Managing Rheumatoid Arthritis Post Malignancy: A Case-Based Discussion Maria E. Suarez-Almazor, MD, PhD Barnts Family Distinguished Professor Section of Rheumatology and Clinical Immunology University of Texas M. D. Anderson Cancer Center Houston, Texas Supported by an independent educational grant from AbbVie.

About These Slides Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

Faculty Maria E. Suarez-Almazor, MD, PhD Barnts Family Distinguished Professor Section of Rheumatology and Clinical Immunology University of Texas M. D. Anderson Cancer Center Houston, Texas Maria E. Suarez-Almazor, MD, PhD, has disclosed that she has received funds for research support from Pfizer. This slide lists the faculty who was involved in the production of these slides.

Standardized Incidence Ratio Cancer Risk in RA Pts Meta-analysis of observational studies reporting risk of malignancy in RA pts vs general population[1,2] Possible increase in melanoma and nonmelanoma skin cancer[5,6] Overall Cancer Lung Cancer Non-Hodgkin’s Lymphoma Hodgkin’s Lymphoma Lymphoma RA, rheumatoid arthritis. Breast Cancer Colorectal Cancer 1 2 3 4 5 Standardized Incidence Ratio 1. Cush JJ, et al. DSQ. 2012;4:1-4. 2. Smitten AL, et al. Arthritis Res Ther. 2008;10:R45. 5. Raaschou P, et al. BMJ. 2013;346:f1939. 6. Askling J, et al. Ann Rheum Dis. 2005;64:1421-1426.

RA Treatment and the Risk of Lymphoma Analysis of 18,572 RA pts enrolled in the US National Data Bank for Rheumatic Diseases[7] Treatment Group Pts at Risk, n Lymphomas, n SIR (95% CI)* All pts 18,572 29 1.9 (1.3-2.7) No MTX/biologics 3504 5 1.3 (0.5-3.1) All biologics 8614 14 2.9 (1.7-4.9) MTX only 6396 10 1.5 (0.8-2.7) INF ± ETN 6465 9 2.6 (1.4-4.5) ETN ± INF 3381 8 3.8 (1.9-7.5) ETN, etanercept; INF, infliximab; MTX, methotrexate; NCI, National Cancer Institute; RA, rheumatoid arthritis; SEER, Surveillance, Epidemiology, and End Result; SIR, standardized incidence ratio; tx, treatment. *SIRs calculated based on age- and sex-matched data from the NCI SEER resource. Other studies, including a large meta-analysis, have not found a significant association between biologic RA tx and lymphoma risk[8,9] 7. Wolfe F, et al. Arthritis Rheum. 2004;50:1740-1751. 8. Lopez-Olivo M, et al. JAMA. 2012;308:898-908. 9. Askling J, et al. Ann Rheum Dis. 2009;68:648-653.

RA Treatment and the Risk of Solid Tumors Analysis of RA pts without prior cancer in the British Society for Rheumatology Biologics Assessed risk of solid tumors in pts who received TNFis (n = 11,767) vs patients nbDMARDs (n = 3249) No difference in relative risk of cancer for specific TNFis nbDMARD TNFi Pts, n 3249 11,767 Total follow-up, PY 11,672 52,549 Solid cancers, n 136 427 Unadjusted HR (95% CI) 0.70 (0.58-0.85) Adjusted HR* (95% CI) 0.83 (0.64-1.07) nbDMARD, nonbiologic disease-modifying antirheumatic drug; PY, patient-years; RA, rheumatoid arthritis; TNFi, tumor necrosis factor inhibitor. *Adjustment using propensity score stratified into deciles. 10. Mercer LK, et al. Ann Rheum Dis. 2015;74:1087-1093.

RA Treatment and the Risk of Melanoma Analysis of data from Swedish ARTIS register Assessed melanoma incidence in RA pts treated with TNFis (n = 10,878) or not treated with TNFis (n = 42,198) and in general population (n = 162,743) Cancer Type No Biologic Treatment TNFi Treatment Adjusted HR (95% CI) Invasive malignant melanoma, events/PY 113/203,345 38/57,223 1.5 (1.0-2.2) Invasive all site cancer,* events/PY 2788/196,826 558/55,947 1.0 (0.9-1.1) Second primary melanoma, events/pts† 10/295 3/54 3.2 (0.8-13.1) NS, not significant; PY, person years; RA, rheumatoid arthritis; TNFi, tumor necrosis factor inhibitor. *All sites except basal cell skin cancer. †Pts with a history of melanoma at the start of RA treatment. 5. Raaschou P, et al. BMJ. 2013;346:f1939.

Biologic Therapy and Risk of Malignancy: Meta-Analysis Meta-analysis of 63 RCTs comparing biologic therapy with nbDMARD therapy or placebo for treating RA (N = 29,423) 211 pts (0.72%) developed malignancy during RCT No consistent significant differences in risk of any malignancy TNFis vs placebo or nbDMARD TNFis + nbDMARD vs nbDMARD No specific TNFi was associated with increased risk of malignancy (assessed ADA, CTZ, ETN, GLM, INF) No significant increases in risk of NMSC, melanoma, solid tumors, or lymphoma for RA pts treated with TNFi Risk for lymphoma: OR 2.14 (NS) ADA, adalimumab; CTZ, certolizumab; ETN, etanercept; GLM, golimumab; INF, infliximab; nbDMARD, nonbiologic disease-modifying antirheumatic drug; NMSC, nonmelanoma skin cancer; NS, not significant; OR, odds ratio; RA, rheumatoid arthritis; RCT, randomized controlled trial; TNFi, tumor necrosis factor inhibitor. 8. Lopez-Olivo M, et al. JAMA. 2012;308:898-908.

Cancer Prognosis and Recurrence After TNFi Treatment: Swedish Registries Analysis of primary cancers and postcancer survival[12] 302 cancers in 8562 RA pts treated with biologics* (from ARTIS registry); 586 cancers from matched controls RA pts not treated with biologics Adjusted HR for death (biologic vs non-biologic tx) = 1.1 (95% CI: 0.8-1.6) No significant differences in survival for specific cancers: breast, colorectal, prostate, lung, or malignant melanoma Analysis of breast cancer recurrence[13] TNFi-treated RA pts with history of breast cancer prior to TNFi tx (n = 120) compared with matched controls not treated with TNFis (n = 120) Breast cancer recurrences not increased with TNFi: adjusted HR 1.1 (95% CI: 0.4-2.8); median time to TNFi treatment after primary cancer: 9.4 yrs NMSC, nonmelanoma skin cancer; RA, rheumatoid arthritis; TNFi, tumor necrosis factor inhibitor; tx, treatment. *300 of 302 patients were treated with TNFis; 2 patients were treated exclusively with biologic agents other than TNFis. 12. Raaschou P, et al. Arthritis Rheum. 2011;63:1812-1822. 13. Raaschou P, et al. Ann Rheum Dis. 2015;74:2137-2143. 9 9

TNF Inhibitors for RA Pts With Prior Malignancy Analysis of RA pts in a British registry (BSRBR) study with a history of malignancy prior to treatment with TNFis or without TNFis TNFi Treatment nbDMARD Treatment Pts with prior malignancy, n 177 117 Malignancy recurrence, n (%) 11 (6.2) 9 (7.7) Recurrence rate per 1000 PY (95% CI) 25.3 (13.4-43.2) 38.3 (17.5-72.7) Pts with prior melanoma, n 17 10 Melanoma recurrence, n (%) 3 (17.6) 0 (0) BSRBR, British Society for Rheumatology Biologics Register; PY, patient-years; RA, rheumatoid arthritis; TNF, tumor necrosis factor; TNFi, tumor necrosis factor inhibitor. 14. Dixon WG, et al. Arthritis Care Res. 2010;62:755-763.

Cancer Recurrence Risk by Treatment Regimen Analysis of cancer recurrence in RA patients in a German registry (RABBIT) with a history of malignancy prior to treatment with TNFis, rituximab, or nbDMARDs nbDMARDs Rituximab TNFi* Pts, n 3399 770 5231 Pts with prior solid malignancies, n (%) 112 (3.3) 77 (10) 109 (2.1) Median yrs between malignancy and treatment start 5.9 3.3 6.8 Recurrence rate per 100 PY (95% CI) 3.6 (1.9-6.1) 3.9 (1.6-8.0) 5.7 (3.5-8.8) nbDMARD, nonbiologic disease-modifying antirheumatic drug; PY, patient years; TNFi, tumor necrosis factor inhibitor. *Adalimumab, certolizumab pegol, etanercept, golimumab, infliximab. 15. Strangfeld A, et al. ACR 2013. Abstract 806.

Summary RA pts have an increased risk of specific malignancies Lymphoma, lung cancer, melanoma, NMSC Treatment of RA pts with biologic therapy does not increase the risk of malignancies vs pts not treated with biologics Most observational studies suggest that biologic therapy does not increase the risk of recurrence for RA pts with a history of treated cancer diagnosed several yrs before biologic therapy Risk for melanoma recurrence might be increased, but the data are not robust NMSC, nonmelanoma skin cancer; RA, rheumatoid arthritis.

2015 ACR Guidelines: Biologic Use in RA Pts With History of Malignancy Recommendation Previously treated/untreated melanoma or NMSC Use DMARDs over biologics Use DMARDs over tofacitinib Previously treated lymphoproliferative disorder Use rituximab over TNFi* Use combination DMARD OR abatacept OR tocilizumab over TNFi Previously treated solid organ malignancy Same recommendations as in pts without condition ACR, American College of Rheumatology; DMARD, disease-modifying antirheumatic drug; HCQ, hydroxychloroquine; LEF, leflunomide; MTX, methotrexate; NMSC, non-melanoma skin cancer; RA, rheumatoid arthritis; SSZ, sulfasalazine; TNFi, tumor necrosis factor inhibitor. DMARD = HCQ, LEF, MTX, or SSZ. *Strongly recommended. 16. Singh JA, et al. Arthritis Care Res. 2015;[Epub ahead of print].

Management of RA Pts With Current or Recent Malignancy Goals of management in RA pts with current malignancy Improve/maintain quality of life Maximize survival Considerations for informed shared decision-making RA Cancer Disease activity Type and stage Prognostic features Duration from diagnosis Quality of life Recurrences Previous response to therapy Probability of survival Comorbidities Median survival Concurrent treatments Treatment (curative vs palliative) Patient preferences RA, rheumatoid arthritis.

Case 1: History of Breast Cancer 50-yr-old woman Diagnosed with stage II breast cancer 7 yrs ago Underwent mastectomy and radiation therapy; received chemotherapy and tamoxifen for 5 yrs No recurrences Developed symmetric polyarthritis involving wrists and MCP, PIP, knee joints 1 yr ago Positive RF and anti-CCP tests; diagnosed with RA Initiated treatment with MTX (escalated to 20 mg PO QW) and prednisone 10 mg/day PO 10 mos ago SSZ and HCQ added 4 mos ago CCP, cyclic citrullinated peptide; HCQ, hydroxychloroquine; MCP, metacarpophalangeal; MTX, methotrexate; PIP, proximal interphalangeal; PO, by mouth; QW, weekly; RA, rheumatoid arthritis; RF, rheumatoid factor; SSZ, sulfasalazine.

Case 1: Current Status At current visit, pt presents with: VAS pain: 7/10 Morning stiffness: 2 hrs Joint tenderness and swelling in wrists/MCP, PIP, knee joints DAS28: 5.2; ESR: 32 Hand radiographs: 2 MCP erosions DAS28, disease activity score in 28 joints; ESR, erythrocyte sedimentation rate; MCP, metacarpophalangeal; PIP, proximal interphalangeal; VAS, visual analogue scale.

Case 1: Management Management considerations: RA Pt has established RA with high disease activity despite treatment with steroids and triple DMARD therapy along with features of poor prognosis Management considerations: cancer History of breast cancer (diagnosed 7 yrs ago) No recurrences after treatment Treatment options ACR guidelines: pts with prior solid organ malignancy can be treated as any other RA pt Prednisone already at maximum dose; pt should initiate treatment with biologic agent ACR, American College of Rheumatology; DMARD, disease-modifying antirheumatic drug; RA, rheumatoid arthritis. 16. Singh JA, et al. Arthritis Care Res. 2015;[Epub ahead of print].

Case 2: Recent History of NSCLC 58-yr-old man Diagnosed with seropositive RA 5 yrs ago Initial treatment: MTX followed by triple therapy (MTX + SSZ + HCQ); little response Switched to MTX + ETN 3 yrs ago; excellent control of disease activity Diagnosed with stage IB NSCLC 18 mos ago Solitary 4-cm nodule in right lung RA medications stopped Underwent surgery; histology showed positive margins Chemoradiation completed 8 mos ago ETN, etanercept; HCQ, hydroxychloroquine; MTX, methotrexate; NSCLC, non-small-cell lung cancer; RA, rheumatoid arthritis; SSZ, sulfasalazine.

Case 2: Current Status Developed synovitis of MCP, PIP, and knee joints 5 mos ago DAS28 score: 5.6 Hand radiographs: several PIP erosions Started on MTX (increasing to 25 mg PO QW) and prednisone 7.5 mg/day PO with no improvement Completed cancer staging 1 mo ago; no recurrences DAS28, disease activity score in 28 joints; MCP, metacarpophalangeal; MTX, methotrexate; PIP, proximal interphalangeal; PO, by mouth; QW, weekly.

Case 2: Management Management considerations: RA Pt has high disease activity and poor prognostic factors despite MTX and prednisone Poor prior response to triple therapy; excellent prior response to ETN Management considerations: cancer Recent history of NSCLC (stage IB, diagnosed 18 mos ago); biopsy showed poor margins; currently no recurrences Treatment options ACR guidelines: pts with prior treated solid organ malignancy can be treated as any other RA pt However, due to cancer type and recent diagnosis/treatment, recurrence a possibility; as prednisone/MTX already at maximum doses, consider rituximab ACR, American College of Rheumatology; ETN, etanercept; MTX, methotrexate; NSCLC, non-small-cell lung cancer; RA, rheumatoid arthritis. 16. Singh JA, et al. Arthritis Care Res. 2015;[Epub ahead of print].

Case 3: Current Metastatic Pancreatic Cancer 62-yr-old woman Diagnosed with RA 17 yrs ago Receiving MTX 15 mg PO QW and IV abatacept Excellent response; no evidence of disease activity in past 1 yr Developed severe back pain and epigastric discomfort 4 mos ago Diagnosed with unresectable pancreatic cancer with liver metastases MTX and abatacept discontinued Pt started gemcitabine and oxycodone for pain control IV, intravenous; MTX, methotrexate; PO, by mouth; QW, weekly; RA, rheumatoid arthritis.

Case 3: Current Status Developed synovitis of her elbows, wrists, MCP and PIP joints 2 mos ago Severe shoulder pain Marked decrease in ability to perform usual daily activities Initiated treatment with prednisone 10 mg/day PO with mild improvement MCP, metacarpophalangeal; PIP, proximal interphalangeal; PO, by mouth.

Case 3: Management Management considerations: RA Pt has high disease activity and poor quality of life Excellent prior response to MTX + abatacept; MTX not good choice, as pt is on chemotherapy and has liver metastases Management considerations: cancer Current metastatic disease; no curative therapy (median expected survival from diagnosis ~ 6 mos to 1 yr) Treatment options ACR guidelines: no specific guidance for pts with current solid tumors/metastases Pt preferences and shared decision-making; abatacept a possibility ACR, American College of Rheumatology; MTX, methotrexate; RA, rheumatoid arthritis. 16. Singh JA, et al. Arthritis Care Res. 2015;[Epub ahead of print]. 21. Weinberg BA, et al. Oncology. 2015;29:pii:214216.

Case 4: History of Recurrent Melanoma 42-yr-old woman First diagnosed with melanoma 3 yrs ago 0.5-cm lesion in her arm with negative sentinel nodes Underwent wide excision Developed a new lesion 4 cm proximal to the primary tumor 2 yrs ago Lesion was excised and pt underwent chemotherapy with no recurrences in the past 2 yrs Developed polyarthritis and was diagnosed with RA 6 mos ago Initiated treatment with MTX; minimal response after 4 mos Positive RF, negative anti-CCP, normal hand radiographs, DAS28 score: 4.8 CCP, cyclic citrullinated peptide; DAS28, disease activity score in 28 joints; MTX, methotrexate; RA, rheumatoid arthritis; RF, rheumatoid factor.

Case 4: Management Management considerations: RA Early onset RA; moderate disease; no radiographic evidence of structural damage Poor response to MTX Management considerations: cancer Young pt with recurrent melanoma; no current evidence of disease Treatment options ACR guidelines: use DMARDs over biologics/tofacitinib Triple combination DMARD therapy ACR, American College of Rheumatology; DMARD, disease-modifying antirheumatic drug; MTX, methotrexate; RA, rheumatoid arthritis. 16. Singh JA, et al. Arthritis Care Res. 2015;[Epub ahead of print].

Case 5: No Prior Malignancy but Elevated Risk 36-yr-old woman Diagnosed with RA 4 yrs ago Well-controlled on SC adalimumab for past 2 yrs No swollen joints, mild pain, morning stiffness: 10 mins RF positive and anti-CCP negative Hand radiographs show juxta-articular osteoporosis but no erosions Does not want to receive MTX because of desire to get pregnant/have second child CCP, cyclic citrullinated peptide; MTX, methotrexate; RA, rheumatoid arthritis; RF, rheumatoid factor; SC, subcutaneous.

Case 5: Current Status Pt concerned about her genetic predisposition to cancer Mother died from ovarian cancer 7 yrs ago Older sister diagnosed with breast cancer 4 mos ago Recently underwent genetic testing: BRCA1 mutation carrier MTX, methotrexate

Case 5: Management Management considerations: RA Patient is well-controlled with TNFi; has not tried MTX or other DMARDs Prognostic factors are moderate: positive RF, negative anti-CCP, no hand erosions Future pregnancy a possibility Management considerations: cancer Young patient with no current/prior cancer; increased risk for breast and ovarian cancer due to BRCA1 mutation Treatment options ACR guidelines: no specific guidance for at-risk pts with no history of malignancy Discuss uncertainties with pt If mastectomy/oophorectomy are desirable, no need to alter RA management If mastectomy/oophorectomy are not desirable, consider switch to another DMARD/biologic in view of uncertainty Pregnancy considerations with choice of therapy ACR, American College of Rheumatology; CCP, cyclic citrullinated peptide; DMARD, disease-modifying antirheumatic drug; MTX, methotrexate; RA, rheumatoid arthritis; RF, rheumatoid factor; TNFi, tumor necrosis factor inhibitor. 16. Singh JA, et al. Arthritis Care Res. 2015;[Epub ahead of print].

Summary Prior malignancy Risk of malignancy Current malignancy ACR guidelines offer recommendations for pts with history of solid tumors, lymphoma, and skin cancer TNFis should be avoided in pts with lymphoma/skin cancers Risk of malignancy No clear evidence or guidelines; focus on shared decision making Current malignancy Personalized approach required for pt with RA and cancer Goal is to maximize quality of life with no significant detriment to survival Consider cancer features Focus on shared decision making, both for known and unknown issues ACR, American College of Rheumatology; RA, rheumatoid arthritis; TNFi, tumor necrosis factor inhibitor.

Go Online for More CCO Coverage! Clinical Focus discussion exploring the clinical implications of the data Downloadable slides clinicaloptions.com/immunology