What exactly is cancer immunotherapy?
The field of cancer immunotherapy covers multiple therapeutic approaches that may involve stimulation or enhancement of the immune system or blockage of immune inhibitory pathways. Immunotherapeutic modalities may include cancer vaccines, oncolytic viruses, adoptive transfer of ex-vivo activated T-cells and natural killer cells, and the administration of antibodies or recombinant proteins that block immune checkpoint pathways.
This post will focus on the immunotherapy checkpoint inhibitors that target PD-1 or PD-L1, a class of biologic agents for which the 2018 Nobel Prize in Physiology or Medicine was recently awarded to Drs. James P. Allison and Tasuko Honjo for their seminal discoveries. In cases where the metastatic tumor type is unclear, molecular-based tests can provide additional information to help resolve diagnostic ambiguity and make the patient eligible for one of the approved immunotherapy indications.
Clinical scenarios where molecular-based tests may be useful
The following diagram illustrates certain scenarios where a molecular tumor classifier test based on gene expression may prove useful in helping the physician determine the appropriate (i.e., potentially effective) immunotherapy or combination therapies.
Considerations for the use and interpretation of PD-L1 biomarker tests
While it seems intuitive that patients whose tumors express high levels of PD-L1 protein will be more likely respond to PD1 pathway blockage, several studies have been unable to correlate PD-L1 expression with response to PD-1/L1 targeted therapy.6-10 For example, PD-L1 expression on tumor cells did not correlate with clinical response to pembrolizumab8 or avelumab in advanced Merkel cell carcinoma9 or metastatic urothelial carcinoma treated with atezolizumab.7,10 In addition, objective response rate to the immunotherapy combination nivolumab plus ipilimumab was independent of PD-L1 expression in patients with metastatic melanoma.6 The lack of data establishing a strong correlation between objective response to different immunotherapies in multiple tumors with varying levels of PD-L1 expression suggests that PD-L1 protein expression may have limited clinical utility to select which patients should receive anti-PD1/PD-L1 therapy.11,12
A recent comparison of analytical performance of 4 immunohistochemistry-based assays to determine the levels of PD-L1 protein in lung tumors highlights the challenges of individual biomarker testing for selecting patients to receive PD1 blockade therapy. In a statistically-powered, multi-institutional study, 3 of 4 immunohistochemistry tests demonstrated concordant and reproducible assessment of tumor cell PD-L1 expression.13 While there are two FDA-cleared tests to measure PD-L1 expression, it should be noted that pembrolizumab treatment for first-line treatment NSCLC is the only indication that requires that tumors have high PD-L1 expression [tumor proportion score (TPS) ≥ 50%] as determined by the companion diagnostic IHC test. This serves to underline the major argument we put forward in our February 7 2017 blog, namely that biomarker status alone―without tumor context―does not always predict the efficacy or eligibility for treatment with targeted agents.
Additional information summarizing some of the pivotal immunotherapy clinical trials and future directions of cancer immunotherapy for metastatic tumors can be found in a published review article entitled Advances in Cancer Immunotherapy in Solid Tumors by Menon, Shin, and Dy in the journal Cancers12. The article can be freely accessed via the NCBI Pubmed Central website at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5187504/pdf/cancers-08-00106.pdf.14
This blog is brought to you by Biotheranostics, Inc., the company that developed and offers CancerTYPE ID®
CancerTYPE ID is a molecular cancer classifier that helps identify the site of origin for cancers with indeterminate, uncertain, or differential diagnoses. The test uses real-time RT-PCR to measure the expression of 92 genes in the patient’s tumor and classifies the tumor by matching the gene expression pattern of the patient’s tumor to a database of known tumor types and subtypes, encompassing 50 tumor types.. NOTE: NOTE: CancerTYPE ID test is not a companion diagnostic cleared or approved by the FDA; and it does not determine whether or not a specific drug will be beneficial to a specific patient.
For CancerTYPE ID Intended Use and Limitations, visit www.cancertypeid.com
DISCLAIMER: This material was created by or on behalf of Biotheranostics, Inc. The content, products and services discussed in this material are offered to educate healthcare providers and/or consumers on molecular diagnostic testing performed by Biotheranostics, and should not be considered or used as a substitute for medical advice, diagnosis or treatment of specific medical conditions.
- Nivolumab (OPDIVO®) Prescribing Information (Bristol-Myers Squibb; Revised 06/2018)
- Pembrolizumab (KEYTRUDA®) Physician Information (Merck, Sharpe & Dohme; Revised 08/2018.
- Atezolizumab (TECENTRIQ®) Physician Information (Genentech; Revised 2018)
- Durvalumab (IMFINZI®) Physician Information (AstraZeneca; Revised 2018).
- Avelumab (BAVENCIO®) Physician Information (EMD Serono, Pfizer; Revised 2017).
- Postow, MA, et al. N Engl J Med. 2015; 372:2006-2017.
- Rosenberg, JE, 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; 387:1909-1920.
- Nghiem, PT, et al. PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma. N Engl J Med. 2016; 374: 2542–2552
- Kaufman, HL, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Onc. 2016; 17:1374-1385.
- Balar, AV, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 389:67-76, 2017.
- Farkona, S et al. Cancer immunotherapy: the beginning of the end of cancer? BMC Medicine. 2016 14:73.
- Balar, AV and Weber, JS. Published online: Cancer Immunol Immunother. 2017, Feb 17; DOI 10.1007/s00262-017-1954-1956.
- Rimm, DL, et al. A Prospective, Multi-institutional, Pathologist-Based Assessment of 4 Immunohistochemistry Assays for PD-L1 Expression in Non-Small Cell Lung Cancer. JAMA Onc. 2017; Mar 9. doi: 10.1001/jamaoncol.2017.0013.
- Menon, S., Shin, S., and Dy, G. Advances in Cancer Immunotherapy in Solid Tumors. Cancers. 2016; 8: pii:E106.