Adaptimmune Provides Update on Study of NY-ESO SPEAR® T-cell Therapy in Synovial Sarcoma at the European Society for Medical Oncology (ESMO) 2016 Congress

On October 9, 2016 Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in T-cell therapy to treat cancer, reported a poster presentation of updated data on its lead clinical program, an NY-ESO SPEAR (Specific Peptide Enhanced Affinity Receptor) T-cell receptor therapy, in patients with synovial sarcoma at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2016 Congress (Press release, Adaptimmune, OCT 9, 2016, View Source;p=RssLanding&cat=news&id=2210294 [SID:SID1234515673]).

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"These data help clarify the design of our upcoming pivotal studies in sarcoma," said Dr. Rafael Amado, Adaptimmune’s Chief Medical Officer. "We have seen durable tumor responses to our SPEAR T-cells and the preliminary benefit:risk profile appears favorable. Further, although the data are preliminary, we do see activity against tumors with lower levels of NY-ESO expression, which we hope will further expand the utility of this therapy, and we have evidence that fludarabine is required in the pre-conditioning regimen. With these data in hand, we will initiate Cohort 4 with our modified fludarabine pre-conditioning regimen, and continue toward our goal of bringing this novel TCR-based immunotherapy to sarcoma patients."

In a poster presentation entitled, "Open Label Non-Randomized Multi-Cohort Pilot Study of Genetically Engineered NY-ESO-1 Specific NY-ESO SPEAR T-cells in HLA-A*02+ Patients with Synovial Sarcoma," Crystal Mackall, M.D., Professor of Pediatrics and Medicine; Associate Director of the Stanford Cancer Institute, provided an update on the following synovial sarcoma cohorts:

Cohort 1: Subjects with high (≥50 percent 2+/3+ by IHC) NY-ESO-1 antigen expression and lymphodepletion with cyclophosphamide and fludarabine
Cohort 2: Subjects with low (>1 percent to <50 percent 2+/3+ by IHC) NY-ESO-1 antigen expression and lymphodepletion with cyclophosphamide and fludarabine
Cohort 3: Subjects with high (≥ 50 percent 2+/3+ by IHC) NY-ESO-1 antigen expression and lymphodepletion with cyclophosphamide alone (no fludarabine)
Cohort 4: Subjects with high (≥ 50 percent 2+/3+ by IHC) NY-ESO-1 antigen expression and lymphodepletion with a modified (lower) dose than Cohort I of cyclophosphamide and fludarabine
Cohort 1
Adaptimmune has previously announced that in the first cohort of synovial sarcoma patients, NY-ESO SPEAR T-cells demonstrated a robust clinical response, including a 50 percent (6/12) response rate, and a 60 percent response rate (6/10) in those who received the target dose of at least 1×109 transduced cells. The median duration of response is reported to be approximately 31 weeks (August 31 data cutoff). Ongoing NY-ESO SPEAR T-cell persistence has been observed for up to 36 months.

Cohort 2
Four subjects of a targeted 10 are currently enrolled in the second cohort; three patients have been treated with NY-ESO SPEAR T-cells. As of August 31, 2016 best responses seen in these three patients were: one partial response (PR), one stable disease (SD), and one progressive disease (PD).

Cohorts 3 and 4
Five patients are currently enrolled in the third cohort; no objective responses have been observed to date. As pre-specified in the protocol, enrollment in cohort 3 has ceased, and company has initiated enrollment in Cohort 4.

Tolerability
NY-ESO SPEAR T-cells continue to demonstrate a generally acceptable benefit: risk profile in all treated patients to date. The most common (>30%) related adverse events include pyrexia, lymphopenia, decreased white blood cell (WBC), nausea, anemia, neutropenia, fatigue, decreased platelet count (PLT), sinus tachycardia, and rash. Most common toxicities related to therapy can be monitored and managed with medical intervention and supportive care. While there are differences in the patient populations, incidence of cytokine release syndrome (CRS) with NY-ESO-1c259 SPEAR T appears to be of lower frequency and severity than reported with CD19 CAR-T therapy. As previously reported at the 2016 Annual American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Meeting, there was one fatal SAE of bone marrow failure in Cohort 2 of our synovial sarcoma trial. Internal investigations have not identified a mechanism by which NY-ESO SPEAR T-cells may have caused bone marrow failure.

Adaptimmune’s SPEAR T-cell candidates are novel cancer immunotherapies that have been engineered to target and destroy cancer cells by strengthening a patient’s natural T-cell response. T-cells are a type of white blood cell that play a central role in a person’s immune response. Adaptimmune’s goal is to harness the power of the T-cell and, through its multiple therapeutic candidate, significantly impact cancer treatment and clinical outcomes of patients with solid and hematologic cancers.

Overall survival data from LUX-Lung 7 head-to-head trial of Gilotrif® (afatinib) versus Iressa® (gefitinib) presented at ESMO

On October 9, 2016 Boehringer Ingelheim reported results from the LUX-Lung 7 trial that directly compared the efficacy and safety of second-generation EGFR-directed therapy Gilotrif (afatinib) and first-generation Iressa (gefitinib), in the first-line treatment of patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC) (Press release, Boehringer Ingelheim, OCT 9, 2016, View Source [SID:SID1234515672]). The trial investigated overall survival (OS) as a primary endpoint and a reduction in the risk of death (14%) was observed for patients treated with afatinib versus gefitinib. The median survival of patients treated with afatinib was 27.9 months compared to 24.5 months for those receiving gefitinib, without reaching significance. The OS outcomes observed with afatinib were consistent across common EGFR mutation types.

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Details of the analysis will be presented today at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) 2016 Congress in Copenhagen, Denmark, October 7 – 11 (abstract #LBA43 – Oral presentation, NSCLC, metastatic 1, Sunday, October 9, 11:45 – 12:00 CEST (5:45 – 6:00 ET)).

"The LUX-Lung 7 trial provides new insight into first-line treatment options for EGFR mutation-positive NSCLC patients and is the first global head-to-head trial directly comparing two EGFR-directed therapies," commented Shirish Gadgeel, M.D., leader of the Thoracic Oncology Multidisciplinary, Karmanos Cancer Center, Detroit. "These study findings may help inform treatment decisions for patients whose tumors have EGFR mutations."

Updated results also confirmed the primary analysis that showed the global Phase IIb LUX-Lung 7 trial met two of its three co-primary endpoints of progression-free survival (PFS) by independent review and time to treatment failure (a measure of time between start and discontinuation of treatment for any reason). Results from the primary analysis, presented in 2015, showed that afatinib significantly reduced the risk of lung cancer progression and the risk of treatment failure, both by 27% versus gefitinib. The improvement in PFS became more pronounced over time. After two years of treatment, more than twice as many patients on afatinib were alive and progression-free than those on gefitinib (after 18 months; 27% vs 15% and after 24 months; 18% vs 8%). Additionally, significantly more patients experienced an objective response (ORR; a clinically meaningful decrease in tumor size) with afatinib when compared to gefitinib.

Both afatinib and gefitinib demonstrated similar improvements in patient-reported outcome measures in the LUX-Lung 7 trial with no significant differences in health-related quality of life with afatinib compared to gefitinib treatment. Treatment with both afatinib and gefitinib were generally tolerable, leading to an equal rate of treatment-related discontinuation in both arms (6%). Adverse events (AEs) observed in the trial were consistent with the known safety profiles of both treatments. The overall frequency of serious AEs was 44.4% for afatinib and 37.1% for gefitinib. The most common grade ≥3 related AEs with afatinib were: diarrhea (13%) and rash/acne (9%), and with gefitinib: aspartate aminotransferase (AST)/alanine aminotransferase (ALT) increase (9%) and rash/acne (3%). Drug-related interstitial lung disease was reported for four patients on gefitinib and no patients on afatinib. Dose modification of afatinib was available in patients who met a set criteria in order to better manage AEs. As gefitinib is only available in one dose formulation, no dose reduction was administered.

"We believe that the latest results of the LUX-Lung 7 trial data adds to the growing body of evidence that reinforces the treatment benefits of afatanib in patients with these types of tumors," said Martina Flammer, M.D., Vice President, Clinical Development & Medical Affairs Specialty Care, Boehringer Ingelheim.

Afatinib is approved in over 70 countries for the first-line treatment of EGFR mutation-positive NSCLC. Approval of afatinib in this indication was based on the primary endpoint of PFS from the LUX-Lung 3 clinical trial where afatinib significantly delayed tumor growth when compared to standard chemotherapy. In addition, afatinib is the first treatment to have shown an OS benefit for patients with specific types of EGFR mutation-positive NSCLC compared to chemotherapy. A significant OS benefit was demonstrated independently in the LUX-Lung 3 and 6 trials for patients with the most common EGFR mutation (del19) compared to chemotherapy. Afatinib is also approved in the U.S., EU and other markets for the treatment of patients with advanced squamous cell carcinoma (SqCC) of the lung whose disease has progressed on or after treatment with platinum-based chemotherapy. Approval of afatinib in this indication is based on results of the LUX-Lung 8 study, which showed a significantly improved overall survival and progression-free survival compared to Tarceva (erlotinib) in patients with SqCC of the lung.

About the LUX-Lung 7 trial
LUX-Lung 7 is the first global, head-to-head trial comparing second- and first-generation EGFR-directed therapies (afatinib and gefitinib respectively) for patients with EGFR mutation-positive NSCLC who received no prior treatment. The Phase IIb trial included 319 patients with advanced stage NSCLC harboring common EGFR mutations (del19 or L858R). The trial’s co-primary endpoints were PFS by independent review, time to treatment failure and OS; and the secondary endpoints included ORR, disease control rate, tumor shrinkage, patient-reported outcomes and safety.

Results from the primary analysis: compared to gefitinib, afatinib significantly improved:

PFS (HR=0.73; 95% CI, 0.57‒0.95; p=0.017; median: 11.0 months [afatinib] versus 10.9 months [gefitinib]). The improvement in PFS with afatinib was consistent across pre-defined clinical subgroups, including gender, age, race and EGFR mutation type
Time to treatment failure (HR=0.73; 95% CI, 0.58‒0.92; p=0.0073; median: 13.7 months [afatinib] versus 11.5 months [gefitinib])
ORR (70% vs 56%, p=0.0083)
Data from the trial showed a reduction in the risk of death for patients treated with afatinib compared to gefitinib, without reaching significance (HR=0.86; 95% CI, 0.66‒1.12; p=0.2580; median: 27.9 months [afatinib] versus 24.5 months [gefitinib]). These OS data have a maturity of 71%, with further analysis to follow once full maturity has been reached.

What is GILOTRIF?

GILOTRIF is a prescription medicine used to treat people with non-small cell lung cancer (NSCLC):

that has certain types of abnormal epidermal growth factor receptor (EGFR) genes. Your doctor will perform a test to check for certain types of abnormal EGFR genes, and make sure that GILOTRIF is right for you. GILOTRIF may be used when you have not had previous treatment for cancer that has spread to other parts of the body. It is not known if GILOTRIF is safe and effective in treating lung cancer with other abnormal EGFR genes.
or

that is squamous type and has spread to other parts of the body after you have tried chemotherapy that contains platinum.
It is not known if GILOTRIF is safe and effective in children.

IMPORTANT SAFETY INFORMATION ABOUT GILOTRIF

Before you take GILOTRIF, tell your doctor if you:

have kidney or liver problems
have lung or breathing problems other than lung cancer
have a history of severe dry eye or any other eye problems. Tell your doctor if you wear contact lenses.
have heart problems
have any other medical conditions
are pregnant or plan to become pregnant. GILOTRIF can harm your unborn baby. You should not become pregnant while taking GILOTRIF.
Women who are able to become pregnant should use effective birth control during treatment with GILOTRIF and for at least 2 weeks after your last dose of GILOTRIF. Talk to your doctor about birth control methods that may be right for you.
Tell your doctor right away if you become pregnant or think you are pregnant while taking GILOTRIF.
are breastfeeding or plan to breastfeed. It is not known if GILOTRIF passes into your breast milk. Do not breastfeed while taking GILOTRIF and for 2 weeks after your last dose of GILOTRIF. Talk to your doctor about the best way to feed your baby if you take GILOTRIF.
Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. GILOTRIF may affect the way other medicines work, and other medicines may affect the way GILOTRIF works.

What to avoid while taking GILOTRIF

Limit your time in the sun. GILOTRIF can make your skin sensitive to the sun. You could get or have worsening rash or acne. You could get a severe sunburn. Use sunscreen and wear a hat and clothes that cover your skin while you are taking GILOTRIF if you have to be in sunlight.

GILOTRIF may cause serious side effects, including:

Diarrhea. Diarrhea is common with GILOTRIF and may sometimes be severe. Severe diarrhea can cause loss of body fluid (dehydration) and kidney problems that can sometimes lead to death. During your treatment with GILOTRIF, your doctor should prescribe medicines to treat diarrhea. Take this medicine exactly as your doctor tells you to. Tell your doctor if you have diarrhea. Get medical attention right away if your diarrhea does not go away or becomes severe.
Skin reactions. GILOTRIF can cause redness, rash, and acne. It is important to get treatment for skin reactions as soon as you notice them. Take medicines to help skin reactions exactly as your doctor tells you to. Get medical attention right away if you develop severe skin reactions such as peeling or blistering of the skin, or blisters in your mouth.
Lung or breathing problems. GILOTRIF may cause inflammation of the lung that may lead to death. Symptoms may be similar to those symptoms from lung cancer. Tell your doctor right away if you have any new or worsening lung problems, or any combination of the following symptoms: trouble breathing or shortness of breath, cough, or fever.
Liver problems. GILOTRIF can cause liver problems that can sometimes lead to death. Tell your doctor right away if you have any symptoms of a liver problem which may include:
yellowing of your skin or the white part of your eyes (jaundice)
dark or brown (tea-colored) urine
pain on the upper right side of your stomach area (abdomen)
bleeding or bruising more easily than normal
feeling very tired
Your doctor will do blood tests to check your liver function during your treatment with GILOTRIF.

Eye problems. Tell your doctor right away if you have symptoms of eye problems. Symptoms may include:
eye pain, swelling, redness, or tearing
blurred vision
sensitivity to light
other changes in your vision
Heart problems. Tell your doctor right away if you have any symptoms of a heart problem which may include:
new or worsening shortness of breath while at rest or with activity
cough
tiredness
swelling of your ankles, feet, or legs
feeling that your heart is pounding or racing (palpitations)
sudden weight gain
The most common side effects of GILOTRIF include diarrhea, rash, mouth sores, nail inflammation, dry skin, acne, decreased appetite, nausea, vomiting, itching.

GILOTRIF may cause decreased fertility in females and males. Talk to your doctor if you have concerns about your fertility.

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all of the possible side effects of GILOTRIF. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088 .

Please see the full Prescribing Information, including Patient Information.

New Data Presented at ESMO 2016 Further Demonstrates XTANDI(enzalutamide) Significantly Improves Time to PSA Progression in Advanced Prostate Cancer, Compared with Placebo

On October 9, 2016 Astellas Pharma Europe Ltd., a subsidiary of Tokyo-based Astellas Pharma Inc. (TSE:4503), reported the presentation of new data that reaffirms the role of XTANDITM▼ (enzalutamide) in extending time to prostate specific antigen (PSA) progression in men with advanced prostate cancer. The data presented today at the European Society for Medical Oncology Congress (ESMO) (Free ESMO Whitepaper), held in Copenhagen, Denmark, from 7-11 October, confirms the efficacy of enzalutamide vs placebo in Asian men (Press release, Astellas, OCT 9, 2016, View Source [SID:SID1234515671]).

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Data from a study examining the efficacy and safety of enzalutamide versus placebo in 409 Asian patients from China, South Korea, Taiwan and Hong Kong with asymptomatic/mildly symptomatic progressive advanced prostate cancer following androgen deprivation therapy (ADT) found that enzalutamide significantly improved time to PSA progression, compared with placebo (7.46 months vs 2.86 months, respectively (HR* 0.36; 95% CI 0.27**, 0.5; P<0.0001)).1 PSA blood tests are used to monitor the progression of prostate cancer.2

Secondary end points included overall survival, defined as time from randomisation to death from any cause, and radiographic progression free survival (rPFS) defined as the time from randomisation to radiographic progression or death from any cause.a Although the median overall survival was not yet reached at the time of the data cut-off in either treatment arm, enzalutamide significantly reduced the risk of death (HR 0.35; 95% CI 0.17, 0.70; p=0.0021). At data cut-off, enzalutamide significantly reduced the risk of rPFS events with 19.6% (41/209) of patients receiving enzalutamide and 36% (72/200) of patients in the placebo arm experiencing a rPFS event – i.e, spreading of the cancer. While slightly more patients treated with enzalutamide reported at least one treatment-emergent adverse event, enzalutamide was generally well tolerated in the trial.1 These results are consistent with data from the pivotal PREVAIL trial, which considered a patient population with similar clinical characteristics. In the PREVAIL trial, enzalutamide was found to increase the median overall survival in asymptomatic or mildly symptomatic patients with advanced prostate cancer who had not received chemotherapy, compared with placebo.3

__________________

aWithin 168 days of treatment discontinuation, whichever occurred first, assessed during the screening, at day 57, 113, 169 and 253 and every subsequent 12 weeks.

Dr Simon Chowdhury, Consultant Medical Oncologist, Guy’s and St Thomas’ NHS Foundation Trust, "The findings presented today show that enzalutamide can increase the time to PSA progression – an important marker used to monitor disease progression in prostate cancer – compared with placebo, in Asian men. Historically there has been a lack of studies considering this group of men and so these results provide reassurance of enzalutamide’s efficacy and tolerability across the broad population that we tend to see across Europe."

An additional five abstracts focusing on enzalutamide were also presented today, adding further to the body of data supporting the safety and efficacy profile of enzalutamide as a treatment option for advanced prostate cancer.

Enzalutamide data presentation details:

Ye D, Ahn H, Pu Y-S, et al. Efficacy and safety of enzalutamide (ENZ) vs placebo (PL) in chemotherapy-naïve patients (pts) with progressive metastatic castration-resistant prostate cancer (mCRPC) following androgen deprivation therapy (ADT): an Asian multinational study. Poster 760P; 9 Oct 2016 (Sun); 13:00-14:00; Hall E
Chowdhury S, Shore N, Saad f, et al. Fatigue in men with metastatic castration-resistant prostate cancer treated with enzalutamide: data from randomised clinical trials. Poster 739P; 9 Oct 2016 (Sun);13:00-14:00;Hall E
Heidenreich A, Shore N, Villers A, et al. Prognostic factors in men with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide (ENZA) or bicalutamide (BIC) in TERRAIN. Poster 759P; 9 Oct 2016 (Sun); 13:00-14:00; Hall E
Bryce A, Alumkal J, Armstrong A, et al. A post hoc analysis of radiographic progression with nonrising prostate-specific antigen in patients with metastatic castration-resistant prostate cancer (mCRPC) in the PREVAIL study. Poster 760P; 9 Oct 2016 (Sun); 13:00-14:00; Hall E
Stenzl A, Krivoshik A, Baron B, et al. Efficacy and safety of enzalutamide plus androgen deprivation therapy vs placebo plus androgen deprivation therapy in men with metastatic hormone-sensitive prostate cancer: the ongoing ARCHES trial. Poster 767TiP;9 Oct 2016 (Sun);13:00-14:00; Hall E
Miller K, Mulders P, Freedland S, et al. EMBARK: A phase 3, randomized, efficacy and safety study of enzalutamide plus leuprolide, enzalutamide monotherapy and placebo plus leuprolide in men with high-risk nonmetastatic prostate cancer progressing after definitive therapy. Poster 770TiP; 9 Oct 2016 (Sun); 13:00-14:00; Hall E
About PREVAIL

PREVAIL was a Phase 3, randomised, double-blind, placebo-controlled trial of enzalutamide versus placebo in patients with mCRPC who had not received chemotherapy.3

About AFFIRM

AFFIRM was a Phase 3, randomised, double-blind, placebo-controlled study of enzalutamide in patients with mCRPC who had previously been treated with docetaxel-based chemotherapy.4

About TERRAIN

TERRAIN was a Phase 2, randomised, double-blind, efficacy and safety study of enzalutamide vs. bicalutamide in patients with mCRPC.5

About STRIVE

STRIVE was a Phase 2, randomised, double-blind, efficacy and safety study of enzalutamide versus bicalutamide in patients with nonmetastatic or metastatic CRPC.6

About XTANDI (enzalutamide)

Enzalutamide is a novel, oral, once-daily androgen receptor signaling inhibitor. Enzalutamide directly targets the androgen receptors (AR) and exerts its effects on all three steps of AR signaling pathway:

Blocks androgen binding7
Androgen binding induces a conformational change that triggers activation of the receptor8
Prevents nuclear translocation7
Translocation of the AR to the nucleus is an essential step in AR-mediated gene regulation8
Impairs DNA binding7
Binding of the AR to the DNA is essential for modulation of gene expression8
Enzalutamide was first approved by the European Commission in June 2013 for the treatment of adult men with mCRPC whose disease has progressed on or after docetaxel therapy.9 Enzalutamide is also approved in Europe for the treatment of adult men with mCRPC who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated.9

Important Safety Information for XTANDI (enzalutamide)

For important Safety Information for enzalutamide please see the full Summary of Product Characteristics at: View Source

Pfizer Presents Promising New Immunotherapy Combination Data With INLYTA® (axitinib) In Advanced Renal Cell Carcinoma (RCC)

On October 9, 2016 Pfizer Inc. (NYSE:PFE) reported data from an ongoing, investigational Phase 1b study of INLYTA (axitinib) combined with the checkpoint inhibitor pembrolizumab (A4061079, NCT02133742), a PD-1 inhibitor known as KEYTRUDA and marketed by Merck, known as MSD outside the United States and Canada, in treatment-naïve patients with advanced renal cell carcinoma (RCC) (Press release, Pfizer, OCT 9, 2016, View Source [SID:SID1234515670]). The study was designed to establish dosing and evaluate the safety and anti-tumor activity of INLYTA when combined with pembrolizumab in first-line treatment of advanced RCC.

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Preliminary results from a similar, separate study combining INLYTA with avelumab (JAVELIN Renal 100, NCT02493751), an investigational, fully human anti-PD-L1 IgG1 monoclonal antibody that is being co-developed by Merck KGaA, Darmstadt, Germany, and Pfizer were also presented. The data suggest evidence of anti-tumor activity for INLYTA in combination with avelumab and were presented during a poster discussion session at the ESMO (Free ESMO Whitepaper) 2016 Congress, the annual meeting of the European Society for Medical Oncology being held in Copenhagen, Denmark.

Based on these Phase 1 results, two independent global Phase 3 trials evaluating these combinations – INLYTA plus pembrolizumab and INLYTA plus avelumab – each compared with SUTENT (sunitinib) in first-line advanced RCC are now enrolling patients.

"Combining immunotherapy agents with currently approved therapies such as INLYTA may provide a meaningful improvement in outcome for patients with renal cancer," said Chris Boshoff, M.D., Ph.D., head of immuno-oncology, early development and translational oncology, Pfizer Global Product Development. "The results presented today indicate that there is a potential additive or synergistic effect between INLYTA and a checkpoint inhibitor in RCC."

Early indicators from the A4061079 study point to strong response rates with the INLYTA/pembrolizumab combination, with 37 patients (71.2%, confidence internal 56.9, 82.9) achieving objective responses (three complete responses and 34 partial responses); 10 patients had stable disease and 5 patients had disease progression.

Separately, in the JAVELIN Renal 100 study of INLYTA in combination with avelumab, five out of six patients treated so far had confirmed partial responses (objective response rate 83.3%, 95% confidence interval: 35.9, 99.6) and one patient with tumor shrinkage not meeting partial response criteria had stable disease.

INLYTA is an oral vascular endothelial growth factor (VEGF) receptor inhibitor for the treatment of patients with advanced RCC after failure of one prior systemic therapy approved in 63 countries. It was the first treatment to demonstrate superior progression-free survival benefit in a Phase 3 study versus sorafenib, a tyrosine kinase inhibitor, in second-line treatment of advanced RCC.

About Avelumab

Avelumab (also known as MSB0010718C) is an investigational fully human anti-PD-L1 IgG1 monoclonal antibody. By inhibiting PD-L1 interactions, avelumab is thought to enable the activation of T-cells and the adaptive immune system. By retaining a native Fc-region, avelumab is thought to potentially engage the innate immune system and induce antibody-dependent cell-mediated cytotoxicity (ADCC). In November 2014, Merck KGaA, Darmstadt, Germany, and Pfizer announced a strategic alliance to co-develop and co-commercialize avelumab.

About INLYTA (axitinib)

INLYTA is an oral therapy that is designed to inhibit tyrosine kinases, including vascular endothelial growth factor (VEGF) receptors 1, 2 and 3; these receptors can influence tumor growth, vascular angiogenesis and progression of cancer (the spread of tumors). In the U.S., INLYTA is approved for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. INLYTA is also approved by the European Medicines Agency (EMA) for use in the EU in adult patients with advanced RCC after failure of prior treatment with sunitinib or a cytokine.

INLYTA Important Safety Information

Hypertension including hypertensive crisis has been observed. Blood pressure should be well controlled prior to initiating INLYTA. Monitor for hypertension and treat as needed. For persistent hypertension, despite use of antihypertensive medications, reduce the dose. Discontinue INLYTA if hypertension is severe and persistent despite use of antihypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis.

Arterial and venous thrombotic events have been observed and can be fatal. Use with caution in patients who are at increased risk or who have a history of these events.

Hemorrhagic events, including fatal events, have been reported. INLYTA has not been studied in patients with evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose.

Cardiac failure has been observed and can be fatal. Monitor for signs or symptoms of cardiac failure throughout treatment with INLYTA. Management of cardiac failure may require permanent discontinuation of INLYTA.

Gastrointestinal perforation and fistula, including death, have occurred. Use with caution in patients at risk for gastrointestinal perforation or fistula. Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment.

Hypothyroidism requiring thyroid hormone replacement has been reported. Monitor thyroid function before initiation of, and periodically throughout, treatment.

No formal studies of the effect of INLYTA on wound healing have been conducted. Stop INLYTA at least 24 hours prior to scheduled surgery.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been observed. If signs or symptoms occur, permanently discontinue treatment.

Monitor for proteinuria before initiation of, and periodically throughout, treatment. For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment.

Liver enzyme elevation has been observed during treatment with INLYTA. Monitor ALT, AST, and bilirubin before initiation of, and periodically throughout, treatment.

For patients with moderate hepatic impairment, the starting dose should be decreased. INLYTA has not been studied in patients with severe hepatic impairment.

Women of childbearing potential should be advised of potential hazard to the fetus and to avoid becoming pregnant while receiving INLYTA.

Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the dose. Grapefruit or grapefruit juice may also increase INLYTA plasma concentrations and should be avoided.

Avoid strong CYP3A4/5 inducers and, if possible, avoid moderate CYP3A4/5 inducers.

The most common (≥20%) adverse events (AEs) occurring in patients receiving INLYTA (all grades, vs sorafenib) were diarrhea (55% vs 53%), hypertension (40% vs 29%), fatigue (39% vs 32%), decreased appetite (34% vs 29%), nausea (32% vs 22%), dysphonia (31% vs 14%), hand-foot syndrome (27% vs 51%), weight decreased (25% vs 21%), vomiting (24% vs 17%), asthenia (21% vs 14%), and constipation (20% vs 20%).

The most common (≥10%) grade 3/4 AEs occurring in patients receiving INLYTA (vs sorafenib) were hypertension (16% vs 11%), diarrhea (11% vs 7%), and fatigue (11% vs 5%).

The most common (≥20%) lab abnormalities occurring in patients receiving INLYTA (all grades, vs sorafenib) included increased creatinine (55% vs 41%), decreased bicarbonate (44% vs 43%), hypocalcemia (39% vs 59%), decreased hemoglobin (35% vs 52%), decreased lymphocytes (absolute) (33% vs 36%), increased ALP (30% vs 34%), hyperglycemia (28% vs 23%), increased lipase (27% vs 46%), increased amylase (25% vs 33%), increased ALT (22% vs 22%), and increased AST (20% vs 25%).

Opdivo (nivolumab) Shows Durable Response in Longest Follow-up for a PD-1 Inhibitor in Previously Treated Advanced Non-Small Cell Lung Cancer

On October 9, 2016 Bristol-Myers Squibb Company (NYSE: BMY) reported updated results from two pivotal Phase 3 studies, CheckMate -057 and CheckMate -017, which showed more than one-third of previously treated metastatic non-small cell lung cancer (NSCLC) patients in both trials experienced ongoing responses with Opdivo, compared to no ongoing responses in the docetaxel arm (Press release, Bristol-Myers Squibb, OCT 9, 2016, View Source [SID:SID1234515666]). The median duration of response (DOR) with Opdivo versus docetaxel in CheckMate -057 was 17.2 months (95% CI: 8.4, NE) and 5.6 months (95% CI: 4.4, 6.9), respectively, and in CheckMate -017 it was 25.2 months (95% CI: 9.8, 30.4) and 8.4 months (95% CI: 8.4, NE), respectively. In CheckMate -057, patients with PD-L1 ≥1% had a median DOR of 17.2 months (95% CI: 8.4, NE) and in patients with PD-L1 <1%, it was 18.3 months (95% CI: 5.5, NE). In both studies, durability of response was observed in both PD-L1 expressors and non-expressors, and in CheckMate -057, one out of the four complete responses occurred in a patient with <1% PD-L1 expression.

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There were no new safety signals identified for Opdivo in the pooled safety analysis from both studies. No new treatment-related deaths occurred between one and two years’ minimum follow-up despite the longer treatment exposure, and new events were observed in 11/418 patients with an additional one year of follow up.

These findings were presented today, October 9, during a poster discussion session at the 2016 European Society for Medical Oncology Congress from 3:46-4:06 p.m. CEST (Abstract #1215PD).

"Further evaluation of Opdivo in previously treated non-small cell lung cancer showed continued superior survival and the potential for durable responses compared to docetaxel across histologies in this patient population," said Martin Reck, M.D., Ph.D., head of thoracic oncology at the LungenClinic Grosshansdorf. "Notably, the median duration of response with Opdivo was more than three times that observed with docetaxel."

Patient-reported outcomes from CheckMate -057 were also presented today during a poster discussion session from 3:46-4:06 p.m. CEST (Abstract #1217PD). Findings show Opdivo provided better preservation of health status, health-related quality of life and symptom control versus docetaxel, as assessed by the EuroQoL-5 Dimensions (EQ-5D) visual analog scale (VAS) and the Lung Cancer Symptom Score (LCSS).

Nick Botwood, M.D., Development Lead, Lung and Head & Neck, Bristol-Myers Squibb, commented, "Opdivo, a standard of care in the second-line non-small cell lung cancer treatment setting continues to show durable survival based on updated findings from CheckMate -057 and -017. In addition, based on patient-reported outcomes data from CheckMate -057, Opdivo shows favorable overall health status compared to chemotherapy. These pivotal data continue to inform the scientific community on the use of Opdivo in previously treated NSCLC, a difficult-to-treat cancer."

About CheckMate -057 and CheckMate -017

CheckMate -057 is a landmark Phase 3, open-label, randomized clinical trial that evaluated patients with advanced non-squamous non-small cell lung cancer (NSCLC) who had progressed during or after one prior platinum doublet-based chemotherapy regimen. The trial included patients regardless of PD-L1 status. The study’s primary endpoint was overall survival (OS), and secondary endpoints included objective response rate (ORR), progression-free survival (PFS) and efficacy by tumor PD-L1 expression. Patients enrolled in the trial were administered Opdivo 3 mg/kg every two weeks versus docetaxel at 75 mg/m2 every three weeks.

CheckMate -017 was a Phase 3, open-label, randomized clinical trial that evaluated Opdivo 3 mg/kg every two weeks versus docetaxel 75 mg/m2 every three weeks in patients with advanced squamous NSCLC who had progressed during or after one prior platinum doublet-based chemotherapy regimen. The study’s primary endpoint was OS, and secondary endpoints included PFS and response rate. The trial included patients regardless of PD-L1 expression status.

In pooled safety analyses of CheckMate -057 and CheckMate -017, after a minimum of two years of follow-up, treatment-related adverse events (AE) were reported in fewer Opdivo-treated patients than docetaxel-treated patients (any grade: 68% versus 88%; Grade 3/4: 10% versus 55%) and less frequently led to discontinuation (any grade: 6% versus 13%; Grade 3/4: 4% versus 7%). Frequencies of the most common treatment-related AEs were lower with Opdivo than docetaxel. The majority of treatment-related select AEs occurred within the first three months of Opdivo treatment and were resolved using standard management algorithms. Pooled Grade 3/4 treatment-related select AEs for Opdivo include skin (1%), gastrointestinal (1.2%), endocrine (0%), hepatic (1%), pulmonary (1.2%), renal (0.2%) and hypersensitivity/infusion reaction (0%).

In CheckMate -057, patient-reported outcomes (PROs) were measured using the Lung Cancer Symptom Scale (LCSS) and European Quality of Life (EuroQol)-5 Dimensions visual analog scale (EQ-5D VAS) and EQ-5D utility index (UI). These PROs were assessed every other cycle for Opdivo and every cycle for docetaxel for the first six months of treatment and then every six weeks and at two post-treatment follow-up visits. The EQ-5D also was assessed during survival follow-up, including every three months for the first year and then every six months thereafter. While improvements were seen earlier with the LCSS than with the EQ-5D VAS, both PRO instruments indicated benefit before the separation of the survival curves, which also favored Opdivo.

Bristol-Myers Squibb: At the Forefront of Immuno-Oncology Science & Innovation

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 that will raise survival expectations in hard-to-treat cancers and will change the way patients live with cancer.

We are leading the scientific understanding of I-O through our extensive portfolio of investigational and approved agents, including the first combination of two I-O agents in metastatic melanoma, and our differentiated clinical development program, which is studying broad patient populations across more than 20 types of cancers with 11 clinical-stage molecules designed to target different immune system pathways. Our deep expertise and innovative clinical trial designs uniquely position us to advance the science of combinations across multiple tumors and potentially deliver the next wave of I-O combination regimens 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 inform which patients will benefit most from I-O therapies.

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 57 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 47 countries, including the United States and the European Union.

U.S. FDA-APPROVED INDICATIONS FOR OPDIVO

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

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 confirmatory trials.

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 patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post- transplantation brentuximab vedotin. 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.

Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the CheckMate 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

Immune-mediated pneumonitis, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience with solid tumors, fatal immune-mediated pneumonitis occurred with OPDIVO. In addition, in CheckMate 069, there were six patients who died without resolution of abnormal respiratory findings. Monitor patients for signs with radiographic imaging and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In CheckMate 069 and 067, immune-mediated pneumonitis occurred in 6% (25/407) of patients receiving OPDIVO with YERVOY: Fatal (n=1), Grade 3 (n=6), Grade 2 (n=17), and Grade 1 (n=1). In CheckMate 037, 066, and 067, immune-mediated pneumonitis occurred in 1.8% (14/787) of patients receiving OPDIVO: Grade 3 (n=2) and Grade 2 (n=12). In CheckMate 057, immune- mediated pneumonitis, including interstitial lung disease, occurred in 3.4% (10/287) of patients: Grade 3 (n=5), Grade 2 (n=2), and Grade 1 (n=3). In CheckMate 025, pneumonitis, including interstitial lung disease, occurred in 5% (21/406) of patients receiving OPDIVO and 18% (73/397) of patients receiving everolimus. Immune-mediated pneumonitis occurred in 4.4% (18/406) of patients receiving OPDIVO: Grade 4 (n=1), Grade 3 (n=4), Grade 2 (n=12), and Grade 1 (n=1). In CheckMate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 4.9% (13/263) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 3.4% (9/263) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=8).

Immune-Mediated Colitis

Immune-mediated colitis can occur with OPDIVO treatment. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. As a single agent, withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon restarting OPDIVO. When administered with YERVOY, withhold OPDIVO for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis upon restarting OPDIVO. In CheckMate 069 and 067, diarrhea or colitis occurred in 56% (228/407) of patients receiving OPDIVO with YERVOY. Immune-mediated colitis occurred in 26% (107/407) of patients: Grade 4 (n=2), Grade 3 (n=60), Grade 2 (n=32), and Grade 1 (n=13). In CheckMate 037, 066, and 067, diarrhea or colitis occurred in 31% (242/787) of patients receiving OPDIVO. Immune-mediated colitis occurred in 4.1% (32/787) of patients: Grade 3 (n=20), Grade 2 (n=10), and Grade 1 (n=2). In CheckMate 057, diarrhea or colitis occurred in 17% (50/287) of patients receiving OPDIVO. Immune-mediated colitis occurred in 2.4% (7/287) of patients: Grade 3 (n=3), Grade 2 (n=2), and Grade 1 (n=2). In CheckMate 025, diarrhea or colitis occurred in 25% (100/406) of patients receiving OPDIVO and 32% (126/397) of patients receiving everolimus. Immune-mediated diarrhea or colitis occurred in 3.2% (13/406) of patients receiving OPDIVO: Grade 3 (n=5), Grade 2 (n=7), and Grade 1 (n=1). In CheckMate 205 and 039, diarrhea or colitis occurred in 30% (80/263) of patients receiving OPDIVO. Immune-mediated diarrhea (Grade 3) occurred in 1.1% (3/263) of patients.

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

Immune-mediated hepatitis can occur with OPDIVO treatment. 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 CheckMate 069 and 067, immune-mediated hepatitis occurred in 13% (51/407) of patients receiving OPDIVO with YERVOY: Grade 4 (n=8), Grade 3 (n=37), Grade 2 (n=5), and Grade 1 (n=1). In CheckMate 037, 066, and 067, immune-mediated hepatitis occurred in 2.3% (18/787) of patients receiving OPDIVO: Grade 4 (n=3), Grade 3 (n=11), and Grade 2 (n=4). In CheckMate 057, one patient (0.3%) developed immune-mediated hepatitis. In CheckMate 025, there was an increased incidence of liver test abnormalities compared to baseline in AST (33% vs 39%), alkaline phosphatase (32% vs 32%), ALT (22% vs 31%), and total bilirubin (9% vs 3.5%) in the OPDIVO and everolimus arms, respectively. Immune-mediated hepatitis requiring systemic immunosuppression occurred in 1.5% (6/406) of patients receiving OPDIVO: Grade 3 (n=5) and Grade 2 (n=1). In CheckMate 205 and 039, hepatitis occurred in 11% (30/263) of patients receiving OPDIVO. Immune-mediated hepatitis occurred in 3.4% (9/263): Grade 3 (n=7) and Grade 2 (n=2).

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 Dermatitis

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 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

Hypophysitis, adrenal insufficiency, thyroid disorders, and type 1 diabetes mellitus can occur with OPDIVO treatment. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency during and after treatment, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer 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. Administer insulin for type 1 diabetes. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

In CheckMate 069 and 067, hypophysitis occurred in 9% (36/407) of patients receiving OPDIVO with YERVOY: Grade 3 (n=8), Grade 2 (n=25), and Grade 1 (n=3). In CheckMate 037, 066, and 067, hypophysitis occurred in 0.9% (7/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=3), and Grade 1 (n=2). In CheckMate 025, hypophysitis occurred in 0.5% (2/406) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 1 (n=1). In CheckMate 069 and 067, adrenal insufficiency occurred in 5% (21/407) of patients receiving OPDIVO with YERVOY: Grade 4 (n=1), Grade 3 (n=7), Grade 2 (n=11), and Grade 1 (n=2). In CheckMate 037, 066, and 067, adrenal insufficiency occurred in 1% (8/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=5), and Grade 1 (n=1). In CheckMate 057, 0.3% (1/287) of OPDIVO-treated patients developed adrenal insufficiency. In CheckMate 025, adrenal insufficiency occurred in 2.0% (8/406) of patients receiving OPDIVO: Grade 3 (n=3), Grade 2 (n=4), and Grade 1 (n=1). In CheckMate 205 and 039, adrenal insufficiency (Grade 2) occurred in 0.4% (1/263) of patients receiving OPDIVO. In CheckMate 069 and 067, hypothyroidism or thyroiditis occurred in 22% (89/407) of patients receiving OPDIVO with YERVOY: Grade 3 (n=6), Grade 2 (n=47), and Grade 1 (n=36). Hyperthyroidism occurred in 8% (34/407) of patients: Grade 3 (n=4), Grade 2 (n=17), and Grade 1 (n=13). In CheckMate 037, 066, and 067, hypothyroidism or thyroiditis occurred in 9% (73/787) of patients receiving OPDIVO: Grade 3 (n=1), Grade 2 (n=37), Grade 1 (n=35). Hyperthyroidism occurred in 4.4% (35/787) of patients receiving OPDIVO: Grade 3 (n=1), Grade 2 (n=12), and Grade 1 (n=22). In CheckMate 057, Grade 1 or 2 hypothyroidism, including thyroiditis, occurred in 7% (20/287) and elevated thyroid stimulating hormone occurred in 17% of patients receiving OPDIVO. Grade 1 or 2 hyperthyroidism occurred in 1.4% (4/287) of patients. In CheckMate 025, thyroid disease occurred in 11% (43/406) of patients receiving OPDIVO, including one Grade 3 event, and in 3.0% (12/397) of patients receiving everolimus. Hypothyroidism/thyroiditis occurred in 8% (33/406) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=17), and Grade 1 (n=14). Hyperthyroidism occurred in 2.5% (10/406) of patients receiving OPDIVO: Grade 2 (n=5) and Grade 1 (n=5). In CheckMate 205 and 039, hypothyroidism/thyroiditis occurred in 12% (32/263) of patients receiving OPDIVO: Grade 2 (n=18) and Grade 1: (n=14). Hyperthyroidism occurred in 1.5% (4/263) of patients receiving OPDIVO: Grade 2: (n=3) and Grade 1 (n=1). In CheckMate 069 and 067, diabetes mellitus or diabetic ketoacidosis occurred in 1.5% (6/407) of patients: Grade 4 (n=3), Grade 3 (n=1), Grade 2 (n=1), and Grade 1 (n=1). In CheckMate 037, 066, and 067, diabetes mellitus or diabetic ketoacidosis occurred in 0.8% (6/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=3), and Grade 1 (n=1). In CheckMate 025, hyperglycemic adverse events occurred in 9% (37/406) patients. Diabetes mellitus or diabetic ketoacidosis occurred in 1.5% (6/406) of patients receiving OPDIVO: Grade 3 (n=3), Grade 2 (n=2), and Grade 1 (n=1). In CheckMate 205 and 039, diabetes mellitus occurred in 0.8% (2/263) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 1 (n=1).

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

Immune-mediated nephritis can occur with OPDIVO treatment. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 increased serum creatinine, withhold and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue. In CheckMate 069 and 067, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients: Grade 4 (n=4), Grade 3 (n=3), and Grade 2 (n=2). In CheckMate 037, 066, and 067, nephritis and renal dysfunction of any grade occurred in 5% (40/787) of patients receiving OPDIVO. Immune-mediated nephritis and renal dysfunction occurred in 0.8% (6/787) of patients: Grade 3 (n=4) and Grade 2 (n=2). In CheckMate 057, Grade 2 immune-mediated renal dysfunction occurred in 0.3% (1/287) of patients receiving OPDIVO. In CheckMate 025, renal injury occurred in 7% (27/406) of patients receiving OPDIVO and 3.0% (12/397) of patients receiving everolimus. Immune-mediated nephritis and renal dysfunction occurred in 3.2% (13/406) of patients receiving OPDIVO: Grade 5 (n=1), Grade 4 (n=1), Grade 3 (n=5), and Grade 2 (n=6). In CheckMate 205 and 039, nephritis and renal dysfunction occurred in 4.9% (13/263) of patients treated with OPDIVO. This included one reported case (0.3%) of Grade 3 autoimmune nephritis.

Immune-Mediated Rash

Immune-mediated rash can occur with OPDIVO treatment. Severe rash (including rare cases of fatal toxic epidermal necrolysis) occurred in the clinical program of OPDIVO. Monitor patients for rash. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4. In CheckMate 069 and 067, immune-mediated rash occurred in 22.6% (92/407) of patients receiving OPDIVO with YERVOY: Grade 3 (n=15), Grade 2 (n=31), and Grade 1 (n=46). In CheckMate 037, 066, and 067, immune-mediated rash occurred in 9% (72/787) of patients receiving OPDIVO: Grade 3 (n=7), Grade 2 (n=15), and Grade 1 (n=50). In CheckMate 057, immune-mediated rash occurred in 6% (17/287) of patients receiving OPDIVO including four Grade 3 cases. In CheckMate 025, rash occurred in 28% (112/406) of patients receiving OPDIVO and 36% (143/397) of patients receiving everolimus. Immune- mediated rash, defined as a rash treated with systemic or topical corticosteroids, occurred in 7% (30/406) of patients receiving OPDIVO: Grade 3 (n=4), Grade 2 (n=7), and Grade 1 (n=19). In CheckMate 205 and 039, rash occurred in 22% (58/263) of patients receiving OPDIVO. Immune-mediated rash occurred in 7% (18/263) of patients on OPDIVO: Grade 3 (n=4), Grade 2 (n=3), and Grade 1 (n=11).

Immune-Mediated Encephalitis

Immune-mediated encephalitis can occur with OPDIVO treatment. 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 CheckMate 067, encephalitis was identified in one patient (0.2%) receiving OPDIVO with YERVOY. In CheckMate 057, fatal limbic encephalitis occurred in one patient (0.3%) receiving OPDIVO. In CheckMate 205 and 039, encephalitis occurred in 0.8% (2/263) of patients after allogeneic HSCT after OPDIVO.

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. In < 1.0% of patients receiving OPDIVO, the following clinically significant, immune-mediated adverse reactions occurred: uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, and sarcoidosis. Across clinical trials of OPDIVO as a single agent administered at doses of 3 mg/kg and 10 mg/kg, additional clinically significant, immune- mediated adverse reactions were identified: motor dysfunction, vasculitis, and myasthenic syndrome.

Infusion Reactions

Severe infusion reactions have been reported in <1.0% of patients in clinical trials of OPDIVO. 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 CheckMate 069 and 067, infusion- related reactions occurred in 2.5% (10/407) of patients receiving OPDIVO with YERVOY: Grade 2 (n=6) and Grade 1 (n=4). In CheckMate 037, 066, and 067, Grade 2 infusion related reactions occurred in 2.7% (21/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=8), and Grade 1 (n=11). In CheckMate 057, Grade 2 infusion reactions requiring corticosteroids occurred in 1.0% (3/287) of patients receiving OPDIVO. In CheckMate 025, hypersensitivity/infusion-related reactions occurred in 6% (25/406) of patients receiving OPDIVO and 1.0% (4/397) of patients receiving everolimus. In CheckMate 205 and 039, hypersensitivity/infusion- related reactions occurred in 16% (42/263) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=24), and Grade 1 (n=16).

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 SCT 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 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 relative to the OPDIVO arm. 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 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO. 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. 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 057, serious adverse reactions occurred in 47% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in ≥2% of patients were pneumonia, pulmonary embolism, dyspnea, pleural effusion, and respiratory failure. In CheckMate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO. 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, among all patients (safety population [n=263]), adverse reactions leading to discontinuation (4.2%) or to dosing delays (23%) occurred. The most frequent serious adverse reactions reported in ≥1% of patients were infusion-related reaction, pneumonia, pleural effusion, pyrexia, rash and pneumonitis. Ten patients died from causes other than disease progression, including 6 who died from complications of allogeneic HSCT. Serious adverse reactions occurred in 21% of patients in the safety population (n=263) and 27% of patients in the subset of patients evaluated for efficacy (efficacy population [n=95]).

Common Adverse Reactions

In CheckMate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm 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 arm were fatigue (53%), rash (40%), diarrhea (31%), and nausea (28%). In CheckMate 037, the most common adverse reaction (≥20%) reported with OPDIVO was rash (21%). In CheckMate 066, the most common adverse reactions (≥20%) reported with OPDIVO vs dacarbazine were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In CheckMate 057, the most common adverse reactions (≥20%) reported with OPDIVO were fatigue (49%), musculoskeletal pain (36%), cough (30%), decreased appetite (29%), and constipation (23%). In CheckMate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO vs everolimus 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, among all patients (safety population [n=263]) and the subset of patients in the efficacy population (n=95), respectively, the most common adverse reactions (reported in at least 20%) were fatigue (32% and 43%), upper respiratory tract infection (28% and 48%), pyrexia (24% and 35%), diarrhea (23% and 30%), and cough (22% and 35%). In the subset of patients in the efficacy population (n=95), the most common adverse reactions also included rash (31%), musculoskeletal pain (27%), pruritus (25%), nausea (23%), arthralgia (21%), and peripheral neuropathy (21%).

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%).

CheckMate Trials and Patient Populations

CheckMate 069 and 067 – advanced melanoma alone or in combination with YERVOY; CheckMate 037 and 066 – advanced melanoma; CheckMate 057 – non-squamous non-small cell lung cancer (NSCLC); CheckMate 025 – renal cell carcinoma; CheckMate 205/039 – classical Hodgkin lymphoma