2016 Updates in Oncology & Malignant Hematology Brendan Curley, DO

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1 2016 Updates in Oncology & Malignant Hematology Brendan Curley, DO Disclosures I received final support from ASCO Conquer Cancer foundation in two Merit Awards and one travel award I am on the speakers Bureau currently for Janseen (Xarelto) and Genomic Health (Oncotype Test) 1

Objectives At the end of the lecture, participants should be able to: Identify new, novel agents that have been approved by the FDA in 2015 and early 2016 for Oncology and Malignant Hematology

2 Objectives At the end of the lecture, participants should be able to: Identify new, novel agents that have been approved by the FDA in 2015 and early 2016 for Oncology and Malignant Hematology Understand their roles in cancer care Understand their side effect profiles and management of those side effects Have an understanding where future areas of research and development of Oncology Care So really, how are we doing? 2

Drugs Approved by the FDA 2015 Daratumumab Myeloma Alectinib ALK + Lung CA Elotuzumab Myeloma Lenvatinib Thyroid Cancer Trifluridine and tipiracil Colon CA Necitumumab NSCLC Squam Trabecedin

3 Drugs Approved by the FDA 2015 Daratumumab Myeloma Alectinib ALK + Lung CA Elotuzumab Myeloma Lenvatinib Thyroid Cancer Trifluridine and tipiracil Colon CA Necitumumab NSCLC Squam Trabecedin Leiomyosarcoma Melanoma Panobinostat Myeloma Cobimetinib BRAF + melanoma Palbociclib HR + Breast Cancer Ixazomib Myeloma Nivolumab NSCLC Osimertinib EGFR + Lung CA Talimogene laherparepvec FDA Approving New Drugs quickly and for multiple different cancers and treatment types. 3

4 4

Immunotherapy A new mode of treatment Advancement of the Year Immunotherapy Immunotherapy has its roots going back to IL 2 therapy First FDA approved immune

5 Immunotherapy A new mode of treatment Advancement of the Year Immunotherapy Immunotherapy has its roots going back to IL 2 therapy First FDA approved immune checkpoint inhibitor was Ipilimumab Blocks the CLTA 4 molecule on T cells increases immune response Attacks cancer cells Ipi approved for Melanoma based on NEJM study in

6 Immunotherapy End of 2014, 3 immunotherapies were approved: Ipilimumab Nivolumab Pembrolizumab MANY other PD 1/PDL 1 therapies are in development and undergoing clinical trials Exploding area of research 6

7 How does it work? First paper about Immunotherapy in lung cancer in NEJM in May

Trial Design Originally approved in Squamous Cell carcinoma of the Lung Now approved in Adenocarcinoma and SCC, not yet in Small Cell (however there is Phase II

8 Trial Design Originally approved in Squamous Cell carcinoma of the Lung Now approved in Adenocarcinoma and SCC, not yet in Small Cell (however there is Phase II Data) Randomized patients at 1:1 ratio Primary end point was overall survival Balance between two arms Compared those with relapsed Stage III or Stage IV disease 8

Nivolumab in Adenocarcinoma Study presented at ASCO 2015 Among patients with nonsquamous non small cell lung cancer who progressed after platinum based doublet chemotherapy, overall survival

9 Nivolumab in Adenocarcinoma Study presented at ASCO 2015 Among patients with nonsquamous non small cell lung cancer who progressed after platinum based doublet chemotherapy, overall survival was 12.2 months for those treated with nivolumab vs 9.4 months for those treated with docetaxel. Median duration of response was 17.1 months with nivolumab group vs 5.6 months with docetaxel. 9

10 Nivolumab in Adenocarcinoma CheckMate 057 study randomly assigned 582 patients with advanced nonsquamous NSCLC to treatment with nivolumab or docetaxel. The 292 patients in the nivolumab group received 3 mg/kg every 2 weeks, and the 290 patients in the docetaxel group received 75 mg/m 2 every 3 weeks. Response rates were higher in the nivolumab group compared to the docetaxel group (19.2% vs 12.4%). To PD L1 or Not to PD L1? For the subgroup of patients with high levels of PD L1 in their tumor ( 1% cells), median overall survival was even higher than the 12.2 months in the entire nivolumab group, exceeding 17 months. Overall, patients who received nivolumab had a 27% lower risk of death compared to those who received docetaxel, but the subgroup of patients with the high levels of PD L1 had a 41% to 60% reduction in risk of death, which was not observed in cases of low or undetectable PD L1 levels. 10

11 So, surely we test for it, right? Other PD L1 inhibitors Pembrolizumab also approved in lung cancer and melanoma Pembrolizumab + Ipi approved in Melanoma (high discotinuiaton rate of 40%) Pembrolizumab REQUIRES positive PD L1 testing; testing can take days to get back. Both work very well, no clear standard of care of which should be used first at this point 11

12 National Guidelines for workup Note the incorporation into National Guidelines 12

13 Melanoma Immunotherapy is now the standard of care in non BRAF mutated patients up front Is starting to become more and more frequently used in BRAF positive patients Which one to use??? Trials underway to evaluate where the proper treatment will be Combination of Immunotherapy 13

14 Trial Design Patients were assigned, in a 1:1:1 ratio, 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab alone, nivolumab plus ipilimumab, or ipilimumab alone. Progression free survival and overall survival were coprimary end points Results The median progression free survival was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) with nivolumab plus ipilimumab, 2.9 months (95% CI, 2.8 to 3.4) with ipilimumab (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to months (95% CI, 4.3 to 9.5) with nivolumab Patients with tumors positive for the PD 1 ligand (PD L1), the median progression free survival was 14.0 months in the nivolumab plus ipilimumab group and in the nivolumab group, but in patients with PD L1 negative tumors, progression free survival was longer with the combination therapy than with nivolumab alone (11.2 months [95% CI, 8.0 to not reached] vs. 5.3 months 14

15 Side effect Profile Treatment related adverse events of grade 3 or 4 occurred in 16.3% of the patients in the nivolumab group, 55.0% of those in the nivolumab plus ipilimumab group, and 27.3% of those in the ipilimumab group AEs leading to discontinuation were more common with the combination (43% vs 11%) 15

16 My take Have to carefully select these patients for combination therapy What to do if patient has to discontinue? High burden of disease Good performance status Needs quick response based on symptoms How far have we come? 16

$Guidelines Let s Dissect Speaking of dissecting Head & Neck Checkmate 141 Patients treated with Nivolumab after refractory platinum based chemotherapy The study was stopped early after an independent$

17 Guidelines Let s Dissect Speaking of dissecting Head & Neck Checkmate 141 Patients treated with Nivolumab after refractory platinum based chemotherapy The study was stopped early after an independent monitoring panel determined the primary endpoint of improvement in OS was met with the anti PD 1 agent versus the investigator's choice of cetuximab, methotrexate, or docetaxel. The primary endpoint was OS, with secondary outcome measures focused on response rates and progression free survival. The study was initiated in May 2014 and was not scheduled to complete until October

18 Pembrolizumab in H&N For pembrolizumab the objective response rate was 24.8% in 117 evaluable patients enrolled in the KEYNOTE 012 study. Tumor shrinkage was experienced by 56% of patients and another 25% had stable disease. The response rate seen with pembrolizumab was similar, regardless of HPV infection status. In those with HPV positive disease, the ORR was 20.6% compared with 27.2% in the negative group. HPV status was not a consideration in the enrollment criteria for the CheckMate 141 study. More data coming Can be used on compassionate use for those who would qualify (from both companies) Breast PD L1 Attempting to use in triple negative breast cancer who have had refractory disease on multiple therapies Data presented in December 2015 at SABC After a median follow up of 10 months, the ORR in patients with PD L1 expressing metastatic breast cancer was 33.3%. In patients with PD L1 positive triple negative breast cancer (TNBC), the ORR was 44.4% with avelumab. Across the full study population, which included PD L1 negative patients, the ORR was 4.8% 18

19 Breast Immunotherapy not ready for prime time Avelumab is a fully human IgG1 antibody that inhibits PD 1/PD L1 interaction by binding to PD L1. The agent may also elicit antitumor activity through antibody dependent cellular cytotoxicity Of those who responded, 5 had TNBC (8.6%), 4 of which were PD L1 positive. Responses were also observed in patients with HER2 negative/hr positive breast cancer (2.8%) and for those with HER2 positive disease (3.8%) Kidney 19

Trial Design/Outcomes A total of 821 patients with advanced clear cell renal cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy were

20 Trial Design/Outcomes A total of 821 patients with advanced clear cell renal cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy were randomly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10 mg everolimus tablet orally once daily. The median overall survival was 25.0 months (95% confidence interval [CI], 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus Kidney 20

21 Kidney Grade 3 or 4 treatment related adverse events occurred in 19% of the patients receiving nivolumab and in 37% of the patients receiving everolimus; the most common event with nivolumab was fatigue (in 2% of the patients), and the most common event with everolimus was anemia (in 8%) Patients with previously treated advanced renal cell carcinoma, overall survival was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus. Atezolizumab (MPDL3280A) in platinum treated locally advanced or metastatic urothelial carcinoma (muc). Data presented at ASCO GU Symposium 2016 Enrolled 316 muc pts who progressed during or following platinum based chemotherapy Demonstrated significantly improved ORR vs historic controls. Responses were durable and associated with higher PD L1 IC expression; poor prognostic factors did not preclude response. Atezo was well tolerated, and a randomized Ph 3 study vs ctx is ongoing 21

22 PD 1 Toxicities Most common side effects across multiple trials: fatigue, rash, musculoskeletal pain, pruritus, diarrhea, and nausea, pyrexia, vomiting, and dyspnea. Important side effects Most Important Slide of the Talk! Immune mediated pneumonitis (Grade 2), Colitis, Hepatitis, Nephritis, Grade 4 rash, Thyroid Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for severe (Grade 3) or life threatening (Grade 4) colitis. Administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents followed by corticosteroid taper for moderate (Grade 2) colitis of more than 5 days duration; if worsening or no improvement occurs despite initiation of corticosteroids, increase dose to 1 to 2 mg/kg/day prednisone equivalents. 22

23 PD 1 Wrap up Prostate Cancer August 5 th 2015 published in NEJM Data presented in June 2015 at ASCO 23

STAMPEDE Assigned men with metastatic, hormone sensitive prostate cancer to receive either ADT plus docetaxel (at a dose of 75 mg per square meter of body surface area every 3 weeks for six cycles)

24 STAMPEDE Assigned men with metastatic, hormone sensitive prostate cancer to receive either ADT plus docetaxel (at a dose of 75 mg per square meter of body surface area every 3 weeks for six cycles) or ADT alone. The primary objective was to test the hypothesis that the median overall survival would be 33.3% longer among patients receiving docetaxel added to ADT early during therapy than among patients receiving ADT alone. A total of 790 patients (median age, 63 years) underwent randomization. After a median follow up of 28.9 months, the median overall survival was 13.6 months longer with ADT plus docetaxel (combination therapy) than with ADT alone (57.6 months vs months Side Effect Profile 24

25 Results A high volume of metastases was defined by the presence of visceral metastases or four or more bone lesions with at least one beyond the vertebral bodies and pelvis Impression For the subset of patients with metastatic disease, the average improvement in overall survival was even higher, 22 months. Consider offering docetaxel to men newly diagnosed with metastatic prostate cancer, if they are healthy enough for chemotherapy. Men with locally advanced, nonmetastatic prostate cancer may also consider docetaxel as part of upfront therapy, as it clearly delays relapse Although docetaxel was associated with some additional toxicity compared with standard of care alone, the side effects were manageable, and few patients discontinued docetaxel due to side effects 25

26 Breast Cancer Will breeze over as lecture later today San Antonio Breast Conference the leader in Breast Research/Data Meeting is in December every year Two trials to discuss Phase III ABCSG 18 trial The trial followed 3,425 patients for 4 years, showed that denosumab (Xgeva) reduces the risk of recurrence by about 18% among postmenopausal women with early, hormone receptor positive breast cancer who are taking aromatase inhibitors. Disease free survival was 83.5% in the denosumab arm and 80.4% in the control arm (HR = 0.816; P =.0515) Decreases risk of fracture by 50% Most physicians are incorporating these results into clinical practice 26

27 Triple Negative Breast Cancer Platinum based therapy? CALGB and GeparSixto evaluated the benefit of adding carboplatin to neoadjuvant chemotherapy in patients with triple negative breast cancer. CALGB 40603, in 443 patients, showed that rates of pathologic complete response could be increased with the addition of carboplatin, but there was no association between carboplatin use and disease free or overall survival Perhaps in young patients with high risk disease, one might consider using neoadjuvant carboplatin, but we are awaiting results of the important NSABP B56 trial, which is evaluating the role of carboplatin in the neoadjuvant setting. Many Oncologists are early adapters of this type of treatment Updates in Myeloma Increasingly complex field with multiple lines of therapy with no clear sequence after the initial induction therapy Increasing evidence that VRD (Velcade/Rev/Dex x 4 cycles) is the standard of care in upfront, transplant eligible patients and has now moved west After induction therapy, options for transplant and nontransplant regimens have exploded 27

Daratumumab Daratumumab is a human IgG1k monoclonal antibody (mab) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells.

28 Daratumumab Daratumumab is a human IgG1k monoclonal antibody (mab) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. It is believed to induce rapid tumor cell death through programmed cell death, or apoptosis, and multiple immune mediated mechanisms, including complement dependent cytotoxicity, antibodydependent cellular phagocytosis and antibodydependent cellular cytotoxicity Daratumumab FDA Approved for patients who have gone through 3 or more lines of therapy Probably has the most promise of the drugs approved in 2015 Single agent activity is impressive Good drug to combine with other therapies Watch for infusion reactions 28

Ixazomib Is the first and only oral proteasome inhibitor, indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least

29 Ixazomib Is the first and only oral proteasome inhibitor, indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy Oral therapy is convenient Attractive and a good fit in older or less fit patients All oral therapy Decrease in neuropathy, which is a big problem in Velcade (Bortizimib) based therapy, even with the decrease in the subq administration Elotuzumab No single agent activity Immune effect Needs combination with lenalidomide 29

treatment of acute myeloid leukemia (AML), with rare exceptions, have

30 A New hope in AML? Promising novel agents evaluated over the past 40 years for the treatment of acute myeloid leukemia (AML), with rare exceptions, have been relegated to the dustbin of history. 1/7/2016, Blood Promising data with targeted therapy in works Updates in Prevention in Cancer 30

31 Thank you! Make sure to come Saturday at 2:15 to learn about therapy dogs and to meet the STAR, Princess Danger! 31

Highlights from AACR 2015: The Emerging Potential of Immunotherapeutic Approaches in Non-Small Cell Lung Cancer

Highlights from AACR 2015: The Emerging Potential of Immunotherapeutic Approaches in Non-Small Cell Lung Cancer Transcript Details This is a transcript of a continuing medical education (CME) activity accessible on the ReachMD network. Additional media formats for the activity and full activity details (including