Biomarker Dilemma Persists With Immunotherapy in Bladder Cancer

Kathryn E. Beckermann, MD, PhD

Kathryn E. Beckermann, MD, PhD

Nancy B. Davis, MD

Nancy B. Davis, MD

Group Leader, Urology Oncology

Assistant Professor of Medicine

Division of Hematology/Oncology

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee

In metastatic bladder cancer, cytotoxic chemotherapy using a cisplatin backbone has long been the standard of care. First-line therapy using a dose-dense chemotherapy combination of methotrexate, vinblastine, doxorubicin, and cisplatin, along with granulocyte colong-stimulating factor, has resulted in progression-free survival (PFS) of 9 months and median overall survival (mOS) of approximately 15 months.¹ In the second-line setting, treatment with single-agent chemotherapy has yielded abysmal results, with objective response rates (ORRs) of 10% to 20% and PFS of 2 to 3 months, demonstrating the desperate need for more effective treatment options.²

Table. Checkpoint Inhibitor Clinical Trials and Results With Associated Biomarker Studies^3-9

Findings With PD-L1 Inhibitors

Blocking either PD-1, the negative regulatory surface receptor on T cells, or its ligand PD-L1, found on normal, cancerous, and immune cells, has been shown to relieve the immune escape mechanism cancer cells employ. In just 1 year, the FDA approved 5 monoclonal antibodies targeting the PD-1 or PD-L1 immune checkpoint pathways for the secondline treatment of metastatic bladder cancer. Pembrolizumab (Keytruda) and nivolumab (Opdivo) block PD-1 while atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi) block PD-L1. Additionally, pembrolizumab and atezolizumab are approved for first-line use in patients who are ineligible to receive cisplatin. The FDA granted several of these therapies accelerated approval, and now it is the clinician’s role to thoughtfully discern which agent to use (Table^3-9).Atezolizumab was granted accelerated access based on phase II trial results compared with historical controls in the second-line setting, with an ORR of 14.8% and a mOS of 7.9 months. Corresponding use of the Ventana SP142 PD-L1 assay suggested an improved ORR, 9.5% versus 26%, using an under or over 5% cutoff of PD-L1 expression, respectively, measured only on tumor-infiltrating immune cells.3 In a follow-up phase III trial that enrolled 931 patients, atezolizumab failed to meet its primary endpoint of improved OS compared with chemotherapy in patients with >5% PD-L1 expression in the immune infiltrating cells. The mOS was 11.1 versus 10.6 months, and there were similar ORRs of 23% and 22% for atezolizumab compared with chemotherapy, respectively.⁴ An exploratory analysis of the intention-to-treat population suggested a higher median duration of response with immunotherapy. After a median follow-up of 17.3 months, ongoing responses were observed in 63% of those who responded to atezolizumab therapy compared with 21% who responded to chemotherapy.

The phase Ib trial testing avelumab enrolled 249 patients and demonstrated a 17% ORR among 161 evaluable patients with at least 6 months of follow-up. When responses were evaluated using the Dako assay with the 73-10 antibody, the ORRs were 24% for participants with ≥5% PD-L1 expression on tumor cells alone versus 13% for those with negative PD-L1 expression.⁵

Trial Results With PD-1 Inhibitors

PD-L1 Expression as a Biomarker

Durvalumab received approval after a phase I/II trial in 191 patients resulted in a 17.8% ORR. When assessed using the Ventana PD-L1 assay and SP263 antibody measuring combined tumor and immune cells high PD-L1 cutoff at >25%, the ORR was 27.6% compared with 5.1% in PD-L1 negative patients.6 The Ventana SP263 assay was granted FDA approval as a complementary diagnostic. Although a positive test result is not required to use durvalumab in metastatic bladder cancer, it may provide information regarding the likelihood of response for a patient.In clinical trials studying PD-1 blockade, the results of a randomized phase III trial in the second-line setting showed an ORR of 21.1% for pembrolizumab versus 11.4% for investigator’s choice of chemotherapy. The study met its primary endpoint, with an improved mOS of 10.3 months for pembrolizumab compared with 7.4 months for chemotherapy, regardless of PD-L1 status (HR, 0.73; P = .002).7 The companion study in this trial used the Dako PD-L1 assay, with the 22C3 antibody assessing a 10% cutoff of PD-L1 expression on combined tumor and infiltrating immune cells that did not show a higher ORR at 21.6% compared with the entire study population.7 The single-arm phase II trial evaluating nivolumab in metastatic bladder cancer found an ORR of 19.6% and revealed ORRs of 16.1%, 23.8%, and 28.4%, respectively, using the Dako PD-L1 assay with the 28-8 antibody evaluated at a <1%, >1%, and >5% PD-L1 expression on tumor cells only.⁸Although there can be some enrichment for response to therapy with PD-1/PD-L1 blockade in patients with high PD-L1 expression, PD-L1 as a single biomarker is fraught with problems. As demonstrated above, assays measuring PD-L1 vary widely in the antibody-detection method used, the chosen cutoff for positivity and the cells being evaluated for PD-L1 expression, whether tumor or immune cells or both. Comparison of 4 PD-L1 assays in lung cancer by 13 blinded pathologists showed that the highest concordance could be found scoring tumor cell PD-L1 expression, but only 3 of the 4 antibodies were reproducible.⁹

Evidence from studies in multiple tumor types now shows that prior therapies such as cytotoxic chemotherapy or radiation may alter PD-L1 expression.¹⁰ Further investigation is needed to understand if this correlates with response to checkpoint inhibitor therapy.^11,12 Similarly, if the pursuit of tissue for PD-L1 expression testing is guiding treatment decisions, we must be cognizant of PD-L1 heterogeneity within tumors, suggesting that a single fine-needle aspiration of primary or metastatic disease may not adequately portray PD-L1 expression for a patient.¹³

These challenges have led to a fast-paced research effort to better understand the biology behind responses to checkpoint inhibitor therapy. Exploratory endpoints in several of these trials have sought to find correlations between patterns of response and The Cancer Genome Atlas subtypes of bladder cancer, but the results have been inconsistent and varied among trials.^3,8,14 Tumor mutational burden suggestive of response to PD-1 and PD-L1 blockade classically described in melanoma and lung cancer is also thought to be true in bladder cancer.^15,16 Characterization of tumor-infiltrating lymphocytes using protein detection by flow cytometry panels and gene expression signatures, such as interferon gamma— related pathways, are being investigated as putative predictors of clinical response to PD-1 blockade.^17,18

The quest continues to identify a predictive biomarker of response to more precisely treat patients with checkpoint inhibitors that, while markedly beneficial to some patients, are not without their own costs and associated immune-related adverse effects.

References

1. Sternberg CN, de Mulder PH, Schornagel JH, et al; European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group. Randomized phase III trial of high—dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol No. 30924. J Clin Oncol. 2001;19(10):2638-2646. doi: 10.1200/JCO.2001.19.10.2638.
2. Chism DD. Urothelial carcinoma of the bladder and the rise of immunotherapy. J Natl Compr Canc Netw. 2017;15(10):1277-1284. doi: 10.6004/jnccn.2017.7036.
3. Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387(10031):1909-1920. doi: 10.1016/S0140-6736(16)00561-4.
4. Powles T, Durán I, van der Heijden MS, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018;391(10122):748-757. doi: 10.1016/S0140-6736(17)33297-X.
5. Patel MR, Ellerton J, Infante JR, et al. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol. 2018;19(1):51-64. doi: 10.1016/S1470-2045(17)30900-2.
6. Powles T, O’Donnell PH, Massard C, et al. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma; updated results from a phase 1/2 open-label study. JAMA Oncol. 2017;3(9):e172411. doi: 10.1001/jamaoncol.2017.2411.
7. Bellmunt J, de Wit R, Vaughn DJ, et al; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015-1026. doi: 10.1056/NEJMoa1613683.
8. Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017;18(3):312-322. doi: 10.1016/S1470-2045(17)30065-7.
9. Rimm DL, Han G, Taube JM, et al. A prospective, multi-institutional, pathologist-based assessment of 4 immunohistochemistry assays for PD-L1 expression in non-small cell lung cancer. JAMA Oncol. 2017;3(8):1051-1058. doi: 10.1001/jamaoncol.2017.0013.
10. Lim SH, Hong M, Ahn S, et al. Changes in tumour expression of programmed death-ligand 1 after neoadjuvant concurrent chemoradiotherapy in patients with squamous oesophageal cancer. Eur J Cancer. 2016;52:1-9. doi: 10.1016/j.ejca.2015.09.019.
11. Leduc C, Adam J, Louvet E, et al. TPF induction chemotherapy increases PD-L1 expression in tumour cells and immune cells in head and neck squamous cell carcinoma. ESMO Open. 2018;3(1):e000257. doi: 10.1136/esmoopen-2017-000257.
12. Pelekanou V, Carvajal-Hausdorf DE, Altan M, et al. Effect of neoadjuvant chemotherapy on tumor-infiltrating lymphocytes and PD-L1 expression in breast cancer and its clinical significance [erratum in Breast Cancer Res. 2017;19(1):109. doi: 10.1186/s13058-017-0898-2]. Breast Cancer Res. 2017;19(1):91. doi: 10.1186/s13058-017-0884-8.
13. Casadevall D, Clavé S, Taus Á, et al. Heterogeneity of tumor and immune cell PD-L1 expression and lymphocyte counts in surgical NSCLC samples. Clin Lung Cancer. 2017;18(6):682-691.e5. doi: 10.1016/j.cllc.2017.04.014.
14. The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014;507(7492):315-322. doi: 10.1038/nature12965.
15. Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124-128. doi: 10.1126/science.aaa1348.
16. Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med. 2017;377(25):2500-2501. doi: 10.1056/NEJMc1713444.
17. Ayers M, Lunceford J, Nebozhyn M, et al. IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest. 2017;127(8):2930-2940. doi: 10.1172/JCI91190.
18. Aggen DH, Drake CG. Biomarkers for immunotherapy in bladder cancer: a moving target. J Immunother Cancer. 2017;5(1):94. doi: 10.1186/s40425-017-0299-1.