David Palchak MD Erick Hjortsvang MD Phone: 805.474.9143 Fax: 805.474.9569 [email protected] 10-9-16

There are at least 5 articles published in paper or on line this week that represent advances in cancer treatment. With this much progress I’ll limit myself to very brief summaries: 1. Relapsed multiple myeloma: a. Treatment for multiple myeloma has improved to the point that chemotherapy is infrequently used in my practice and death from myeloma has become uncommon. The vast majority of my patients respond to the combination of lenalidomide and dexamethasone with or without bortezomib. However after a period of years the myeloma progresses. We have a gradually increasing number of treatments to choose from as second treatments. Dimopoulos MA et al (New England Journal of Medicine 375;14 October 6, 2016) describe the an experiment in which patients with myeloma that had progressed on a first line treatment were treated with either lenalidomide and dexamethasone or the same drugs plus daratumumab. Daratumumab is a humanized IgG-kappa antibody that targets CD38. The response rate was 92.9% in the daratumumab arm compared with 76.4% without daratumumab. Median progression free survival was 18.4 months without daratumumab but had not been reached at the time the paper went to press in the daratumumab arm. Ninety-two% of patients were alive 12-months after study entry in the daratumumab arm compared with 86.8% who were treated without daratumumab. 2. Metastatic breast cancer: a. While cure rates for breast cancer are fairly high the disease is so common that metastatic breast cancer is not rare. Previous data in metastatic breast cancer tested a “targeted therapy” named palbociclib as a second treatment (after failure of hormonal treatment) and demonstrated that palbociclib plus letrozole (a drug that blocks production of estrogen in postmenopausal women) was more effective than letrozole alone as a second treatment. Palbociclib blocks 2 enzymes: Cyclin dependent kinases 4 and 6. These enzymes promote cell division and blocking these enzymes interferes with cell division. Ribociclib is another cyclin dependent kinase 4 and 6 inhibitor. Hortobagyi G et al (New England Journal of Medicine published on line in advanced of the paper journal) tested letrozole with or without ribociclib in patients with metastatic breast cancer that expressed the estrogen receptor, but did not over-express Her-2/neu. Unlike the palbociclib study these authors tested ribociclib as an initial treatment. They report a response rate of 40.7% in the ribociclib group and 27.5% in the group treated with letrozole alone. Progression free survival was not reached (thus >24 months) in the ribociclib group compared with 14.7 months in the letrozole-alone group. Side effects were increased by ribociclib, but few patients chose to stop treatment due to side effects. 3. Niraparib in platinum-sensitive ovarian cancer: a. Some ovarian cancers are due, in part, to mutations of one of the BRCA genes. These tumors have a modest response rate to oliparib, an inhibitor of PARP. The combination of BRCA mutation and PARP inhibition is lethal to many cells. Mirza M et al (New David Palchak MD Erick Hjortsvang MD Phone: 805.474.9143 Fax: 805.474.9569 [email protected] 10-9-16

England Journal of Medicine, published on line ahead of the paper journal) report on a trial of niraparib (a different PARP inhibitor) or placebo in women with recurrent ovarian cancer defined as “platinum sensitive”. They found that niraparib prolonged the interval to disease progression from a median of 5.5 months to 21 months in patients with BRCA mutations and from 3.9 to 9.3 months in women without BRCA mutations. The surprising finding was the efficacy of the drug in all subsets of women without regard to BRCA mutation status. 4. Adjuvant ipilimumab for stage III melanoma: a. Stage III melanoma is melanoma that has spread to lymph nodes near the original tumor. The 8-10 year survival of patients treated with surgery alone is 20-30%. Interferon alpha improves survival a bit at the cost of severe side effects. Ipilimumab is an immunostimulant that blocks the Cytotoxic T-lymphocyte antigen 4, stimulating the immune system and exposing some tumors to cytotoxic T lymphocytes. Eggermont A et al (New England Journal of Medicine, published on line ahead of the paper journal) describe and experiment in which 951 patients with stage III melanoma were randomly assigned to receive ipilimumab or placebo following surgery. Five-year disease free survival was 40.8% with ipilimumab and 30.3% without. Toxicity of ipilimumab is appreciable and 1.1% of patients actually died from ipilimumab. In spite of this survival with ipilimumab was higher than survival without it (because of a higher melanoma cure rate) 5. Immunotherapy for metastatic non-small cell lung cancer: a. Lung cancer remains a disease with a poor prognosis. Reck M et al tested pembrolizumab or standard chemotherapy in patients with a subset of non-small cell lung cancers that expressed a molecule called PDL1. These tumors use PDL1 to evade the immune system and the hypothesis of the investigators was that pembrolizumab would expose these tumors to the immune system. Three-hundred and five patients with newly diagnosed advanced non-small cell lung cancer that expressed PDL1 on at least half of tumor cells were randomly assigned to treatment with either pembrolizumab or standard chemotherapy. Median progression-free survival was 10.3 months with pembrolizumab and only 6 months with chemotherapy. Six month survival was 80.2% in the pembrolizumab arm and 72.4% in the chemotherapy arm. Side effects were generally milder with pembrolizumab than with chemotherapy. The publication of 5 articles that will change the practice of cancer medicine in one week is a dramatic demonstration of the rapid pace of progress in oncology. When I gave my annual talk on progress in cancer medicine in September I was unable to pick one topic that was most important for the year. Instead I pointed out that the biggest change in cancer medicine from Sept 2015 to Sept 2016 was the accelerating pace of progress. Thus a blog I had planned to use to provide a little more in depth look at one-two papers per month is providing brief overviews of 5 significant papers this week.

David Palchak MD Erick Hjortsvang MD Phone: 805.474.9143 Fax: 805.474.9569 [email protected] 10-9-16

David Palchak MD