Emerging Strategies in Triple-Negative Breast Cancer

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1 Expert Review in Immunotherapy in Breast Cancer Emerging Strategies in Triple-Negative Breast Cancer Reference Slide Deck

2 Is Breast Cancer Immunogenic? Recent proof that breast cancer may elicit an immune response: Presence of infiltrating immune cells and tumor infiltrating lymphocytes (TILs) in the tumor microenvironment Varies by subtype Immune infiltration most prevalent in triple-negative breast cancer (TNBC), followed by HER2-positive breast cancer Prognostic value of immunity-related gene signature Genetic instability leading to increased number of mutations, leading to more neoantigens Pusztai L, et al. Clin Cancer Res. 2016;22(9):

3 Mutation Rate is Higher in TNBC Than in Other Subtypes Modified from Banerji S, et al. Nature. 2012;486(7403): Schmid P, et al. Ann Oncol. 2016;27(Suppl 6): Abstract 309TiP.

4 Higher Levels of Tumor Infiltrating Lymphocytes (TILs) in Triple-Negative Breast Cancer (TNBC) and HER2-Positive Subtypes Loi S, et al. J Clin Oncol. 2013;31(7): Loi S, et al. Ann Oncol. 2014;25(8):

5 TNBC Is Particularly Attractive for Cancer Immunotherapy Higher density of TILs than tumors with lower proliferative rate Relatively high mutational burden that can produce neoantigens leading to an immune response Higher rates of PD-L1 expression, which can inhibit T-cell antitumor responses Loi S, et al. Ann Onc. 2014;25(8): Mittendorf EA, et al. Cancer Immunol Res. 2014;2(4): Lehman BD, et al. J Clin Invest. 2011;121(7): Cimino-Mathews A, et al. Hum Pathol. 2016;47(1):52-63.

6 TILs Are Associated With Prognosis in Triple-Negative Breast Cancer [0% to 1%] [2% to 10%] [11% to 40%] [41% to 80%] stil, stromal tumor infiltrating lymphocytes Adams S, et al. J Clin Oncol. 2014;32(27):

7 Higher Expression of PD-L1 in TNBC PD-L1 expression of 26.4% by IHC in a mixed cohort of TNBC patients (n = 193) Role of PD-L1 as a biomarker is unclear in breast cancer Tung N, et al. NPJ Breast Cancer. 2016;2:16002.

8 Heterogeneity of TNBC and Immunotherapy Strategies Modified from Burstein MD, et al. Clin Cancer Res. 2015;21(7): Schmid P, et al. Ann Oncol. 2016;27(Suppl 6): Abstract 309TiP.

9 PD-1/PD-L1 Checkpoint Inhibitors May Restore Tumor-Specific T-Cell Immunity Modified from Drake CG, et al. Nat Rev Clin Oncol. 2014;11(1):24-37.

10 Phase Ib KEYNOTE-012: Pembrolizumab in Advanced TNBC 111 patients with TNBC were screened; 58.6% had PD-L1 positive tumors Heavily pretreated: 25% had 5 systemic therapies for metastatic disease, 49.6% with at least 3 prior therapies, median: 2 prior therapies Response assessment: Performed every 8 weeks per RECIST 1.1 CR, complete response; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria In Solid Tumors; SD, stable disease Nanda R, et al. J Clin Oncol. 2016;34(21):

11 KEYNOTE-012: Efficacy Efficacy (N = 27) ORR 18.5% Stable disease 25.9% Median duration of response Median PFS NR (15.0 to 47.3 weeks) 1.9 months 6-month PFS 24.4% Median OS 12-month OS 43.1% 11.2 months ORR, overall response rate; OS, overall survival PFS, progressive-free survival Nanda R, et al. J Clin Oncol. 2016;34(21):

12 KEYNOTE-012: Toxicity Adverse Events in 5%, % N = 32 Any Grade (%) Grade 3-5 Arthralgia Fatigue Myalgia Nausea Diarrhea AST increased ALT increased Erythema Headache (1 patient) Grade 3 events (n = 1 for all): Anemia, aseptic meningitis, headache, lymphopenia, pyrexia Grade 5 event (n = 1): Disseminated intravascular coagulation Possible immune-related AEs (n = 1 for each): grade 3 colitis, grade 3 hepatitis, grade 2 hypothyroidism Nanda R, et al. J Clin Oncol. 2016;34(21):

13 Phase Ia Study of the Anti-PD-L1 Antibody Atezolizumab in Solid Tumors Phase Ia Expansion Ongoing Atezolizumab doses: IV q3w 15 mg/kg, 20 mg/kg, or 1200 mg Key eligibility criteria: Measurable disease per RECIST v1.1 and ECOG PS 0 or 1 TNBC cohort objective: To explore the safety, efficacy, and biomarkers of atezolizumab in women with metastatic TNBC in an ongoing phase Ia trial in solid tumors The TNBC cohort originally enrolled PD-L1-selected patients, then all comers PD-L1 expression was centrally evaluated on tumor-infiltrating immune cells (ICs) based on an immunohistochemistry (IHC) assay using a proprietary assay Emens LA, et al. Presented at: 2015 American Association of Cancer Research Annual Meeting; April 18-22, 2015: Philadelphia, Pennsylvania.

14 Atezolizumab: Clinical Activity in PD-L1-Selected Patients With TNBC ORR of 19% (n = 21) PFS rate at 24 weeks (n = 21): 27% 2 CRs and 2 PRs, with 3 of 4 responses ongoing and 3 pseudoprogressors PD-L1 expression was assessed on tumor-infiltrating immune cells IHC Investigator-assessed confirmed ORRs per RECIST v1.1. Efficacy population includes patients dosed by July 21, 2014; clinical data cutoff, December 2, New lesions at consecutive visits for the same patient might be the same lesion. PD-L1 positivity was defined as IHC 3 ( 10% of ICs PD-L1 positive) or IHC 2 ( 5% but <10% of ICs PD-L1 positive); 23% of screened patients were PD-L1 positive Emens LA, et al. Presented at: 2015 American Association of Cancer Research Annual Meeting; April 18-22, 2015: Philadelphia, Pennsylvania.

15 Atezolizumab: Treatment-Related Adverse Events (AEs) Safety evaluable population (N = 54) with TNBC in phase Ia expansion Median duration of treatment was 6 weeks (range, 0 to 85 weeks) 63% of patients experienced a treatmentrelated AEs, of which most were grade 2 11% of patients experienced a treatmentrelated grade 3 AEs One case of grade 4 pneumonitis Two deaths, assessed as related by the investigator, currently under investigation a Additional grade 3 AEs include: dyspnea, adrenal insufficiency, decreased white blood cell count, hypokalemia, and lichen planus (1 patient each) Treatment-Related Adverse Event All-Grade in 3 Patients n (%) Grade 3-4 n (%) a Fatigue 8 (15%) 0 Nausea 8 (15%) 1 (2%) Pyrexia 8 (15%) 0 Asthenia 6 (11%) 0 Decreased appetite 6 (11%) 0 Diarrhea 5 (9%) 0 Headache 4 (7%) 0 Pruritus 4 (7%) 0 Vomiting 4 (7%) 1 (2%) Anemia 3 (6%) 1 (2%) Influenza-like illness 3 (6%) 0 Neutropenia 3 (6%) 1 (2%) Pain 3 (6%) 0 Rash 3 (6%) 0 Emens LA, et al. Presented at: 2015 American Association of Cancer Research Annual Meeting; April 18-22, 2015: Philadelphia, Pennsylvania.

16 JAVELIN: Phase I Study of PD-L1 Antibody Avelumab in Metastatic Breast Cancer (MBC) Patients Histologically confirmed locally advanced or MBC refractory to or progressing after standard-of-care therapy 3 prior lines of cytotoxic therapy* Must have received prior treatment with taxane or anthracycline Biopsy or surgical specimen collected within 90 days prior to first administration of avelumab Unselected for PD-L1 expression or for HER2/ER/PR molecular subtype ECOG PS 0-1 and estimated life expectancy of >3 months Dosing Avelumab 10 mg/kg IV Q2W until progression Select assessments Safety and tolerability BOR by RECIST 1.1 PD-L1 expression status by IHC at various cut offs * Excluding systemic therapy that was not considered cytotoxic Patients must have received prior treatment with taxane and anthracycline (any therapeutic setting), unless contraindicated Dirix L, et al. Cancer Res. 2015;75(9 Suppl): Abstract S1-S9.

17 Avelumab: Activity in Nonselected TNBC Patients ORR breast cancer = 4.8% ORR TNBC = 8.6% ORR PD-L1+ TNBC = 33.3% Dirix L, et al. Cancer Res. 2015;75(9 Suppl): Abstract S1-S9.

18 Patients experiencing event (n = 168) JAVELIN: Most Common Treatment-Related AEs Most common treatmentrelated TEAEs, any grade, n (%)* Treatment-related TEAEs, grade 3, n (%) Any treatment-related event 115 (68.5) 23 (13.7) Fatigue 32 (19.0) 3 (1.8) Infusion-related reactions 24 (14.3) 0 Nausea 22 (13.1) 0 Diarrhea 15 (8.9) 0 Arthralgia 13 (7.7) 1 (0.6) Decreased appetite 12 (7.1) 0 Influenza-like illness 11 (6.5) 0 GGT increase 4 (2.4) 3 (1.8) Autoimmune hepatitis 3 (1.8) 3 (1.8) Anemia 3 (1.8) 3 (1.8) GGT, gamma-glutamyl transferase; TEAEs, treatment-emergent adverse event *Based on incidence criteria of >5% for most common treatment-related TEAEs Based on incidence criteria of >1% for any grade 3 treatment-related TEAE Dirix L, et al. Cancer Res. 2015;75(9 Suppl): Abstract S1-S9.

19 How to Enhance Immunogenicity?

20 Combination Therapy May Widen the Target Population and Increase Efficacy Chemotherapy + immunotherapy Immunotherapy + novel targeted agents Immunotherapy combination Adapted from Ribas A, et al. Clin Cancer Res. 2012;18(2): Schmid P, et al. Ann Oncol. 2016;27(Suppl 6): Abstract 309TiP.

21 The Combination of Immune Checkpoint Inhibitors and Chemotherapy May Be Synergistic Preclinical data showing synergistic activity between nab-paclitaxel and anti-pd-l1 Treatment with platinum agents or taxanes increased the percentage of CD8+ TILs in immunocompetent mouse models Adams S, et al. Presented at: 2015 San Antonio Breast Cancer Symposium; December ; San Antonio, Texas. Abstract P

22 Why Use Nab-Paclitaxel in Combination With Immunotherapy? Nab-paclitaxel is approved chemotherapy for metastatic breast cancer, including TNBC Does not require premedication with steroids, which cause immunosuppression Preclinical models have shown synergy between atezolizumab and nab-paclitaxel Adams S, et al. Presented at: 2015 San Antonio Breast Cancer Symposium; December ; San Antonio, Texas. Abstract P

23 Atezolizumab + Nab-Paclitaxel in Metastatic TNBC: Phase Ib Study Design GP28328: a multicenter, multicohort phase Ib study Atezolizumab (800 mg) + nabpaclitaxel (125 mg/m 2 ), as long as clinical benefit received Primary endpoint: Safety and tolerability Secondary endpoints: Response per RECIST v1.1 (ORR, duration of response [DoR], PFS) and immune-modified response criteria; pharmacokinetics; biomarker analyses Adams S, et al. Presented at: 2015 San Antonio Breast Cancer Symposium; December ; San Antonio, Texas. Abstract P Adams S, et al. J Clin Oncol. 2016;34(suppl): Abstract Nab-paclitaxel for at least 4 cycles, unless disease progression or unacceptable toxicity; if discontinued, atezolizumab as monotherapy

24 Atezolizumab + Nab-Paclitaxel in mtnbc: Safety and Tolerability (Primary Endpoint) Median safety follow-up: 6.1 months (range: ) Median duration of exposure: 5.4 months (range: 0-17) for atezolizumab; 4.2 months (range: 0-12) for nab-paclitaxel No reported deaths were related to study treatment Treatment-Related AEs (Grade 3/4 AEs occurring in 1% of patients), % Patients (N = 32) All Grades Grade 3 All Neutropenia/decreased neutrophil count Thrombocytopenia and decreased platelet count 16 9 Diarrhea 41 6 Anemia 22 6 Decreased white blood cell count 9 6 Adams S, et al. J Clin Oncol. 2016;34(suppl): Abstract 1009.

25 Atezolizumab + Nab-Paclitaxel in Metastatic TNBC: Updated Efficacy Best Overall Response (RECIST v1.1) First Line (n = 13) Second Line (n = 9) Third Line+ (n = 10) All (N = 32) Confirmed ORR, % CR, % PR, % SD, % PD, % Missing or not estimable, % Median DoR, months (range) NE (2.9 to 11.5+) NE (9.1 to 13.1+) NE (1.9+ to 5.6+) Among 12 responders, 6 (50%) remain on atezolizumab; 1 for >17 months Median DoR not reached; PFS and OS data not yet mature Responses observed in patients regardless of PD-L1 expression level; trend toward increase in baseline TILs for responding patients Adams S, et al. J Clin Oncol. 2016;34(suppl): Abstract 1009.

26 IMpassion 130: Nab-Paclitaxel ± Atezolizumab First-Line in Metastatic TNBC Randomized phase III Patients with metastatic or unresectable locally advanced TNBC (N = 900) Stratification Presence of liver metastases Prior taxane treatment Tumor PD-L1 status (IC0 or IC1/2/3) R A N D O M I Z E D 1:1 Atezolizumab 840 mg q2wk + nab-paclitaxel 100 mg/m 2 qwk 3/4 weeks Placebo q2wk + nab-paclitaxel 100 mg/m 2 qwk 3/4 weeks Co-primary endpoints: Progression-free survival (RECIST 1.1), overall survival Secondary endpoints: ORR, DOR, time to deterioration in global health status/hrqol, percentage of patients with AEs National Institutes of Health. Available at: Accessed: November 4, 2016.

27 Select Randomized Trials With Immune Checkpoint Inhibitors in Metastatic TNBC Study Treatment Setting Phase Status Patients Estimated Completion Atezolizumab IMpassion130 NCT nab-paclitaxel ± atezolizumab Metastatic 3 Recruiting 900 April 2020 NCT Nivolumab TONIC NCT Pembrolizumab KEYNOTE-119 NCT atezolizumab or veliparib alone or in combination Nivolumab with radiation therapy or chemo after induction treatment Pembrolizumab vs TPC chemo (capecitabine, eribulin, gemcitabine, or vinorelbine) Stage III-IV 2 Recruiting 90 August 2018 Metastatic 2 Recruiting 84 August 2022 Metastatic 3 Recruiting 600 November 2017 KEYNOTE-355 NCT Chemo ± pembrolizumab Metastatic 3 Recruiting 858 December 2019 NCT Carbo/gem ± pembrolizumab Metastatic 2 Recruiting 87 June 2019 NCT Pembro Metastatic 2 Recruiting 245 November 2019 TPC, trastuzumab, paclitaxel, carboplatin National Institutes of Health. Available at: Accessed: November 4, 2016.

28 Select Randomized Neoadjuvant Trials With Immune Checkpoint Inhibitors in TNBC Study Treatment Setting Phase Status Patients Estimated Completion Atezolizumab NeoTRIPaPDL1 NCT Durvalumab GeparNuevo NCT Carbo + nab-paclitaxel ± atezolizumab followed by adjuvant AC/EC/FEC nab-paclitaxel + EC ± durvalumab Neoadjuvant 3 Recruiting 272 October 2022 Neoadjuvant 2 Recruiting 174 March 2018 AC, doxorubicin and cyclophosphamide; EC, epirubicin, and cyclophosphamide; FEC, fluorouracil, epirubicin, and cyclophosphamide National Institutes of Health. Available at: Accessed: November 4, 2016.

29 Neoadjuvant Phase III NeoTRIPaPDL1: Carboplatin + Nab-Paclitaxel ± Atezolizumab N = 272 Primary endpoint: Event-free survival Secondary endpoint: pcr (ypt0 yptis ypn0 National Institutes of Health. Available at: Accessed: November 4, 2016.

30 Randomized Phase II GeparNuevo Trial: Durvalumab + Nab-Paclitaxel 2 weeks 2 weeks 8 weeks 174 Clinical Response SURGERY Biopsy Biopsy Biopsy Primary endpoint: pcr e National Institutes of Health. Available at: Accessed: November 4, 2016.

31 Strategies for Inflamed and Noninflamed Tumors eg, eg, eg, Schmid P, et al. Ann Oncol. 2016;27(Suppl 6): Abstract 309TiP.

32 Clinical Trial Endpoints for Immunotherapy Trials

33 Challenges and Recommendations for Assessment of Cancer Immunotherapy Hoos A, et al. J Natl Cancer Inst. 2010;102(18):

34 PFS May Not Accurately Reflect Immunotherapy Benefits Study Design N PFS HR (95% CI) P Value POPLAR 1 CHECKMATE CHECKMATE Randomized phase II atezolizumab vs docetaxel for non-small cell lung cancer Phase III nivolumab vs docetaxel for non-small cell lung cancer Phase III nivolumab vs everolimus for 2 nd- and 3 rd -line renal cell carcinoma (0.72, 1.23) NS (0.77, 1.11) P = (0.75, 1.03) P =.11 OS HR (95% CI) P Value 0.73 (0.53, 0.99) P = (0.59, 0.89) P = (0.57, 0.93) P =.002 Pseudoprogression obscures sustained clinical benefit in some patients 1. Vansteenkiste J, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract LBA Borghaei H, et al. N Engl J Med. 2015;373(17): Motzer RJ, et al. N Engl J Med. 2015;373(19):

35 Pseudoprogression Pseudoprogression with subsequent durable response on atezolizumab in TNBC West HJ. JAMA Oncol. 2015;1(1):115. Emens LA, et al. Presented at: 2015 American Association of Cancer Research Annual Meeting; April 18-22, 2015: Philadelphia, Pennsylvania.

36 Immunotherapy: Atypical Patterns of Response Four patterns of tumor response to immunotherapy have been described: Regression of the initial lesions without appearance of new lesions Unchanged tumor burden, but followed by a slow, continuous regression of the overall tumor burden in some patients Regression of initial lesions associated with the appearance of new lesions Regression of lesions after an initial increase of the overall tumor burden (flare) Initial response Initial of T volume then response Stable disease New lesions then response Wolchok JD, et al. Clin Cancer Res. 2009;15(23):

37 Evaluation of Response to Immunotherapy: Immune Related Response Criteria Differ From RECIST New, measurable lesions (ie, 5 5 mm) New, nonmeasurable lesions (ie, <5 5 mm) Nonindex lesions CR PR SD PD irrc, immune related response criteria Always represent PD Always represent PD RECIST 1 irrc 2 Changes contribute to defining best overall response of CR, PR, SD, and PD Disappearance of all lesions in one observation in randomized studies. Confirmation is needed for nonrandomized studies, according to study protocol At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, in the absence of new lesions or unequivocal progression of nonindex lesions Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters, in absence of new lesions or unequivocal progression of nonindex lesions At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. The sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression Incorporated into tumor burden Do not define progression (but preclude irrc) Contribute to defining irrc (complete disappearance required) Disappearance of all lesions in two consecutive observations not less than four weeks apart A 50% decrease in tumor burden compared with baseline in two observations at least four weeks apart A 50% decrease in tumor burden compared with baseline cannot be established nor 25% increase compared with nadir At least 25% increase in tumor burden compared with nadir (at any single time point) in two consecutive observations at least four weeks apart 1. Eisenhauer EA, et al. Eur J Cancer. 2009;45(2): Wolchok JD, et al. Clin Cancer Res. 2009;15(23):

38 Subsets of breast cancer can be immunogenic, particularly the triple-negative and HER2-positive subtypes TNBC is an attractive subtype for the use of immunotherapy High number of TILs High mutational burden Higher rates of PD-L1 expression Encouraging results from early trials of immunotherapy in TNBC Chemotherapy (eg, taxanes and platinum) can augment the efficacy of immunotherapy The future is in combination immunotherapies, strategically integrating vaccines and immune checkpoint modulators with standard breast cancer treatments, and other immune modulators