Joseph J. Muscato, M.D., FACP Missouri Cancer Associates, Columbia Medical Director Virginia and Norm Stewart Cancer Center Boone Hospital

Transcription

1 Joseph J. Muscato, M.D., FACP Missouri Cancer Associates, Columbia Medical Director Virginia and Norm Stewart Cancer Center Boone Hospital

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5 One of the things we oncologists face is criticism for small increases in median survival These small advances really do add up over the years into major advances. Home runs are rare, but they do occur occasionally! Most of our progress comes as singles and doubles.

6 CAR-T-cell therapy CDK 4/6 inhibition for breast cancer PARP inhibition ovarian cancer Life style changes Lung cancer therapy (including immunotherapy) Targeted therapies Understanding of genomic abnormalities Possible stopping of TKI therapy for CML

7 Targeted therapies in CLL Adherence to adjuvant endocrine therapy for breast cancer related to socio-economic factors Obesity and risk of breast cancer recurrence HPV related oropharyngeal cancers PCP involvement in breast cancer decisions improves satisfaction

8 Immunotherapy for multiple cancers

9 Highly risky therapy for untreatable lymphocytic leukemias, possibly others Initially tried in children with multiply refractory ALL, including failure of bone marrow transplant Specific remodeling of T-cells engineered to attack the leukemia cells Severe and life threatening cytokine-release syndrome is the major toxicity

10 Second-generation CAR used in current clinical studies at Penn and CHOP. CTL, cytotoxic T lymphocyte; MHC, major histocompatibility complex. Shannon L. Maude et al. Blood 2015;125: by American Society of Hematology

11 Event-free survival in 30 children and adults treated with CTL019 therapy. Shannon L. Maude et al. Blood 2015;125: by American Society of Hematology

12 Less is More: Making Hormone Therapy Great Again

13 Widespread adoption of gene expression testing (OncotypeDx, Mammoprint) for early breast cancer Avoidance of axillary dissection with sentinel nodes Coming soon, avoiding axillary dissection post neo-adjuvant chemotherapy Avoidance of RT in elderly ER positive patients after lumpectomy Better decision making for adjuvant hormonal therapy- the 5 vs. 10 year problem 3D mammography

14 For ER + cancers, half of the recurrences are after 5 years. It is fairly common for me to see recurrences years after initial diagnosis Have we learned anything in the last year about how long we should give tamoxifen or an aromatase inhibitor such as letrozole or others?

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16 In general, tamoxifen for premenopausal women, AI for post-menopausal women Tamoxifen: 10 years is better than 5 years 5 years of an AI is beneficial after 5 years of tamoxifen But: 2 out of 3 studies did not show a benefit to more than 5 years of an AI

17 The Cyclin D Kinases are important for cell cycling and cancer cell reproduction By itself, blockage of the CDK proteins will not treat breast cancer Combination of CDK 4/6 blockade plus antiestrogen therapy significantly improves progression-free survival

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19 Progression-free Survival.

20 Randomized trials have shown a doubling of progression free survival in first line ER+ metastatic disease Randomized studies have also shown a similar improvement in second line therapy with fulvestrant This is now standard therapy for these patients, with the major side effect some modest neutropenia

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22 Poly(adenosine diphosphate [ADP] ribose) polymerase is important in repairing DNA damage One would want to inhibit cancer cells from repairing DNA damage from chemotherapy Previous studies have confirmed that PARP inhibition is helpful for BRCA related ovarian cancers (where DNA repair is already impaired) This was study was in all comers with recurrent platinum sensitive ovarian cancer

23 Platinum-sensitive, recurrent ovarian, fallopian tube, or primary peritoneal cancer; 2 prior platinum-based regimens with CR/PR and progression > 6 mos after most recent platinum-based therapy (N = 553) Germline BRCA mutation cohort (n = 203) No germline BRCA mutation cohort (n = 350) Primary endpoint: PFS Niraparib 300 mg QD (n = 136) Placebo QD (n = 65) Niraparib 300 mg QD (n = 231) Placebo QD (n = 114) Treatment until disease progression with no crossover allowed Mirza MR, et al. N Engl J Med. 2016;[Epub ahead of print]. Slide credit: clinicaloptions.com

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26 Immunotherapy has turned the treatment of lung cancer upside down this year Honestly, most of us in the field felt that this would be the last disease to benefit from immunotherapy. Targeted therapies or immunotherapy are now appropriate for at least 40% of patients for first line metastatic disease, and for all the rest for second line.

27 Stratified by ECOG PS (0 vs 1), histology (squamous vs nonsquamous), and enrollment region Pts with stage IV NSCLC and ECOG PS 0/1, no previous systemic therapy, no actionable EGFR/ALK mutations, and PD-L1 TPS 50%* (N = 305) Pembrolizumab 200 mg IV Q3W for up to 35 cycles (n = 154) Chemotherapy (histology based) for up to 6 cycles (n = 151) Until PD or unacceptable toxicity Until PD (crossover to pembrolizumab allowed) * 50% tumor cell staining using 22C3 companion diagnostic IHC assay. Primary endpoint: PFS Secondary endpoints: ORR, OS, and safety Reck M, et al. N Engl J Med. 2016;[Epub ahead of print]. Slide credit: clinicaloptions.com

28 PFS (%) OS (%) PFS OS 100 HR for PFS: 0.50 (95% CI: ; P <.001) 100 Pembrolizumab Chemotherapy Pts at Risk, n Pembrolizumab Chemotherapy Mos Mos HR for OS: 0.60 (95% CI: ; P =.005) Reck M, et al. N Engl J Med. 2016;[Epub ahead of print]. Slide credit: clinicaloptions.com

29 All patients with adenocarcinoma (and some physicians squamous also): Test for EGFR, ALK, ROS1 There will be new treatments down the road for other mutations, and therefore next-generation sequencing might be helpful All patients with non-small cell lung cancer need to be tested for PD-L1.

30 EGFR, ALK or ROS1 mutated: treat with the appropriate targeted drug (eg, erlotinib, gefitinib for EGFR mutation) PD-L1 over 50%: treat with pembrolizumab immunotherapy Neither of these: chemotherapy For groups 1 and 3, immunotherapy second line

31 Your patients might ask about this, although current use is somewhat limited Refers to plasma based cell-free DNA testing with next generation sequencing About 70-75% of EGFR mutations will show up. A positive test is pretty definitive. I ve also used it for mutation testing for EGFR

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33 This has become very important in the management of many cancers At least 30% of cancers are related to obesity, and these include all types of cancer from breast cancer to myeloma The causes are uncertain, but insulin resistance and secretion of insulin-like growth factor seem important

34 As a result, you might be surprised that as an oncologist I spend a whole lot more time counseling patients to lose weight than I do about gaining weight. Exercise is also important, probably for the same issue of insulin resistance Trials of metformin are underway (because it s much easier to take a pill than diet!)

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36 ASCO added this to the list of important cancer advances, or at least issues On the positive side, one study showed that close involvement of the PCP in the decisions about breast cancer management, including initial surgical decisions, led to greater patient satisfaction

37 Many new therapies are oral and very expensive. Several studies show that adherence is related to co-pays for drugs If we cannot get foundation help for most patients, they would never be able to get appropriate cancer treatment

38 The cost of cancer therapy is a huge national issue and increases seem to have no end The laws of supply and demand seem to be magically suspended in this area Lower socioeconomic patients on a average have lower survivals

39 A New Standard

40 ESPAC-4 for Resected Pancreatic Carcinoma

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43 Role of Active Surveillance Indications for treatment: Significant disease-related symptoms Progressive bulky disease Threatened end-organ function Progressive anemia Progressive thrombocytopenia 43

44 Before 1985 Single-agent alkylators Single-agent purine analogs Combinations of purine analogs with alkylators Chemoimmunotherapy After Small molecule inhibitors of critical survival pathways

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46 Progression-free Survival with Ibrutinib versus Chlorambucil.

47 NR 5.5 mo At 12 mo 92% 80% Furman R, 47et al. N Engl J Med; 2014.

48 Relapsed/refractory CLL/SLL Use in combination with rituximab Alternative when there are contraindications to ibrutinib for relapsed/refractory disease 48

49 Venetoclax is a member of a new class of specific of bcl-2 inhibitors Bcl-2 is upregulated in CLL and some other B- cell malignancies Blockade of Bcl-2 is a new, powerful tool in the treatment of CLL

50 Pt PD PD PD PD PD-RT PD Ibrutinib arm Idelalisib arm Discontinued Mos on Venetoclax Jones J, et al. ASCO Abstract Reprinted with permission. Slide credit: clinicaloptions.com

51 Make sure you know about mutations, especially 17p deletion Decide if the patient needs treatment If one decides to treat, the current paradigm is: Age less than 60, FCR chemotherapy Age 60-80, bendamustine-rituxan chemotherapy Age over 80, Chlorambucil-Obinotizumab

52 But in 2017, we are beginning to change: Age less than 60, FCR for long duration of response, but willing to take risk of toxicity, including long term marrow damage, severe infection Over 60, consider bendamustine-rituximab (BR) if patient wants to receive finite therapy and be done for an average of 5-7 years before needing more treatment. BR is also all IV, so covered better by Medicare Alternative, ibrutinib (the BTK inhibitor) indefinitely Relapse: many alternatives, including idelalisib, venetoclax if 17p deleted, chemo

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54 Immunotherapy is spreading out to many cancers We have, in many ways, broken through the wall and we are beginning to better understand the immune system Melanoma is the poster child of treatment advances, but we will see many others Treatment of cancer will never be the same given this

55 Metastatic melanoma historically carried a horrible prognosis. Previous Phase III trials of new drugs over the last 30 years have been uniformally negative except for dacarbazine (DTIC) many years ago. Dacarbazine has a 12% response rate and, depending on the study, a complete response rate of 0-3%.

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59 The toxicities of immunotherapy are unique and need to be recognized by all physicians to avoid serious problems The toxicities are basically from the stimulation of the immune system and include many forms of autoimmune disease Some of these are life-threatening

60 I personally have seen the following: Severe autoimmune diarrhea lasting weeks and refractory to steroids, finally improved with infliximab Autoimmune pneumonitis Hypothyroidism Nephritis Panhypopitutarism Skin rashes Autoimmune hepatitis Adrenal insufficiency FUO

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62 New therapies are raining down on us at a rapid rate, and all VERY expensive but useful This change is a challenge for all oncologists, as you can imagine We are learning more and more of the basic mechanisms of cancer Immunotherapy, using the patient s own T-cells to combat the cancer has been a huge advance

63 It s pretty humbling for us to realize that our own immune cells are much better at recognizing and killing cancer cells than almost all of our drug therapy. With immunotherapy, we basically light the fire and step back. The immune cells continue the fight even after we stop for toxicity (and likely more so if we have to stop for toxicity).

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