Case #6 Optimal Management of Cervical Cancer. Nicoletta Colombo, MD University of Milan-Bicocca and European Institute of Oncology, Milan, Italy

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1 Case #6 Optimal Management of Cervical Cancer Nicoletta Colombo, MD University of Milan-Bicocca and European Institute of Oncology, Milan, Italy

2 The Case: Key Elements Pelvic examination: tumor 4 cm in size; bilateral parametrial involvement Cervical biopsy: moderately differentiated invasive squamous cell carcinoma Pelvic MRI: irregular cervical lesion 5 cm in size, extension into parametria, tumor is not invading vaginal wall, and there is no clear evidence of lymphadenopathy 35-year-old G3P3 with stage IIB squamous cell carcinoma, N-

3 Part I: Would you consider additional staging for this patient? Laparoscopic/robotic paraaortic lymphadenectomy Cystoscopy PET/CT Different combinations of the above

4 Marth C, et al. Ann Oncol. 2017;28(Suppl 4):iv72-iv83.

5 Cervical Cancer Staging Cervical cancer is the only gynecologic cancer that is clinically staged based on tumor size, vaginal or parametrial involvement, bladder/rectum extension, and distant metastases It requires examination under anesthesia, radiologic imaging such as chest X-ray, and intravenous pyelogram Other imaging studies are used routinely to more accurately define the extent of disease and to allow tailoring of treatment, but do not affect the clinical stage Marth C, et al. Ann Oncol. 2017;28(Suppl 4):iv72-iv83.

6 Cervical Cancer Staging Computed tomography (CT) can detect pathologic lymph nodes, while magnetic resonance imaging (MRI) can determine tumor size, degree of stromal penetrations, parametrial involvement, vaginal extension, and corpus extension with high accuracy Positron emission tomography (PET) has been seen to have the potential to accurately delineate the extent of disease, particularly in lymph nodes with high sensitivity and specificity. In early-stage disease, PET/CT has a sensitivity of 53% 73% and specificity of 90% 97% for the detection of lymph node involvement In more advanced stages the sensitivity for detecting the involvement of paraaortic nodes increases to 75% with 95% specificity The need for pretreatment surgical paraaortic lymph node assessment in locally advanced cervical cancer (LACC) is still a matter of debate Patel CN, et al. AJR Am J Roentgenol. 2011;196(5): Brockbank E, et al. Cochrane Database Syst Rev. 2013;28(3): CD

7 Cervical Cancer Staging Computed tomography (CT) can detect pathologic lymph nodes, while magnetic resonance imaging (MRI) can determine tumor size, degree of stromal penetrations, parametrial involvement, vaginal extension, and corpus extension with high accuracy From the one available RCT we found insufficient Positron evidence emission that tomography pre-treatment (PET) has surgical been seen para-aortic to have lymph the potential to accurately delineate the extent of disease, particularly in lymph nodes with node assessment for locally advanced cervical cancer high sensitivity and specificity. is beneficial, and it may actually have an adverse effect on survival. Brockbank E, et al In early-stage disease, PET/CT has a sensitivity of 53% 73% and specificity of 90% 97% for the detection of lymph node involvement In more advanced stages the sensitivity for detecting the involvement of paraaortic nodes increases to 75% with 95% specificity The need for pretreatment surgical paraaortic lymph node assessment in locally advanced cervical cancer (LACC) is still a matter of debate Patel CN, et al. AJR Am J Roentgenol. 2011;196(5): Brockbank E, et al. Cochrane Database Syst Rev. 2013;28(3): CD

8 Randomized Trial of Surgical Staging (Extraperitoneal or Laparoscopic) vs Clinical Staging in Locally Advanced Cervical Cancer Lai CH, et al. Gynecol Oncol. 2003;89(1):

9 Lai CH, et al. Gynecol Oncol. 2003;89(1):

10 Lai CH, et al. Gynecol Oncol. 2003;89(1): Limited role for removal of enlarged aortic nodes

11 Lai CH, et al. Gynecol Oncol. 2003;89(1): Possible therapeutic value of surgery and/or radiation therapy in node metastases not detected at PET-CT

12 Part II: Which of the following best describes your initial treatment approach for this patient with FIGO IIB cervical cancer? Neoadjuvant chemotherapy followed by surgery or radiotherapy Radiation Concurrent chemoradiation+/-chemotherapy Radical hysterectomy + bilateral salpingooophorectomy + pelvic lymphadenectomy Other

13 Locally Advanced Cervical Cancer All Treatments Require a Multimodality Approach Chemo/radiation chemotherapy NACT Surgery (or radiotherapy) chemo/radiation Surgery + chemo/radiation

14 NCI Issues Clinical Announcement on Cervical Cancer: Chemotherapy Plus Radiation Improves Survival. National Cancer Institute Press Office 1999 National Institutes of Health. Chemoradiation is considered the world standard treatment for LACC Feb-1999: NCI issues clinical announcement on cervical cancer The results of 5 large studies have shown that women with invasive cervical cancer have better survival when they receive chemotherapy that includes the drug cisplatin along with radiation therapy.

15 Chemoradiation Chemoradiotherapy for Cervical Cancer Meta-Analysis Collaboration (CCCMAC). Cochrane Database Syst Rev. 2010;(1):CD

16 HR correlated with stage Chemoradiation HR similar for CDDP-based and non CDDP based chemo-rt HR best for two trials with concurrent and adjuvant CT Neoadjuvant Chemotherapy for Cervical Cancer Meta-Analysis Collaboration (NACCCMA) Collaboration. Cochrane Database Syst Rev. 2004;(2):CD

17 THE OUTBACK TRIAL A phase III trial of adjuvant chemotherapy following chemoradiation as primary treatment for locally advanced cervical cancer compared to chemoradiation alone ANZGOG

18 INTERLACE Randomize Carboplatin AUC2 & Paclitaxel 80 mg/m 2 Weeks 1-6 Weeks 7 13 Standard CRT Standard CRT Standard CRT : Gy in fractions plus intracavitary brachytherapy to give total of EQD2 dose Gy to point A/volume. Weekly cisplatin 40 mg/m 2 x 5 weeks Follow-up 3 monthly for 2 years; 6 monthly for 3 years

19 Is NACT followed by RT better than RT alone?

20 NACT & RT vs RT Neoadjuvant Chemotherapy for Cervical Cancer Meta- Analysis Collaboration (NACCCMA) Collaboration. Cochrane Database Syst Rev. 2004;(2):CD

21 Locally Advanced Cervical Cancer NACT & RT vs RT Neoadjuvant Chemotherapy for Cervical Cancer Meta- Analysis Collaboration (NACCCMA) Collaboration. Cochrane Database Syst Rev. 2004;(2):CD

22 Is NACT followed by radical surgery better than RT alone?

23 Locally Advanced Cervical Cancer NACT & S vs RT Favors NACT-S Favors RT Neoadjuvant Chemotherapy for Cervical Cancer Meta-Analysis Collaboration (NACCCMA) Collaboration. Cochrane Database Syst Rev. 2004;(2):CD

24 Is NACT followed by radical surgery better than radical surgery alone?

25 NACT + Radical Surgery vs Radical Surgery Alone Better OS and PFS for NACT/RS vs RS Fewer local recurrences Fewer distant recurrences More radical resections Less N + Less parametrial involvement Rydzewska L, et al. Cochrane Database Syst Rev. 2010;(1):CD

26 What Have We Learned So Far? Take-Home Messages 1. Chemoradiation is better than radiation alone in the treatment of LACC 2. NACT followed by RT might be detrimental or beneficial according to platinum dose and schedule 3. NACT followed by radical surgery is better than radiation alone in the treatment of LACC 4. NACT followed by radical surgery is better than surgery alone in the treatment of LACC 5. NACT followed by radical surgery VS chemoradiation?

27 What Have We Learned So Far? Take-Home Messages 1. Chemoradiation is better than radiation alone in the treatment of LACC 2. Chemotherapy NACT followed by RT might be is detrimental needed or beneficial in according to platinum dose and schedule the treatment of locally advanced cervical cancer 3. NACT followed by radical surgery is better than radiation alone in the treatment of LACC 4. NACT followed by radical surgery is better than surgery alone in the treatment of LACC 5. NACT followed by radical surgery VS chemoradiation?

28 Study Design Squamous carcinoma Stage IB2, IIA, or IIB ECOG 0-1 No prior treatment Stratify by stage 1:1 N = 317 Experimental NACT X 3 cycles followed by surgery No distant metastases Control Adequate hematologic & renal function N = 318 Concomitant CTRT Gupta S, et al. Ann Oncol. 2017;28(Suppl 5): Abstract 9280_PR. Neoadjuvant chemotherapy Paclitaxel (175 mg/m 2 ) + Carboplatin: (AUC 5-6) every 3 weeks X 3 cycles Concomitant chemotherapy Cisplatin (40 mg/m 2 /week) X 5 weeks Radiotherapy EBRT: 40 Gy/20 fr/5 weeks + (HDR, 7Gy/5 appl or LDR 30 Gy/2 appl

29 Disease-Free Survival in Intention-to-Treat Population Gupta S, et al. Ann Oncol. 2017;28(Suppl 5): Abstract 9280_PR.

30 Overall Survival in Intention-to-Treat Population Gupta S, et al. Ann Oncol. 2017;28(Suppl 5): Abstract 9280_PR.

31 Main Criticisms Methodology: trial stopped prematurely (- 100 patients) Control arm: overperformed (why?) Experimental arm: right chemo? Statistics: is DFS the right endpoint? What about quality of life and long-term effect of radiotherapy in young patients?

32 EORTC - # RCT comparing NACT+RS Versus CT/RT Cervical Cancer IB2, IIA>4cm, IIB RANDOMIZED NACT + SURGERY Exclusive Chemoradiation

33 Marth C, et al. Ann Oncol. 2017;28(Suppl 4):iv72-iv83.

34 In the Meantime, How Would I Treat This Patient? If chemo is needed anyhow even with chemo-rt Optimal response, Node negative on imaging 6 weeks dose dense chemo Suboptimal response Lymphadenectomy Mini-invasive Positive nodes Chemo-RT Negative nodes Radical surgery

35 In the Meantime, How Would I Treat This Patient? If chemo is needed anyhow even with chemo-rt Optimal response, Node negative on imaging Lymphadenectomy Mini-invasive Negative nodes 6 weeks dose dense chemo Patients will receive the best treatment in Suboptimal case of positive nodes: extended-field response chemo-rt + chemo Positive nodes Chemo-RT And in case of negative node: NACT/surgery Radical surgery

36 Part III: Two years after chemo-rt, patient has a relapse in the lung and paraaortic lymph nodes. She is asymptomatic. Which of the following therapeutic strategies would you recommend now for recurrent cervical cancer? Platinum doublet chemotherapy Nonplatinum doublet chemotherapy Platinum doublet + bevacizumab Nonplatinum doublet + bevacizumab Observation Clinical trials

37 Few Advances in Treating Persistent, Recurrent Cervical Cancer Trial (Year) n Regimen OS, Months GOG-0169 (2004) GOG-0179 (2005) PFS, Months RR, % Main Findings Cisplatin Improvement in ORR and PFS Cisplatin + paclitaxel Cisplatin Cisplatin + topotecan Cisplatin + paclitaxel No significant OS improvement Supports cisplatin-topotecan label Some argue that OS in the cisplatin-control arm was low due to high radiotherapy-cisplatin use GOG-0204 (2009) JGOG-0505 (2015) Cisplatin + topotecan Cisplatin + gemcitabine Cisplatin + vinorelbine Study consolidated cisplatin-paclitaxel as SoC No other combination was better Cisplatin + paclitaxel n/a Carboplatin-paclitaxel was non-inferior to cisplatin-paclitaxel in overall population Carboplatin + paclitaxel n/a For patients who had not received prior platinum, OS was better with cisplatinpaclitaxel Longer OS vs other studies may be related to patients studied (Japanese) RR, response rate; OS, overall survival; PFS, progression-free survival; RR, response rate; SoC, standard of care 1. Moore DH et al. J Clin Oncol. 2004;22(15): Long HJ 3 rd, et al. J Clin Oncol. 2005;23(21): Monk BJ, et al. J Clin Oncol. 2009;27(28): Kitagawa R, et al. J Clin Oncol. 2015;33(19): NCCN Clinical Practice Guidelines in Oncology : Cervical Cancer. V Accessed October 17, Colombo N, et al. Ann Oncol. 2012;23 Suppl 7:vII27-32.

38 Few Advances in Treating Persistent, Recurrent Cervical Cancer Trial (Year) n Regimen OS, Months GOG-0169 (2004) GOG-0179 (2005) GOG-0204 (2009) PFS, Months RR, % Main Findings Cisplatin Improvement in ORR and PFS Cisplatin + paclitaxel Cisplatin + topotecan No significant OS improvement Cisplatin is considered Cisplatin the most 6.5 active 2.9 cytotoxic 13 agent for treatment of cervical cancer; however, the duration of response is disappointing 5,6 JGOG-0505 (2015) Supports cisplatin-topotecan label Some argue that OS in the cisplatin-control arm was low due to high radiotherapy-cisplatin use Cisplatin/paclitaxel has shown preferential trends in response rate, PFS, and OS, and Cisplatin has + paclitaxel a preferred 12.9 toxicity profile 5.8 to 29cisplatin/topotecan 5,6 Cisplatin + topotecan Cisplatin + vinorelbine Study consolidated cisplatin-paclitaxel as SoC Carboplatin/paclitaxel is an alternative to cisplatin/paclitaxel, 5 with Cisplatin + gemcitabine similar efficacy and better tolerability in a study of Japanese patients 4 No other combination was better Cisplatin + paclitaxel n/a Carboplatin-paclitaxel was non-inferior to cisplatin-paclitaxel in overall population Carboplatin + paclitaxel n/a RR, response rate; OS, overall survival; PFS, progression-free survival; RR, response rate; SoC, standard of care For patients who had not received prior platinum, OS was better with cisplatinpaclitaxel Longer OS vs other studies may be related to patients studied (Japanese) 1. Moore DH et al. J Clin Oncol. 2004;22(15): Long HJ 3 rd, et al. J Clin Oncol. 2005;23(21): Monk BJ, et al. J Clin Oncol. 2009;27(28): Kitagawa R, et al. J Clin Oncol. 2015;33(19): NCCN Clinical Practice Guidelines in Oncology : Cervical Cancer. V Accessed October 17, Colombo N, et al. Ann Oncol. 2012;23 Suppl 7:vII27-32.

39 Angiogenesis in Cervical Cancer Accumulating evidence supports the concept that angiogenesis plays a central role in cervical carcinogenesis and disease progression Atypical vessels on colposcopy CD31 Intratumoural microvessel density Tewari and Monk. Invasive cervical cancer. In: DiSaia PJ, Creasman WT, eds. Clinical Gynecologic Oncology. 8th ed. Philadelphia, PA, Mosby: 2012.

40 GOG 240 Hypothesis Mechanistic tumor hypoxia and viral oncogenes drive angiogenesis HPV E6 p53 degradation TSP-1 VEGF angiogenesis Anti-VEGF therapy HPV E7 Displacement of HDAC1, HDAC4, HDAC7 prb inactivation HIF1α p21-rb pathway dysregulation Bevacizumab activity in cervical cancer was demonstrated in a phase II single-agent study (GOG 227C) HDAC, histone deacetylase; HIF1α, hypoxia-inducible factor 1-alpha; HPV, human papilloma virus; prb, retinoblastoma protein; TSP1, thrombospondin 1; VEGF, vascular endothelial growth factor Tewari KS, et al. Gyneol Oncol. 2000;77(1): Monk BJ, et al. J Clin Oncol. 2009;27(7):

41 GOG 240: Schema Carcinoma of the cervix Primary stage IVB Recurrent/persistent Measureable disease GOG PS 0 1 No prior chemotherapy for recurrence (N = 452) Stratification factors: Stage IVB vs recurrent/ persistent disease PS Prior cisplatin Rx as radiation sensitizer Activated: 4/6/09 Closed to accrual: 1/3/12 United States, Canada, & Spain R A N D O M I Z E 1:1:1:1 III I Paclitaxel 135 or 175 mg/m2 IV Cisplatin 50 mg/m 2 IV II I V Paclitaxel 135 or 175 mg/m 2 IV Cisplatin 50 mg/m 2 IV Bevacizumab 15 mg/kg IV Paclitaxel 175 mg/m 2 IV Topotecan 0.75 mg/m 2 d1-3 Paclitaxel 175 mg/m 2 IV Topotecan 0.75 mg/m 2 d1-3 Bevacizumab 15 mg/kg IV Chemo alone q21d Rx to PD, toxicity, CR Chemo + bev Bev, bevacizumab; CR, complete response; IV, intravenous; PD, progressive disease; PS, performance status; q21d, every 21 days; Rx, treatment Tewari KS, et al. N Engl J Med. 2014;370(8):

42 GOG-0240: Interim Analysis of Efficacy At data cut-off of 6 February 2012, interim analysis demonstrated that topotecan/paclitaxel was not superior or inferior to the standard therapy of cisplatin/paclitaxel (median follow-up 12.5 months) Overall Survival Progression-Free Survival CI, confidence interval; HR, hazard ratio; PFS, progression-free survival; OS, overall survival Tewari KS, et al. N Engl J Med. 2014;370(8):

43 GOG-0240: Interim Analysis of Efficacy At data cut-off of 6 February 2012, interim analysis demonstrated that topotecan/paclitaxel was not superior or inferior to the standard therapy of cisplatin/paclitaxel (median follow-up 12.5 months) Overall Survival Progression-Free Survival Selection of cisplatin/paclitaxel or topotecan/paclitaxel should be determined by toxicity screening/assessment CI, confidence interval; HR, hazard ratio; PFS, progression-free survival; OS, overall survival Tewari KS, et al. N Engl J Med. 2014;370(8):

44 GOG-0240: Primary Analysis of Efficacy At data cut-off of 12 December 2012, median OS and PFS were both significantly improved in patients who received bevacizumab-based therapy in both chemotherapy backbone groups vs chemotherapy alone (median follow-up 20.8 months) Overall Survival Progression-Free Survival Tewari KS, et al. N Engl J Med. 2014;370(8):

45 GOG-0240: Primary Analysis of Efficacy At data cut-off of 12 December 2012, median OS and PFS were both significantly improved in patients who received bevacizumab-based therapy in both chemotherapy backbone groups vs chemotherapy alone (median follow-up 20.8 months) Overall Survival Progression-Free Survival Response rates were also significantly improved in patients who received bevacizumab-based therapy (48% vs 36%; relative probability of response 1.35 [95% CI, ; P =.008]) Tewari KS, et al. N Engl J Med. 2014;370(8):

46 Probability of OS GOG-0240: Final OS Analysis (ESMO 2014) At data cut-off of 7 March 2014, updated OS analysis demonstrated the sustained clinically meaningful survival benefit of bevacizumab-based therapy (maximum follow-up 50 months) Chemotherapy n = 225 Events, n (%) 178 (79) Median OS, months 13.3 Chemotherapy + Bev n = (75) 16.8 HR = (95% CI, ) P =.0068 Regulatory approvals FDA (August 2014) EMA (April 2015) Months Since Randomization Treatment guidelines Category 1 recommendation in NCCN 2015 guideline Tewari KS, et al. N Engl J Med. 2014;370(8):

47 GOG-0240: Updated GOG Safety Analysis (ESMO 2014; data cut-off 7 March 2014) AE, n (%) Chemotherapy n = 220 Chemotherapy + Bev n = 220 Treatment cycles, median (range) 6 (1 50) 7 (1 40) Grade 5 AE(s) 3 (1.3) 7 (3.2) GI events, Nonfistulae (grade 2) 97 (44) 115 (53) GI perforation (grade 2) 0 5 (2.3) GI fistula (grade 2) 1 (0.5) 11 (5) GU fistula (grade 2) 1 (0.5) 8 (3.6) Hypertension (grade 2) 4 (1.8) 55 (25) Proteinuria (grade 3) 0 5 (2.3) Pain (grade 2) 63 (29) 72 (33) Neutropenia (grade 4) 58 (26) 80 (36) Febrile neutropenia (grade 3) 12 (5.5) 12 (5.5) Thromboembolism (grade 3) 4 (1.8) 18 (8.2) Bleeding CNS (any grade) 0 0 GI (grade 3) 1 (0.5) 4 (1.8) GU (grade 3) 1 (0.5) 6 (2.7) Grade 2 fistulae occurred in 8.6% of bevacizumab-treated patients (all of whom had received prior radiotherapy); grade 2 GI perforation occurred in 2.3% of bevacizumab-treated patients AE, adverse event; CNS, central nervous system; GI, gastrointestinal; GU, genitourinary Tewari KS, et al. Ann Oncol. 2014;25(Suppl 4): Abstract LBA26.

48 Immunotherapy: The Next Frontier Tumor Eskander RN, et al. Clin Ther. 2015;37(1):20-38.

49 Listeria As an Antigen Vector Lm Technology stimulates a tumor-targeted immune response directed by plasmids...so that cancer can be recognized...and killed Attenuated Lm trigger a robust immune response, and bioengineered plasmids generate a fusion protein, tllo-taa TAA activates cytotoxic T cells targeted against the tumor T cells target TAA on tumor cells and tllo inhibits Treg and MDSC in the TME, reducing the tumor s protective shield APC, antigen presenting cell; Lm, Listeria monocytogenes; MHC, major histocompatibility complex; TCR, T-cell receptor; MDSC, myeloid-derived suppressor cells; TAA, tumorassociated antigen; tllo, truncated listeriolysin O; Treg, regulatory T cell; TME, tumor microenvironment

50 NRG-0265: OS Data at 12 Months GOG-0265 OS at 12 Months, % Stage 1 (n = 26) 38.5 Stage 2 (n = 24*) 37.5 Combined (n = 50) 38 Expected outcome based on prognostic factors of enrolled patients (if untreated) 25 Based on protocol-defined prognostic factors of patients who enrolled in the study (n = 50) A 12-month OS rate of 25% would have been expected Comparing this 25% 12-month OS rate with the 38% 12-month OS rate actually observed across the total study population shows a 52% improvement Safety (Stage 2) 15 of 24 patients experienced grade 1 or grade 2 TRAE; most common were hypotension and symptoms related to cytokine release (nausea, chills, fever) 9 of 24 patients experienced grade 3 TRAEs, and 2 of 24 patients experienced grade 4 TRAEs, which were hypotension and symptoms related to cytokine release Based on these data, a global trial with or without nivolumab versus standard of care is about to start TRAE, treatment-related adverse event *These data represent stage 2 results; stage 2 enrolled 24 of planned 37 patients prior to the clinical hold. On October 24, 2016, early closure was announced for stage 2, which is no longer enrolling. Huh W, et al. Gynecol Oncol. 2017;145(Suppl 1): Abstract LBA3.

51 Tisotumab Vedotin Mechanism of Action Tisotumab vedotin is an antibodydrug conjugate (ADC) composed of a human mab specific for tissue factor (TF), a protease-cleavable linker, and the microtubule-disrupting agent MMAE 1,a TF is a transmembrane protein that is the main physiologic initiator of coagulation and is involved in angiogenesis, cell adhesion, motility, and cell survival 3 Mechanism of action 1,2 1. Binding to TF 2. Internalization of tisotumab vedotin 3. Intracellular trafficking to the lysosomes 4. Enzymatic degradation of tisotumab vedotin, intracellular release of MMAE TF is aberrantly expressed in a broad range of solid tumors, including cervical cancer, and is associated with poor prognosis 4,5 5. MMAE induces cell death by microtubule disruption 6. Release of MMAE in tumour microenvironment induces bystander killing of neighbouring cancer cells MMAE, monomethyl auristatin E a Tissue factor is known as TF, CD142, and thromboplastin. 1. Breij EC et al. Cancer Res. 2014;74(4): De Goeij BE et al. Mol Cancer Ther. 2015;14(5): Chu AJ. Int J Inflam. 2011;2011: Förster Y et al. Clin Chim Acta. 2006;364(1-2): Cocco E et al. BMC Cancer. 2011;11:263.

52 Best Percent Change From Baseline, % 32% of Patients With Recurrent/Advanced Cervical Cancer Achieved Response With Tisotumab Vedotin N = 34 a b b b b Change at first scan Maximum reduction Confirmed response PR 50% (17 of 34 patients; 95% CI, 35%-65%) achieved clinical benefit after 12 weeks (DCR) c,d 32% (11 of 34 patients; 95% CI, 17%-50%) achieved response (ORR) d 8 PR, confirmed 3 PR, unconfirmed e CI, confidence interval; CT, computed tomography; DCR, disease control rate; ORR, overall response rate; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease. a Two patients were withdrawn prior to CT scan, and so are not represented in the graph. b PD due to new lesion at same scan. c Clinical benefit was defined as the DCR rate, the proportion of patients who achieved a CR, PR, or SD after 12 weeks. d Response was as assessed by investigators using standard RECIST 1.1 criteria. e One of which is still ongoing. Data cutoff date July 24, Unpublished data

53 HPV-Targeted Tumor-Infiltrating Lymphocytes (HPV-TIL)

54 HPV-Targeted Tumor-Infiltrating Lymphocytes Objective tumor responses in 3/9 patients 1 PR (3 months), 2 CR (22+ months and 15+ months) HPV-reactive infused T cells in 6/8 patients 3/6 patients with reactivity had responses 0/2 patients without reactivity had responses Repopulation of peripheral blood with HPV-reactive T cells in 2/4 patients 2/2 with repopulation had tumor responses 0/2 without repopulation had tumor responses Stevanović S, et al. J Clin Oncol. 2015;33(14):

55 KEYNOTE-028 (NCT ): Phase Ib Multicohort Study of Pembrolizumab for PD-L1 Positive Advanced Solid Tumors Patients Unresectable or metastastic cervical cancer Failure of or inability to receive standard therapy ECOG PS 0 or 1 Measureable disease (RECIST v1.1) PD-L1-positive Pembrolizumab 10 mg/kg IV q2w Response Assessment Complete response, partial response, or stable disease Confirmed progressive disease or unacceptable toxicity Treat for 24 months, or until progression or intolerable toxicity Discontinue pembrolizumab Response assessment: Every 8 weeks for the first 6 months; every 12 weeks thereafter Primary endpoints: ORR per RECIST v1.1 and safety Secondary endpoints: PFS, OS, duration or response Frenel JS, et al. J Clin Oncol. 2016;34(suppl): Abstract 5515.

56 Cervical Cancer: Antitumor Activity (RECIST v1.1, Investigator Review) N = 24 n % 95% CI ORR Partial response Stable disease Progressive disease No assessment 1 4 <1-21 Frenel JS, et al. J Clin Oncol. 2016;34(suppl): Abstract 5515.

57 An Open-label, Multicohort, Phase 1/2 Study of Nivolumab in Patients With Virus-Associated Tumors (CheckMate 358): Efficacy and Safety in Recurrent or Metastatic Cervical, Vaginal, and Vulvar Cancers Hollebecque A, et al. J Clin Oncol. 2016;35(suppl): Abstract 5504.

58 Best Reduction in Target Lesions CheckMate 358: Nivolumab Monotherapy in R/M Cervical, Vaginal, and Vulvar Cancers Best Reduction in Target Lesions<br />CheckMate 358: Nivolumab Monotherapy in R/M Cervical, Vaginal, and Vulvar Cancers Hollebecque A, et al. J Clin Oncol. 2016;35(suppl): Abstract 5504.

59 Overall Survival CheckMate 358: Nivolumab Monotherapy in R/M Cervical, Vaginal, and Vulvar Cancers Overall Survival<br />CheckMate 358: Nivolumab Monotherapy in R/M Cervical, Vaginal, and Vulvar Cancers Hollebecque A, et al. J Clin Oncol. 2016;35(suppl): Abstract 5504.

60 My Opinion I would complete staging with PET scan to assess lymph node status Since she is young, I would try to spare radiotherapy (acute and late side effects) : Dose-dense chemotherapy followed by surgery in case a good response (to avoid further radiotherapy) Chemoradiation if suboptimal response At time of relapse, I would use cisplatin-paclitaxel-bevacizumab In case of no response or further relapse: clinical trials of immunotherapy

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