation highlighting the ongoing Phase 3, randomized, controlled, multi-center, open-label TIVO-3 study comparing tivozanib, the Company’s potent, selective, long half-life inhibitor of all three vascular endothelial growth factor (VEGF) receptors, to sorafenib in subjects with refractory advanced renal cell carcinoma.

The posters are available at www.aveooncology.com. Details of the posters are below:

Phase I study of the anti-HGF mononclonal antibody (mAb), ficlatuzumab, and cetuximab in cetuximab-resistant, recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC)

Presenter: Julie E. Bauman, MD, MPH, Chief, Division of Hematology and Oncology, Associate Director, Translational Research, University of Arizona Cancer Center
Abstract Number: 6038
Session: Head and Neck Cancer
Date and Time: Monday, June 5, 2017, 1:15-4:45 PM CT

In this phase I study, 12 patients with R/M HNSCC who had disease recurrence within 6 months of cetuximab radiation or progression within 6 months of cetuximab treatment in the recurrent metastatic setting were treated with a ficlatuzumab/cetuximab combination. The primary objective was to establish the recommended Phase 2 dose (RP2D) for ficlatuzumab, with the secondary objectives being to evaluate preliminary clinical efficacy of RP2D and to evaluate the relationship between preliminary efficacy and 1) baseline tumor p-Met expression and 2) serum Veristrat.

Cetuximab was administered every 2 weeks at 500 mg/m2, and ficlatuzumab dose tiers were 10 mg/kg (tier 1) or 20 mg/kg IV every 2 weeks (tier 2), with inter-patient escalation or de-escalation based on cumulative dose-limiting toxicities (DLT). RP2D was set at tier 2 if no DLTs were observed after 8 enrolled patients, with expansion continuing to 12 patients. Three patients were treated at dose tier 1 and 9 at dose tier 2. The RP2D is ficlatuzumab 20 mg/kg and cetuximab 500 mg/m2 every 2 weeks. The overall response rate was 17% (1 PR at tier 1; 1 at tier 2) and 50% of patients had stable disease, for a disease control rate of 67%. Median PFS and OS at RP2D were 6.0 mos (90% CI=2 mos-NR) and 8.2 mos (90% CI=2.7 mos-NR).

CyFi: A phase I study exploring the role of cMET pathway inhibition with ficlatuzumab (Fi) combined with high-dose cytarabine (Cy) in patients with high risk relapsed or refractory acute myeloid leukemia (AML)

Presenter: Charalambos (Babid) Andreadis, MD, Hematologic Malignancies and Blood and Marrow Transplantation Program, University of California, San Francisco
Abstract Number: 7040
Session: Hematologic Malignancies – Leukemia, Myelodyplastic Syndromes, and Allotransplant
Date and Time: Monday, June 5, 2017, 8:00-11:30 AM CT

In this ongoing study, the safety and tolerability of ficlatuzumab in combination with cytarabine was assessed in 9 patients with high risk relapsed or refractory acute myeloid leukemia. Ficlatuzumab was given in escalated dosing of 10, 15, or 20 mg/kg for 4 doses every 2 weeks, starting on day 0, and cytarabine was given at a fixed dose of 2g/m2 on days 2-7, using a 3×3 design. Dose-limiting toxicity (DLT) was defined based on toxicities attributable to the combination and unexpected with AML or high-dose cytarabine. Peripheral blood mononuclear cells and serum were collected at defined time points to assess HGF levels and activation of the c-Met pathway. The results showed no DLTs, and the combination has proven well tolerated. The most frequent grade 3-4 adverse events were febrile neutropenia (56%), ventricular tachycardia (22%), respiratory distress (11%), electrolyte disturbance (11%). There was 1 death from sepsis and multi-organ failure on day 23, during count recovery. Of the 8 evaluable patients, 4 achieved a CR (50%), all in the 2nd dose cohort. All patients had detectable circulating HGF levels at baseline and levels increased following exposure to Fi by an average of 193% (p value). Baseline levels or change from baseline were not associated with response.

Title: Tivo-3: A phase 3, randomized, controlled, multi-center, open-label study to compare tivozanib hydrochloride to sorafenib in subjects with refractory advanced renal cell carcinoma (RCC)
Presenter: Brian I. Rini, MD, FACP, Professor of Medicine, Lerner College of Medicine, Leader, GU Program, Department of Hematology and Oncology, Cleveland Clinic Taussig Cancer Institute
Abstract Number: TPS4600
Session: Genitourinary (Non-prostate) Cancer
Date and Time: Sunday, June 4, 2017, 8:00-11:30 AM CT

About Ficlatuzumab

Ficlatuzumab (formerly known as AV-299) is a potent hepatocyte growth factor (HGF) inhibitory antibody that binds to the HGF ligand with high affinity and specificity to inhibit HGF/c-Met biological activities. AVEO and Biodesix, Inc. currently divide all worldwide development costs for ficlatuzumab and are seeking a commercialization partner. Ficlatuzumab is currently being evaluated in investigator-sponsored trials in squamous cell carcinoma of the head and neck (HNSCC) and acute myeloid leukemia (AML).

About Tivozanib

Tivozanib is an oral, once-daily, vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI). It is a potent, selective and long half-life inhibitor of all three VEGF receptors and is designed to optimize VEGF blockade while minimizing off-target toxicities, potentially resulting in improved efficacy and minimal dose modifications. Tivozanib has been investigated in several tumors types, including renal cell, colorectal and breast cancers

On June 5, 2017 Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in T-cell therapy to treat cancer, reported an oral presentation on updated data from its NY-ESO study in synovial sarcoma, as well as four trials in progress posters (Press release, Adaptimmune, JUN 5, 2017, View Source [SID1234519390]). The data were presented at the 2017 ASCO (Free ASCO Whitepaper) annual meeting in Chicago, Illinois.

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The Company will host a live teleconference and webcast slide presentation on June 6th from 8:00–9:00 AM EDT (1:00–2:00 PM BST) to discuss the updated synovial sarcoma clinical data. Call in details and the webcast link are provided below.

"We have seen responses across all of our ongoing cohorts in our NY-ESO study in synovial sarcoma, including in patients who express lower levels of NY‑ESO, and in those receiving conditioning with modified doses of fludarabine / cyclophosphamide," said Rafael Amado, Adaptimmune’s Chief Medical Officer. "A lower response rate was observed in the absence of fludarabine conditioning and that cohort is now closed. For patients from Cohort 1, an updated survival analysis shows a promising median predicted overall survival of 120 weeks or approximately 28 months. The data continue to suggest that NY-ESO is well-tolerated. We have seen no events of seizure, cerebral edema, or encephalopathy; most events of cytokine release syndrome are grades 1-2 and all resolved with supportive care."

He continued: "We are in a period of significant operational momentum with ongoing trials in our three wholly-owned assets, MAGE‑A4, MAGE-A10 and AFP, as well as additional studies through our collaboration with GSK with NY-ESO in myxoid / round cell liposarcoma, ovarian, and non-small cell lung cancer – study designs and screening progress for some of these trials were also presented at ASCO (Free ASCO Whitepaper)."

Data Update from the Ongoing NY-ESO Synovial Sarcoma Study
During an oral presentation on June 5th entitled, "Open label, non-randomized, multi-cohort pilot study of genetically engineered NY-ESO-1 specific NY-ESO-1c259t in HLA-A2+ patients with synovial sarcoma (NCT01343043)," Dr. Sandra P. D’Angelo of the Memorial Sloan Kettering Cancer Center presented an update on all cohorts from Adaptimmune’s ongoing study.

NY-ESO continues to be generally well-tolerated and initial anti-tumor activity has been observed in all ongoing cohorts including low expressors of NY‑ESO (Cohort 2)
Of the twelve patients treated in Cohort 1 (non-modified fludarabine / cyclophosphamide ["Flu/Cy"] lymphodepletion regimen), five remain alive with a median predicted overall survival of 120 weeks (~28 months) (data cutoff March 30, 2017)
Confirmed responses have been observed in all cohorts as follows:
— Cohort 1 (High Flu/Cy, High NY-ESO): 6/12 (50%) patients with a median progression free survival (PFS) of 15 weeks (range:8, 38); 6/10 (60%) response rate in patients who received a target dose of at least one billion cells
— Cohort 2 (High Flu/Cy, Low NY-ESO): 2/5 (40%); ongoing
— Cohort 3: (High cyclophosphamide, no fludarabine, High NY-ESO): 1/5 (20%); cohort closed
— Cohort 4 (Modified Flu/Cy, High NY-ESO): 3/6 (50%); (ongoing)
Peak and long-term expansion of NY-ESO SPEAR T-cells appears to correlate with clinical efficacy
Fludarabine appears to be an important component of the lymphodepletion regimen
All reported events of cytokine release syndrome resolved with supportive care, and the majority of events were Grade 1 or 2
There were no reported events of seizure, cerebral edema, or encephalopathy
Overview of Study Designs from the Trials in Progress Posters
The four trials in progress posters summarized the study designs for Adaptimmune’s ongoing NY‑ESO trials in myxoid/round cell liposarcoma (MRCLS), ovarian cancer, and non-small cell lung cancer (NSCLC); the Company’s ongoing MAGE-A10 trial in NSCLC, and its MAGE-A10 triple tumor study in patients with head and neck, melanoma, or urothelial "bladder" tumors.

NY-ESO in MRCLS (NCT02992743):
— Open-label, non-randomized pilot study evaluating the safety, tolerability, and antitumor activity of NY-ESO SPEAR T-cells in patients with MRCLS
— Initially, 10 subjects are planned to be enrolled, with potential to enroll an additional 5 subjects. Subjects who do not receive the minimum cell dose or who do not receive the T‑cell infusion may be replaced.
— Subjects must be: ≥ 18 yrs old; HLA-A*02:01, *02:05, or *02:06 positive; have advanced (metastatic or inoperable) MRCLS expressing NY-ESO-1 at 2+/3+ intensity in ≥30% of tumor cells by IHC; measurable disease; prior systemic anthracycline therapy; have ECOG status 0 or 1; and adequate organ function.
— Lymphodepletion regimen: fludarabine (30mg/m2/day) and cyclophosphamide (600 mg/m2/day) for 3 days; same as Cohort 4 in Synovial Sarcoma study
— Target dose of 1 – 8 × 109 transduced SPEAR T-cells
— Efficacy assessed by overall response rate, time to response, duration of response, progression-free survival, and overall survival at weeks 4, 8, and 12, month 6, and then every 3 months until confirmation of disease progression
— This study is open and actively enrolling; as of May 18, 2017, 3 subjects have been enrolled

NY-ESO in Ovarian Cancer (NCT01567891):
— Single-arm, open-label clinical trial evaluating the safety, tolerability, and antitumor activity of NY-ESO SPEAR T-cells in patients with ovarian cancer
— Subjects must be ≥ 18 years old; HLA-A*02:01, *02:05, or *02:06 positive; have recurrent epithelial ovarian, primary peritoneal or fallopian tube carcinoma with refractory or platinum-resistant disease expressing NY-ESO-1 at ≥1+ intensity in ≥10% of tumor cells by IHC; have measurable disease; have ECOG status 0 or 1; and have adequate organ function.
— The study evaluates two lymphodepleting regimens: cyclophosphamide alone (enrollment completed; n=7) and cyclophosphamide plus fludarabine (up to 10 subjects to be treated)
— The first 6 subjects were lymphodepleted prior to T-cell infusion with various regimens of cyclophosphamide alone. None of these subjects achieved a response per RECIST v1.1 (ASCO 2016).
— The lymphodepletion regimen has been amended to include both fludarabine and cyclophosphamide (fludarabine [30mg/m2/day] and cyclophosphamide [600 mg/m2/day] for 3 days; same as Cohort 4 in Synovial Sarcoma study)
— Target dose of 1 – 6 × 109 transduced SPEAR T-cells
— Efficacy assessed by response rate, duration of response, progression-free survival, and overall survival at weeks 4, 8, and 12, month 6, and then every 3 months until confirmation of disease progression
— Enrollment is ongoing
NY-ESO (NCT02588612) and MAGE-A10 (NCT02592577) in NSCLC:
— Open-label studies of NY-ESO or MAGE A-10 SPEAR T-cells in patients with NSCLC
— Subjects are screened under a separate protocol (Screening Protocol: NCT02636855) to identify those who have the relevant HLA-A*02 alleles and NY-ESO-1 or MAGE-A10 tumor expression.
— Subjects must have Stage IIIb or IV NSCLC, have failed at least one platinum-containing regimen (may have received CPIs), have measurable disease, ECOG 0-1, adequate organ function, and be without brain metastases, history of severe autoimmune disease or current uncontrolled illness
— The NY-ESO trial is a 10 subject study with a target dose of 1-6 x 109 transduced cells
— The MAGE-A10 trial is a first-in-human study utilizing a modified 3+3 design in up to 28 patients with escalating doses of 0.1, 1.0 and 1-6 x 109 transduced T-cells to evaluate safety, including dose limiting toxicities (DLTs). The DLT observation period will be during the first 30 days following SPEAR T-cell infusion for each patient in all groups.
— For the NY-ESO study, the lymphodepletion regimen is: fludarabine (30mg/m2/day) and cyclophosphamide (600 mg/m2/day) for 3 days; same as Cohort 4 in Synovial Sarcoma study
— For the MAGE-A10 study, the lymphodepletion regimen for the first group is cyclophosphamide alone : cyclophosphamide (1800 mg/m2/day) for 2 days; subsequent groups will receive fludarabine (30mg/m2/day) and cyclophosphamide (600 mg/m2/day) for 3 days; same as Cohort 4 in Synovial Sarcoma study
— For both studies, efficacy assessed by response rate, duration of response, progression-free survival, and overall survival at weeks 4, 8, and 12, month 6, and then every 3 months (for 2 years) and then every 6 months until confirmation of disease progression
— These studies are currently active and enrolling; as of May 18, 2017, 3 subjects have been enrolled in the NY-ESO-1 study and 2 subjects have been enrolled in the MAGE-A10 study

MAGE-A10 Triple Tumor (NCT02989064):
— Open-label first-in-human study utilizing a modified 3+3 design in up to 10 patients receiving the target dose with escalating doses of 0.1, 1.0 and 1-6 x 109 transduced T-cells to evaluate safety, including DLTs. The DLT observation period will be during the first 30 days following SPEAR T-cell infusion for each patient in all groups.
— Subjects are screened under a separate protocol (Screening Protocol: NCT02636855).
— Subjects must be HLA*02:01 and/or *02:06 positive and have inoperable or metastatic (advanced) urothelial "bladder" cancer, melanoma, or squamous cell head and neck tumors with MAGE-A10 expression at ≥1+ intensity in ≥10% of tumor cells by IHC; and, have received standard of care therapies and have progressive disease.
— Lymphodepletion regimen: fludarabine (30mg/m2/day) and cyclophosphamide (600 mg/m2/day) for 3 days; same as Cohort 4 in Synovial Sarcoma study
— Efficacy assessed by overall response rate, best overall response, time to response, duration of response, duration of stable disease, progression-free survival, and overall survival at weeks 6, 12, 18, and 24 weeks, and then every 3 months until confirmation of disease progression
— This study is currently active and enrolling; as of May 18, 2017, 4 subjects have been enrolled