Medical and surgical oncologists commonly encounter patients asking about immunotherapy options. What are the data on immunotherapy, and when should it be considered as a treatment option? Immunotherapy, such as checkpoint inhibitors, has demonstrated durable clinical responses in a variety of solid tumor malignancies leading to widespread excitement and optimism. However, objective response occurs in only a small subset of patients. Furthermore, this treatment modality comes at a high cost financially, as well as in terms of immune-related adverse events. As such, biomarkers identifying patients who are more likely to benefit from immunotherapy could save considerable health care dollars and decrease immune-related adverse events in cancer patients.
Mismatch repair-deficient tumors and immunotherapy
Numerous biomarkers have been suggested as predictive of response to cancer immunotherapy, such as tumor lymphocyte infiltrations, mutational burden, and programmed death ligand 1 (PD-L1) receptor expression. After first demonstrating objective response rates of 40 percent in patients with mismatch repair (MMR)-deficient colorectal cancers,1 Le and colleagues conducted a phase 2 study in patients with MMR-deficient neoplasms in a variety of solid tumor malignancies. A total of 12 different solid tumor types were enrolled, including classically immune-resistant histologies such as cholangiocarcinoma and pancreas cancer. With a nearly 21 percent complete response rate, their findings demonstrate that looking beyond tumor histology is necessary to identify a subset of patients more likely to benefit from checkpoint blockade.2 Approximately 60,000 gastrointestinal, hepatobiliary, and gynecologic MMR-deficient adenocarcinomas occur annually in the U.S. alone (see Figure 1). MMR deficiency testing for tumors is now widely available, is recommended in patients with colon or rectal cancer, and is generally applied to a range of solid tumors.
Figure 1. Percentage of MMR-deficient tumors across 12,019 tumors tested
Precision immunotherapy in solid tumors beyond mutational burden
Improved clinical responses with immunotherapy in MMR-deficient cancers are thought to be secondary to a high tumor mutational burden (TMB). This leads to higher levels of neoantigens, thereby facilitating recognition of non-self-epitopes and generating anti-tumor T-cell responses. Next generation sequencing has become widely used in clinical oncology. Using sequencing to assess TMB is affordable and of great practical relevance. Rizvi et al evaluated TMB in 240 patients with advanced non-small cell lung cancer who received an immune checkpoint inhibitor. Patients with response to immune checkpoint inhibition had a higher TMB (median, 8.5 versus 6.6 single-nucleotide variants/megabase; p = 0.0062).3 Prospective evaluation of TMB as a biomarker to guide checkpoint inhibitor treatment is valuable.
Although an increased expression of tumor antigens appears important, the quality of antigens may also have important therapeutic implications. In a study of long-term pancreatic adenocarcinoma survivors published in Nature, Balachandran and colleagues identified high-quality pancreatic cancer neoantigens via their homology to infectious derived peptides.4 The presence of these high-quality neoantigens was predictive of long-term survival, whereas neoantigen quantity was not. Thus, quality and not solely quantity of neoantigens may play an important role as a biomarker for immunogenic therapies.
Two recent phase 2 trials have demonstrated efficacy of checkpoint blockade in advanced undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLPS). SARC028 (A Phase II Study of the Anti-PD1 Antibody Pembrolizumab (MK-3475) in Patients With Advanced Sarcomas) included four subtypes of soft tissue sarcoma (n = 10/subtype).5 By RECIST (Response Evaluation Criteria In Solid Tumors), 18 percent of patients had a response, with most of the responses seen in patients with UPS or DDLPS. A0911401 (Nivolumab With or Without Ipilimumab in Treating Patients With Metastatic Sarcoma That Cannot Be Removed by Surgery) was a noncomparative, phase 2 study that randomized patients with advanced soft-tissue sarcoma to nivolumab (anti-PD-1) or combination nivolumab and ipilimumab (anti-CTLA-4).6 By RECIST, 8 percent of patients responded to anti-PD-1, and 18 percent had responses to combination checkpoint blockade. Based on the success of these two trials, the role of immunotherapy is being investigated in several clinical trials for patients with early-stage disease, including retroperitoneal DDLPS (NCT03307616). Combination checkpoint blockade and radiation are being evaluated in patients with high-risk extremity sarcoma at single institutions (NCT03307616, NCT03338959) and cooperative groups (NCT03092323).
Future directions and the need for surgeon participation
Abscopal effect describes the phenomenon whereby treatment at one site may lead to regression of distant metastasis. The mechanism of abscopal effect is likely related to the release of tumor-associated antigens due to treatment, which may be presented to CD8+ T-cells to attack both the primary and metastatic tumors. This effect is most commonly seen with radiation to a site. When immunotherapy is given concurrently with radiotherapy, the abscopal effect is likely boosted.7 The combination of radiation, anti-CTLA-4, and anti-PD-L1 promotes immunity and increases tumor response in patients with stage IV melanoma (NCT01497808).8
With the reinvigorated cancer collaborations organized across the globe, the oncology community’s understanding of the genomic basis of cancer initiation, propagation, and implications for treatment are growing at an unparalleled rate. Diverse factors determine response to immunotherapy. Identification of biomarkers predicting immunotherapy response requires multidisciplinary collaborative approaches. To this end, the U.S. National Cancer Institute has developed an important collaboration through the Partnership for Accelerating Cancer Therapies. This effort brings together public and private entities, including 12 pharmaceutical companies, as part of the Cancer Moonshot Initiative and prioritizes the development of cancer biomarkers predictive of immunotherapy treatment response.
Surgeons play a critical role in the management and understanding of the factors that determine responses to therapy. Responses to biologic therapies, the development of resistive clones, and the implications for surgical management requires the surgical community to continue to be at the forefront of multidisciplinary cancer management and research.
- Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509-2520.
- Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409-413.
- Rizvi H, Sanchez-Vega F, La K, et al. Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing. J Clin Oncol. 2018;36(7):633-641.
- Balachandran VP, Luksza M, Zhao JN, et al. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature. 2017;551(7681):512-516.
- Tawbi HA, Burgess M, Bolejack V, et al. Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): A multicentre, two-cohort, single-arm, open-label, phase 2 trial. Lancet Oncol. 2017;18(11):1493-1501.
- D’Angelo SP, Mahoney MR, Van Tine BA, et al. Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): Two open-label, non-comparative, randomised, phase 2 trials. Lancet Oncol. 2018;19(3):416-426.
- Ngwa W, Irabor OC, Schoenfeld JD, Hesser J, Demaria S, Formenti SC. Using immunotherapy to boost the abscopal effect. Nat Rev Cancer. Available at: www.nature.com/articles/nrc.2018.6. Accessed April 17, 2018.
- Twyman-Saint VC, Rech AJ, Maity A, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520(7547):373-377.