WHAT S UP? MY PATIENT IS NOT GETTING CHEMO? Newer targets, Immune Modulation and Molecular characterizations that improve treatment options.

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1 WHAT S UP? MY PATIENT IS NOT GETTING CHEMO? Newer targets, Immune Modulation and Molecular characterizations that improve treatment options.

2 Richard C. Staab, D.O., FACOI

3 Richard C Staab, D.O., FACOI As my mentor he was amongst the 1 st Certified Oncologist If you have read the Emperior of All Maladies you know that after Sydney Farber demonstrated methotrexate had activity in childhood leukemia; then James Holland, Emil Frei and Emil Freireich moved forward with combination chemotherapy at the NCI Dr Freireich moved to MD Anderson in Houston to head Developmental Therapeutic Service the Leukemia service. Richard was amongst his first trained oncologist and returned to Tulsa to be the 3 rd oncologist in Tulsa. Later he would merge our group with Drs. Schnetzer & Sexauer

4 Dr. Richard Staab He Loved medicine and remained excited to find that great case though out his career. Many of those diagnosis would be non-malignant conditions; that demonstrated his competence as an outstanding internist. He worked along side of his wife. Mary Ann Staab, RN. She had scrubbed with Dr DeBakey; and honed her own skills in Oncology while they were in Houston. She returned with him to Tulsa. She preformed many of the new patient H&P, bone marrow procedures and administered chemotherapy; before the advent of long lines (when vesicant treatments were much more risky). She was an advanced Practice Nurse before we coined those terms and licenses. Together the STAAB team brought community standards of care to our physician referral network and the nursing teams that have followed in their steps.

5 New Drug Approvals In 2017 there were 16 oncology & 11 hematology drug approvals What you use to know; will need to updated Options for treatment are widening both in class of drugs and the ability of the host to tolerate the newer modalities of therapy; they frequently are having less toxicity. The genius of a man Richard Staab ; thrived on the changes in his field; He stopped care in 2002; missing these dramatic changes. Subspecialization may become a necessity for the treatment of the large variety of malignancies that we have. Many previously untreatable diagnosis have new modalities of treatment.

6 WHAT S UP? MY PATIENT IS NOT GETTING CHEMO? Newer targets, Immune Modulation and Molecular characterizations that improve treatment options.

7 Lung Cancer Retooling treatment options This lethal diagnosis has been the underdog for decades; a self induced disease now it is becoming a forum for Personalized Medicine with NON-Smoking, Asian Women demonstrating that this is a disease with activated pathways. Subgroups are being identified using genomic testing and molecular expression of cellular functional pathways. We will discuss the New Class Drugs and their mechanisms of action and common side effects; that an Internist would needs to know.

8 Pre pemetrexed NSCL Tx chemo choice made no difference ECOG 1594 presented June 2000

9 Response rates Vary by Cell Type

10 Lung Cancer Subtypes Other (including NSCLC NOS) 26% Adenocarcinoma 38% Large cell carcinoma 5% Large Cell 5% Small cell carcinoma 13% Small Cell 13% Squamous cell carcinoma 20% The World Health Organization classification for primary lung cancer recognizes 4 major histology types 2/3 of patients NOW need molecular characterization for treatment decisions (small cell and Squamous generally do not) NOS, not otherwise specified; NSCLC, non small cell lung cancer.

11 Toxicities Vary by cell type Bevacizumab has increased risk of lethal hemoptysis in Squamous cell ca & is Black Box Contraindicated in this cell type of NSCL Lumping of histology is NOT acceptable TTF1 = Adeno ca P63, CK5/6 are squamous markers Histologic Diagnosis should be pursued, additional tissue is needed

12 Additional tissue allows gene testing The most common driver genes RET, 1% ROS1, 1% ROSPIK3CA, 2% MAP2K1, ROS1 AKT, 1% NRAS, 1% MET 1%s BRAF, 2% MET, 2% 1% HER2 2% 2% BBbHER2, 2% BRAF 2% ALK, 5% EGFR, 15% Other, 42% KRAS, 25% Note no current therapeutic agent is approved for KRAS

13 Driver Genes EGFR, ALK, ROS-1, BRAF & MET Exon14 These are growth promoting genes that can be Over- Expressed or Locked in the ON position of tumors The receptors are present in normal tissue as well and when we block their functional expression; it may overlap with normal wild type tissue and cause systemic side effects.

14 EGFR Epidermoid Growth Factor Receptor Human Epidermoid Growth Factor - Her2neu; has been one of the GREATEST improvements in Oncologic treatment. Trastuzumab (Herceptin) lowered the Highest Risk breast group nearly 40% Gefitinib & Erlotinib were the 1 st two oral EGFR blockers in Lung Cancer & cetuximab and panitumumab are monoclonal blockers (they are more widely used in colon cancer). Wild EGFR blockade can result in diarrhea and classic acneiforme rash and treatment should NOT be DC d as an allergy; but can be held and dose adjusted to modify side effects. Rash predicts therapeutic response.

15 Palliative vs Curative Most patients are palliative Does the patient respond? How completely does the patient respond? How long does the response last? How Many Different times does the patient respond Are there side effects and how well are they tolerated or ameliorated

16 CASE Study:

17 Case Study: Feb A 77 year old male presents with a previous Hx of Lung cancer resected in October of He was considered at high risk of relapse and Adjuvant CisPlatin Chemo was recommended and completed. In Feb he had increasing Shortness of breath and was beginning to be unable to care for himself. He presented with his wife.

18 Treatment vs Best Supportive Care?

19 Treatment vs Best Supportive Care? Old paraffin Blocks were available Exon 19 EGFR mutation was present Within one week his dyspnea is resolved. By Two weeks his CXR had normalized Palliative benefit persisted for 4 yrs with erlotinib alectinib was initiated in 2015 and repeat Bx was obtained at early progression

20 1 st line Erlotinib EGFR inhibitor

21 Durable benefit: 9/ present rociletinib as a 3 rd line investigational A T790M mutation evolved from the prior exon 19 mutation. Osimertinib has now been approved and demonstrated specificity to the mutated receptor; WITHOUT wild type tissue binding and NO rash or diarrhea. My patient continues in remission 3yrs on this investigational agent and 7 years since his metastatic presentation (now age 84) Rare; but excellent LONG Term palliative benefit.

22 Lung EGFR Driver Gene Tx Expressed in up to 7% of Adenocarcinoma of the lung, Rare (less than 1% of Squamous); but would be appropriate to attempt identification in small volume specimens using Gene Sequencing When present Response rates are in excess of 70%, can be rapid (in weeks and durable for months to years

23 Lung EGFR Driver Gene Tx Wild Type normal tissue can respond to the effects with symptoms Facial Acneform rash is expected and if Grade 1 observed, Grade 2 treated with doxycycline or clindamycin. IF tolerable continue or as needed dose reduce. Diarrhea must be suppressed and treated early. Grade 3-4 discontinuation and dose reduction

24 EGFR Rash

25 Personalized Medicine Transition from Histology to Molecular Does my patient have an actionable target? Does my patient respond with tolerable side effects? How long does the response last? It is NO LONGER what is the prognosis of my cancer; it is DO I respond, How completely and for how long and how many times. Would you expect 7 yrs of Near NED status for Advanced Metastatic Lung Cancer.

26 Driver Genes If present for EGFR, ALK, ROS1 or BRAF Then 1 st line therapy with a matched blocker is SUPERIOR to a CisPlatin dublet of chemotherapy with less toxicity and is approved standard of care. Response rate is higher Duration of response is greater Cytotoxic therapy can still have benefit AFTER serial driver gene therapy.

27 Immune Modulation Major Breakthrough for histologies that have not responded well to standard cytotoxic chemotherapy Melanoma, Renal Cell Add additional options for NSCL, Urothelial, Head & Neck, Hodgkins and Gastric carcinoma Front Line approval IF High expression of PD-L1 (>50%) [Program Death Ligand-1] for many of these histologies; in front of chemotherapy, combined with chemo or after chemo/xrt induction of NSCL.

28 MSI-High pembrolizumab (Keytruda) This is the first cancer therapy approved for any histologic type or location of primary; IF there is over expression / INCREASED MUTATIONAL BURDEN from inability to repair DNA transcription errors. MisMatch Repair deficiency (dmmr) Defects in MMR lead to microsatellite instability-high (MSI-H). Segments of genetic sequences that are normally repeated; can accumulate errors in their sequence. Cancer that has spread or cannot be resected in Children and Adults & has progressed post treatment (if Colon post FOLFOX/FOLFIRI) or has no satisfactory tx options

29 PD-L1 Immune treatment Unleashes the immune surveillance Removing the camouflage that protects normal host cells (covered by PD-L1; programmed death receptor & ligand) Blocking PD-L1 removes the inhibition of T-cell activation Activation CAN Awaken Sub-Clinical Autoimmune diseases: Chron s, Colitis, Hepatitis, Pneumonitis, Nephritis, Arthritis, Addison s Ds and very commonly Thyroid ds.

30 Checkpoint Inhibitor Immune Surveilence PD-1 (Programmed cell death protein 1) is a cell surface receptor that promotes self-tolerance; suppressing the T cell immunity This Immune checkpoint guards against autoimmunity; promoting apoptosis of antigen specific T-cells. PD-1 inhibitors ACTIVATE the immune system PDL1 ligand on tumor; inhibits anti-tumor response & expression on tumor correlates with decreased survival. High PL-L1 PREDICTS response to immune treatment

31 Immune Checkpoint Inhibitors nivolumab (Optivo) pembrolizumab (Keytruda) durvalumab (Imfinzi) ipilimumab (Yervoy) CTLA4 inhibitor (More potent immune stimulator alone or combined with PD-1 inhibitor) As a group they demonstrate activity in Cell lines poorly responsive to chemo: Melanoma, Renal/Bladder, NSCLung, Head&Neck; with 30-40% response rates and more Durable than chemo.

32 1 st Line PD1 immune treatment; in NSCL High PD1 expression > 50%; predictes increase response and > than cisplatin chemo

33 Internist Man your battle stations! Lung pneumonitis Intestinal colitis Liver hepatitis Hormonal thyroid, pituitary, adrenal and pancreas. Kidney nephritis & failure Skin pemphigus, Stevens-Johnson Hematologic cytopenia & acquired factor inhibitors with bleeding Musculo/skeletal Rheumatoid flare

34 Auto-Immune Treatment Discontinue treatment if Grade III or IV Solumedrol 125mg IV x 7 days 1-2 mg/kg of prednisone tapered Avoid treatment IF prior history of auto-immune disease; to prevent re-activation. Hyperthyroid transitioning to hypothyroid is common in our experience and easily managed by initial observation and then replacement. Other hormonal deficiencies including adrenal & panhypopituitary can be replaced and continued on treatment.

35 Cyclin Dependent Kinase Inhibitors CDK 4/6 inhibitors Breast Cancer Used in Hormone Receptor (+); Her2 (-) Increased response and Duration as compared to Hormone blockade alone in metastatic disease Abemaciclib (Verzenio), palbociclib (Ibrance), ribociclib (Kisqali) Combined with letrozole or fulvestran as dual blockade of estrogen and CDK pathways at the same time

36 CDK 4/6 Inhibitors Post menopausal patients Neutropenia is common 79% vs 6% with an aromatase inhibitor (AI) hormone treatment alone; especially at initiation and can be improved with dose adjustments. Tends to improve over time Nearly doubles the duration of response on average

37 CDK 4/6 inhibitors Are given intermittently. Three weeks on followed by one week off Neutropenia will generally rapidly resolve with discontinuation and during the week of rest.

38 Questions and Answers Thank you for your time and interest Always feel free to call