Side Effects Management for the Ovarian Cancer Community
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Dr. William Tew of Memorial Sloan Kettering Cancer Center discusses how to manage side effects of targeted therapies for ovarian cancer. Dr. Tew also discusses the severity of your side effects, communicating them to your doctor, and the latest information on symptom-tracking tools.
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Side Effects Management for the Ovarian Cancer Community
- 1. Targeted Therapies: Side effects and management William Tew, MD Associate Attending Clinical Director, Gynecologic Medical Oncology Memorial Sloan Kettering Cancer Center, NY
- 2. VERBAL DISCLOSURE • No conflicts to disclose.
- 3. Ovarian Cancer Type as a Biomarker High Grade Serous Clear Cell Endometrioid Mucinous Low Grade Serous Genetic Risk Factors BRCA 1/2 HNPCC HNPCC None known None known Precursor Lesion Serous Tubal Intraepithelial Carcinoma (STIC) Endometriosis Endometriosis Unknown ?Teratoma Serous Borderline Tumor Molecular Genetics p53, BRCA, HR Defects, Tumor Microenvironment PI3K, ARID1A, MSI PTEN, beta-catenin, ARID1A, MSI KRAS, HER2 BRAF, KRAS, NRAS Potential Drugs •PARP inhibitors •Angiogenesis •mTor •Angiogenesis - •Trastuzumab •TDM-1 •MEKi •Angiogenesis J Natl Cancer Inst 2014;106(4):1-8
- 4. Ovarian Cancer Therapies FDA Approved 1978 Cisplatin 1990 Altretamine 1991 Carboplatin 1992 Paclitaxel 1996 Topotecan 2000 Pegylated liposomal doxorubicin (PLD) 2006 Gemcitabine + Carboplatin 2014 Bevacizumab – platinum resistant (+weekly paclitaxel, PLD or topotecan) 2014 Olaparib 2016 Bevacizumab – platinum sensitive (+paclitaxel/carboplatin; gemcitabine/carboplatin) 2016 Rucaparib 2017 Niraparib/Olaparib – 2nd remission NCCN 1 or 2A • Capecitabine • Cyclophosphamide • Docetaxel • Doxorubicin • Etoposide (oral) • Ifosfamide • Irinotecan • Melphalan • Oxaliplatin • Paclitaxel, albumin bound (nab-paclitaxel) • Pemetrexed • Vinorelbine
- 6. TCGA BRCA1 Germline 8% BRCA2 Germline 6% BRCA1 Somatic 4% BRCA2 Somatic 3% BRCA1 Methylation 11% EMSY Amplification 6% PTEN Loss 6%Other HRD 5% CCNE1 Amplification 14%RB1 Loss 4% MMR Germline 2% Other 31% HRDNot HRD Mutually exclusive events cBio Cancer Genomics Portal, MSKCC BRCA1 Germline, 8% BRCA2 Germline, 6% BRCA1 Soma c, 4% BRCA2 Soma c, 3% BRCA1 Methyla on, 11% PTEN Loss, 6% Other HRD, 10% CCNE1 Amplifica on, 20% RB1 Loss, 15% NF1 Loss, 17% HRDNot HRD Putative driver events cBio Cancer Genomics Portal, MSKCC and Patch et al., Nature, 2015
- 7. Targeted therapies: Toxicity • Immunotherapy • PARP inhibitors • VEGF inhibition
- 8. Harnessing the Power of the Immune System How does the immune system recognize tumor as non-self?
- 9. Kerkar SP , Restifo NP Cancer Res 2012;72:3125-3130 Tumors are not just composed of cancer cells
- 10. Immunotherapy toxicities: Diverse • Cancer vaccines – injection site rxn and constitutional symptoms • Cytokines – induce capillary leak • Adoptive cell therapy – cytopenias (prep chemo), cytokine release syndrome and autoimmunity • T-cell regulation via immunomodulatory Ab…. Weber et al, JCO 2015
- 11. Immunomodulatory antibodies that regulate T cell activity Turning up The Activating Blocking the Inhibiting Slides courtesy of Drs. Dmitriy Zamarin and Alex Snyder
- 12. FDA Approved Targets Turning up The Activating Blocking the Inhibiting
- 13. Year Drug Target Disease Indication 2011 Ipilimumab CTLA-4 Melanoma 2014 Nivolumab, pembrolizumab PD-1 Melanoma 2015 Nivolumab, pembrolizumab PD-1 NSCLC 2015 Nivolumab PD-1 RCC 2015 Nivolumab+ipilimumab PD-1 + CTLA4 Melanoma 2015 Pembrolizumab PD-1 Head and Neck SqCC 2016 Nivolumab PD-1 Hodgkin lymphoma 2016 Atezolizumab PDL-1 Urothelial cancer 2017? Anti-PD-1 MMR-deficient cancers Current FDA Approvals: Checkpoint Inhibitors *as of 10/30/2016 Nivolumab (Opdivo, BMS); Pembrolizumab (Keytruda, Merck); Atezolizumab (Tecentriq, Roche); Ipilimumab (Yervoy, BMS)
- 14. Checkpoint Inhibitors Toxicities • Result from inappropriate recognition of normal tissues by T cells, leading to autoimmune tissue destruction. • Side effects are generally mild and infrequent, but when they do occur, they can be serious and even life threatening if not identified and treated in a timely manner. Early recognition and treatment is essential. • Need to be distinguished from other causes, especially infectious causes or underlying disease • Toxicities can be long-lasting, even after therapy discontinuation. Some toxicities appear after therapy discontinuation. • Some toxicities are irreversible (i.e. hypothyroidism, adrenal insufficiency) and require long-term monitoring
- 15. Immunotherapy toxicities Occasional: •Fatigue, headaches, arthralgia, fever, chills •Skin: rash •Asymptomatic lab abnormalities: elevation of LFT’s, amylase/lipase •GI: colitis, pancreatitis, hepatitis •Endocrine: thyroiditis, hypothyroidism, hypophysitis, hypoadrenalism Rare: •Pulmonary: pneumonitis Very Rare: •Other organs: kidneys, CNS, muscle, heart, bone marrow •Cytokine release syndrome: fever, hypotension, pulmonary edema, multi-organ failure. Can mimic sepsis.
- 16. Kinetics of Appearance of irAEs Weber et al. JCO 2012
- 17. General guidelines: • Low grade toxicities (grade 1-2): observe, hold drug, topical steroids ( Rash – topical hydrocortisone; Diarrhea – budesonide) • Medium grade toxicities (grade 2-3): hold, oral systemic steroids (prednisone, methylprednisolone), closer monitoring • High grade toxicities (grade 3-4): admit, IV steroids • Steroid-refractory toxicities: other immunosuppressant agents (Mycophenolate Mofetil for liver toxicity; Infliximab for other toxicities)
- 18. Toxicity Guidelines (non-protocol) • On-line safety tools – https://www.opdivosafetytool.com • Multidisciplinary expert panel guidelines – “Management of Immunotherapy Side Effects” – American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network® (NCCN®) joint collaboration
- 19. Examples of management protocol algorithms (BMS)
- 20. Immune-related Adverse Events (irAE) ProportionofAffectedPatients Rash/pruritus Pneumonitis Myocarditis, rare neurologic syndromes*, cholangitis*, vasculitis neuropathy*, atrophic exocrine pancreatic insufficiency*, sclerodermoid reaction*, others… Figure legend: Approximate proportion of patients affected by immune-related adverse events of any grade upon treatment with single-agent PD-1 blockade. Endocrinopathies, arthralgia 20% Diarrhea Friedman and Snyder, Annals of Oncology, 2017 Rare Side Toxicities: Long Tail of irAE
- 22. Results on ECG and Immune Effects in Cardiac Muscle after Treatment with Ipilimumab and Nivolumab Johnson DB et al. N Engl J Med 2016;375:1749-1755
- 23. Immunotherapy in Older adults: FDA experience Singh et al, FDA subset analysis of the safety of nivolumab in elderly patients with advanced cancers. J Clin Oncol 34, 2016 (suppl; abstr 10010) - irAE rates similar across age group. - Look at other parameters (which do increase with age) - drug discontinuation - intervention required
- 24. Weber, Immunotherapy: It's Not Getting Old, ASCO 2016
- 25. Toxicity • Immunotherapy • PARP inhibitors • VEGF inhibition
- 26. FDA approved PARP inhibitors Treatment Approval date Rx Indication Data Olaparib 12/2014 400 mg BID (50 mg CAPSULES) Deleterious germline BRCA mut ≥3 more priors Study 42 Rucaparib 12/2016 600 mg BID (200 mg, 300 mg capsules) Deleterious germline OR somatic BRCA mutation & ≥2 more priors Study 10, ARIEL2 Maintenance Niraparib 3/2017 300 mg daily (100 mg capsules) Recurrent ovarian cancer & complete or partial response to platinum based chemotherapy NOVA Olaparib 8/2017 300mg BID (150mg, 100mg TABLETS) Recurrent ovarian cancer & complete or partial response to platinum based chemotherapy SOLO-2 Study 19
- 27. Each PARP inhibitor has DIFFERENT properties/indication… PARP inhibitor CYP enzymes used for metabolism Drug Drug Interactions Effect on renal and hepatic uptake transporters Rucaparib1 CYP2D6 (predominant) CYP1A2 and CYP3A4 (lesser extent) Reversibly inhibits CYP1A2, CYP2C19, CYP2C9, CYP3A Induces CYP1A2 Inhibits MATE1 and MATE2-K (potent), OCT1 (moderate) Olaparib1 CYP3A4* Inhibits CYP3A4 and induces CYP2B6 Inhibits OATP1B1, OCT1, OCT2, OAT3, MATE1, MATE2K Niraparib2 CYP3A4/5 and CYP1A2 CYP2D6 (lesser extent) Amide hydrolysis is main hepatic clearance Can induce CYP1A2 (weak) No interaction with the major hepatic or renal uptake transporters 1 FDA package inserts 2 niraparib IB *Reduce dose if strong or moderate CYP3A inhibitors are co-administered Slides courtesy of Dr. Ursula Matulonis
- 28. GI toxicities are common with all PARP inhibitors Toxicities (%) Grade of Tox Olaparib 1 Rucaparib2 Niraparib3 Nausea All Grades 64 77 73.6 Grade 3 and 4 3 5 3.0 Constipation All 20.65 40 39.8 Grades 3 and 4 0 2 0.5 Vomiting All 43 46 34.3 Grades 3 and 4 4 4 1.9 Decreased appetite All 22 39 25.3 Grades 3 and 4 1 3 0.3 Abdominal pain All 43 32 22.6 Grades 3 and 4 8 3 1.1 Diarrhea All 31 34 19.1 Grades 3 and 4 1 2 0.3 Dyspepsia All 25 104 11.4 Grades 3 and 4 0 <1% 0 Dysgeusia All 215 39 10.1 Grades 3 and 4 0 0.3 0 1 FDA insert, 2 FDA insert, 3 NOVA NEJM 2016, 4 Swisher Lancet Onc 2016, 5 Ledermann Lancet Oncology 2014
- 29. Fatigue is common with all PARP inhibitors Toxicities (%) Grade of Tox Olaparib 1 Rucaparib2 Niraparib3 Fatigue All Grades 66 77 59.4% Grade 3 and 4 8 11 8.2% Insomnia All NR 12% 24.3% Grades 3 and 4 NR 0 0.3% Headaches All Grades 255 174 25.9 Grades 3 and 4 0 04 0.3 1 FDA insert, 2 FDA insert, 3 NOVA NEJM 2016, 4 Swisher Lancet Onc 2016 5
- 30. Hematologic toxicities Toxicities Grade of Tox Olaparib1 Rucaparib2 Niraparib3 Decrease in hemoglobin All Grades 90 67 50.1 Grade 3 and 4 15 23 25.3 Decrease in platelets All 30 39 61.3 Grades 3 and 4 3 6 33.8 Decrease in neutrophil count All 25 35 30.2 Grades 3 and 4 7 10 19.6 1 FDA package insert, 2 FDA package insert, 3 NOVA NEJM 2016 (% of pts)
- 31. Additional toxicities differ between agents Toxicities Grade of Tox Olaparib1 Rucaparib2 Niraparib3 Increased Creatinine All 30 92% NR Grades 3 and 4 2 1 NR Elevated ALT All NR 74% NR Grades 3 and 4 NR 13% NR Elevated AST All NR 73% NR Grades 3 and 4 NR 5% NR Hypertension All NR NR 19.3% Grades 3 and 4 NR NR 8.2% Nasopharyngitis/URI All 26 104 11.2 Grades 3 and 4 0 04 0 Dyspnea All NR 21 19.3 Grades 3 and 4 NR 0.5 1.1 Palpitations All NR NR 10.4 Grades 3 and 4 NR NR 0 1 FDA insert, 2 FDA insert, 3 NOVA NEJM 2016, 4 Swisher Lancet Onc 2016 5 (% of pts)
- 32. Other side effects… • Pneumonitis reported in <1% of pts treated with olaparib • AML/MDS (leukemia, pre-leukemia) OLAP 0.8% (22/2618)1 Rucaparib 0.5% (2/377)2 Niraparib 1.4% (5/367)3 • Increase in cholesterol Rucaparib2 : 40% all grades; 2% grade 3 and 4 • Rash/photosensitivity reaction Rucaparib: 15%/10% Olaparib: 25%/0 1 FDA insert, 2 FDA insert, 3 NOVA NEJM 2016,
- 33. Toxicity • Immunotherapy • PARP inhibitors • VEGF inhibition
- 34. Tumor Angiogenesis and Cancer Treatment Blood vessel Tumor that can grow and spreadSmall localized tumor Signaling molecule Angiogenesis
- 35. AURELIA: Bevacizumab for Platinum-Resistant Ovarian Cancer. Stratification factors: •Chemotherapy selected •Prior anti-angiogenic therapy •Treatment-free interval (PFI <3 vs 3 6 months)‒ Platinum-resistant •≤2 prior regimens •No history of bowel obstruction/fistula, or clinical/radiological evidence of rectosigmoid involvement Treat to PD/toxicity Treat to PD/toxicity Investigator’s choice (without BEV) Optional BEV monotherapy^ BEV 15 mg/kg q3w* + chemotherapy Chemotherapy R 1:1 Chemotherapy options (investigator’s choice): •Paclitaxel 80 mg/m2 days 1, 8, 15 & 22 q4w •Topotecan 4 mg/m2 days 1, 8 & 15 q4w (or 1.25 mg/m2 , days 1–5 q3w) •PLD 40 mg/m2 day 1 q4w * Or 10 mg/kg q2w ^ 15 mg/kg q3w, permitted on clear evidence of progression J Clin Oncol 2014;32(13):1302-8
- 36. AURELIA RR Chemo alone RR Chemo + Bev Median PFS Chemo alone (months) Median PFS Chemo + Bev (months) HR Median OS Chemo Alone (months) Median OS Chemo + Bev (months) HR Overall Study 11.8% 27.3% 3.4 6.7 0.48 (0.38-0.60) 13.3 16.6 0.85 (0.66-1.08) Paclitaxel 30.2% 53.3% 3.9 10.4 0.46 (0.30-0.71) 13.2 22.4 0.65 (0.42-1.02) PLD 7.8% 13.7% 3.5 5.4 0.57 (0.39-0.83) 14.1 13.7 0.91 (0.62-1.36) Topotecan 0% 17% 2.1 5.8 0.32 (0.21-0.49) 13.3 13.8 1.09 (0.72-1.67) J Clin Oncol 2014;32(13):1302-8; J Clin Oncol 2015;33:3836-3838
- 37. HFS = hand-foot syndrome a Preferred terms. b Includes abdominal pain upper Patients(%) Peripheralsensory neuropathy Abdom inalpainb ≈≈ ≈ ≈ 0 2 4 6 8 10 12 14 16 18 CT (n=181) BEV + CT (n=179) J Clin Oncol 2014;32(13):1302-8 AURELIA: Side effects with addition of Bev to chemotherapy
- 38. Older adults: Bevacizumab increases Grade 3-5 toxicity Mohile, Tew et al. The Oncologist 2013;18:408-414 ©2013 by AlphaMed Press Bevacizumab: - Hypertension - Bleed - Clots (arterial, venous) - Proteinuria - Bowel perforation
- 39. Phase II: Olaparib (PARPinh)+ Cediranib (Angiogenesis) • Platinum-sensitive recurrent ovarian cancer • Median PFS improvement in combo (17.7 vs. 9months) • High toxicity, mostly cediranib related: – Grade 3-5 AEs (70%): fatigue, diarrhea, and hypertension. – Drug dose reduction (77%): mostly cediranib • Fit, young pt population: – Median age 58 (42-86) – ECOG PS 0 (71%) – ECOG PS 1 (29%) • NRG studies: – Platinum Sensitive – Platinum Resistant Liu et al, Lancet Oncol, 2015
- 41. Summary • Targeted agents bring unique, yet often manageable side effects. • Special attention to drug combinations and populations not studied in prospective studies (elderly) • With a FDA indication and broader use, very rare side effects can be discovered.
Hinweis der Redaktion
- How does the immune system recognize tumor as non-self?
- Member of CD28 family involved in T cell regulation Expressed by activated T cells, memory T cells and regulatory T cells Down regulates T cell activity upon binding to PD-L1/L2 Tumor PD-L1 expression may correlate with negative prognosis potential mechanism of tumor self defense
- Member of CD28 family involved in T cell regulation Expressed by activated T cells, memory T cells and regulatory T cells Down regulates T cell activity upon binding to PD-L1/L2 Tumor PD-L1 expression may correlate with negative prognosis potential mechanism of tumor self defense
- Fatal autoimmune myocarditis with rhabdomyolysis and refractory arrhythmias developed in two patients treated with a combination of anti–CTLA-4 and anti–PD-1 blockers. On histologic examination, a myocardial infiltrate suggested acute cardiac allograft rejection.
- Figure 1 Results on ECG and Immune Effects in Cardiac Muscle after Treatment with Ipilimumab and Nivolumab in Patient 1. Patient 1 had rapid progression to complete heart block (as shown on electrocardiography [ECG] in Panel A), followed by ventricular tachycardia (Panel B). Autopsy revealed lymphocytic infiltration of the myocardium (shown in the intraventricular septum in Panel C; staining with hematoxylin and eosin). The inflammatory infiltrate included CD3-positive T lymphocytes (Panel D), many of which were positive for CD8 (Panel E). Only cardiac and skeletal muscle was affected; smooth muscle and other tissues were spared (Panel F, hematoxylin and eosin). The black arrow points to esophageal smooth muscle without immune infiltration, and the green arrow points to esophageal skeletal muscle, which is heavily infiltrated by immune cells.
- Background: With recent FDA approvals of immune checkpoint inhibitors for the treatment of advanced cancer, an increasing number of elderly patients will be treated with immunotherapy. Nivolumab is an immune checkpoint inhibitor, currently approved for the treatment of advanced renal cell cancer, melanoma, and non-small cell lung cancer based on significant responses including benefit in overall survival. However, little is known about the safety of nivolumab in an elderly patient population. Methods: Eligible patients received at least one dose of nivolumab as a single agent while enrolled in a phase 3 registration trial for the treatment of advanced renal cell cancer (CA209025), melanoma (CA209066), or non-small lung cancer (CA209057 and CA209017). Adverse events which occurred up to 100 days after last dose of nivolumab based on standardized adverse event datasets submitted by the sponsor were included. Results: See table. Conclusions: Immune therapies can benefit patients across a wide range of tumors. Currently there is little known about the safety of nivolumab in elderly patients. This exploratory analysis suggests that nivolumab is well tolerated in the elderly population in terms of adverse events. These data should be validated in larger patient cohorts, with specifically targeted age ranges to reflect the aging cancer population. The inclusion of greater numbers of elderly patients in registration clinical trials will further inform clinicians on the safety of immune based therapies in the elderly.
- Each drug is metabolized differently Other drugs patients are taking may influence the PARP Inhibitor levels Drug interactions can occur based on CYP inhibition or induction Effect on renal transporter proteins MATE1 and MATE2-K can increase serum creatinine
- Tumor angiogenesis is the proliferation of a network of blood vessels that penetrates into cancerous growths, supplying nutrients and oxygen and removing waste products. Tumor angiogenesis actually starts with cancerous tumor cells releasing molecules that send signals to surrounding normal host tissue. This signaling activates certain genes in the host tissue that, in turn, make proteins to encourage growth of new blood vessels.
- Grade 3 or greater toxicity: black, chemotherapy plus bevacizumab; stripes, chemotherapy alone.