Another annual meeting of the American Society of Clinical Oncology (ASCO) has come and gone. The five days of talks, poster discussions, and educational sessions attracted oncology experts from across the world, and revealed the latest in cutting-edge clinical approaches across a range of cancers.
After the dust from the approximately 40,000 person-strong meeting settled, there was a palpable feeling of optimism. Although many of immunotherapy’s biggest breakthroughs likely still lie ahead, major advances were made in the treatment of some of today’s deadliest cancers, reaffirming immunotherapy’s potential to improve outcomes for patients with many more types of cancers. Below are some of the most impressive advances discussed.
1. Lung cancer
The benefits of PD-1/PD-L1 checkpoint immunotherapy continue to offer hope for patients with advanced non-small cell lung cancer (NSCLC) in a number of settings, especially as a first-line option, including in combination with chemotherapy, in combination with CTLA-4 checkpoint immunotherapy, and in combination with anti-VEGF targeted antibody therapy. The effectiveness of these approaches often manifested itself in the form of increased rates of response, which were often remarkably durable, and improved overall survival for patients. The benefits were often more pronounced in patients whose tumors expressed high levels of PD-L1, especially those patients with high tumor mutational burdens. Combining PD-1 checkpoint immunotherapy with radiation showed impressive efficacy in NSCLC, as it more than doubled response rates and overall survival compared to radiation treatment alone. In addition to PD-L1 and mutational status, other traits associated with durable benefit were also identified, as it was found that patients with long-term responses were more likely to be smokers and less likely to have EGFR mutations.
2. Skin Cancers: Melanoma & Merkel Cell Carcinoma
The long-term benefits of PD-1 checkpoint immunotherapy were also revealed in melanoma, the first tumor type for which these immunotherapies were approved. In one study, 73% of patients who responded had maintained those responses for more than five years, whereas another found that 86% of patients who had completed two years of treatment were still progression-free more than twenty months after their last treatment. Additionally, melanoma patients benefited from receiving the combination of PD-1 and CTLA-4 checkpoint immunotherapy before surgery, in what is called the neoadjuvant setting, where nearly half of patients had complete pathological responses and nearly three out of every four patients had at least a partial clinical response. PD-1 proved effective in combination with a TLR9 agonist too, leading to an 80% response rate and staving off progression in three-fourths of patients for at least six months. Combining a TLR9 agonist with CTLA-4 demonstrated efficacy as well, eliminating tumors entirely in 13.6% of patients and providing disease stabilization in more than 70% of patients. Another advance highlighted the advantages of using PET scans to monitor melanoma patient responses after PD-1 immunotherapy. By measuring the metabolic activity of tumors, PET scans were much more accurate than CT scans when it came to identifying the patients who experienced long-term responses. Lastly, neoadjuvant administration of the oncolytic virus immunotherapy T-VEC was able to induce disease stabilization in half of melanoma patients prior to surgery.
In Merkel cell carcinoma (MCC), PD-1/PD-L1 immunotherapy appeared to be even more effective. When given prior to surgery, 40% of patients responded, an additional 52% stabilized, and only 2 of the 25 patients treated had their disease progress. In the first-line setting, 24% of advanced MCC patients had complete tumor responses and another 32% had partial responses, most of which occurred early and remain ongoing: the three-year overall survival rate was 64% compared to the roughly historical survival rate 10% of patients treated with chemotherapy. Finally, in relapsed or refractory MCC that was metastatic, PD-L1 immunotherapy enabled responses in one in every three patients, and two-thirds of these responses last more than two years.
3. Hard-To-Treat Cancers
In glioblastoma, a personalized peptide vaccine was able to induce immune responses against brain tumor antigens in 80% of the patients vaccinated, and treatment with PD-1 immunotherapy prior to surgery more than doubled the six-month progression-free survival rate and enabled three of every four patients to survive past the one-year mark.
In ovarian cancer, treatment with a dendritic cell vaccine after chemotherapy reduced the risk of progression by 68% and reduced the risk of death by 87% in patients who completed all eight doses. A CD47-targeting immunotherapy that acts to promote phagocytosis demonstrated early promise against heavily pre-treated ovarian cancer and fallopian tube cancer, enabling responses in two patients who each had undergone at least six prior lines of therapy. The combination of PD-1 immunotherapy and PARP inhibition also appeared promising with a 25% response rate and a 67% disease control rate in all patients treated. Patients with BRCA mutations benefited even more frequently.
In pancreatic cancer, the combination of PD-1 immunotherapy and a CSF-1R inhibitor led to four partial responses in patients with advanced, microsatellite stable (MSS) pancreatic cancer.
In sarcoma, the combination of PD-1 immunotherapy and the oncolytic virus immunotherapy T-VEC produced responses in more than one-third of patients with metastatic disease, whereas modified T cells engineered to express a NY-ESO-1-targeting T cell receptor (TCR) produced responses in four of the eight patients that received it.
In triple-negative breast cancer, the combination of PD-1 immunotherapy and radiation was used to treated seventeen patients and produced three responses in which the patients’ metastatic lesions were completely eliminated, for an 18% response rate. Two of those three responses lasted more than six months, while the third remains ongoing at almost one year.
While both tumor mutational burden (TMB) and PD-L1 have previously been associated with responses to PD-/PD-L1 immunotherapy, patients with high TMB tumors were found to be much more likely to experience long-term responses. In addition to the impact of TMB and PD-L1 status, several other biomarkers with the potential to improve current PD-1/PD-L1 immunotherapy applications were revealed. In kidney cancer patients, the infiltration of M2 macrophages was associated with durable clinical benefit, the presence of indel (insertion/deletion) mutations was associated with improved overall survival, and specific gut “fingerprints” were able to predict patient responses. In lung cancer, the administration of steroids prior to treatment was found to be associated with worse outcomes, though fortunately steroids given during treatment to address side effects didn’t appear to negatively impact immunotherapy’s effectiveness, and a high ratio of neutrophils to lymphocytes was found to be associated with worse clinical outcomes in lung cancer patients. With respect to the microbiome, the community of bacteria and viruses within us, it was found that patients who responded to PD-1/PD-L1 immunotherapy tended to have more diverse gut microbiomes, while patients who received antibiotics were found to have decreased overall survival after immunotherapy.
5. Novel Immunotherapy Targets and Combinations
Treatment with an OX40-activating immunotherapy prior to surgery led to promising results in head and neck cancer. No surgical delays resulted from the treatment, which increased T cell activation and proliferation, and all four patients remain free of disease. The combination of PD-1 immunotherapy and a PEGylated IL-10 therapy led to a 41% response rate in patients with kidney cancer, 89% of which remained alive at the one year mark. A bifunctional fusion protein targeting both PD-L1 and TGF-β led to a 30-40% response rate in HPV-associated cancers, with several patients having their tumors completely eliminated. The combination of a CD47-activating immunotherapy and rituximab produced two complete responses in patients with refractory non-Hodgkin lymphoma, whereas the combination of PD-1 immunotherapy and NKTR-214, which is designed to provide sustained precision activation of the IL-2 receptor, led to a 60% response rate in patients with bladder cancer and who were unable to receive cisplatin chemotherapy.
6. Cell-Based Immunotherapies
Cell-based immunotherapies also continued to show promise, both in blood cancers and beyond. Updated results of CD19-targeting CARs revealed an 82% response rate in non-Hodgkin lymphoma. Remarkably, it was found that these responses can deepen over time, and 41% of the patients who had partial responses eventually improved to complete responders by the three-month mark. In multiple myeloma, BCMA-targeting CAR T cells led to promising response rates in patients with advanced disease, and 71% of patients who were treated with the highest dose remained alive at nine months. In addition to the NY-ESO-1 TCR-engineered T cells mentioned above in sarcoma, an immunotherapy strategy that utilized patient-derived HPV-targeting T cells demonstrated great promise in patients with metastatic cervical cancer, two of whom had complete responses that remain ongoing at more than four years and five years.
Bonus: Patient Reported Outcomes
Two advanced lung cancer clinical trials in which patients were treated with first-line combinations containing PD-1 immunotherapy used patient reported outcomes (PROs) to determine immunotherapy’s impact on their lives. Together, these PROs demonstrated that in addition to increasing the time to clinical deterioration, immunotherapy was associated with more durable clinical benefits and a higher health-related quality of life compared to chemotherapy.
Well, that does it for our coverage of ASCO18. If you haven’t already, we strongly encourage you to check out our daily blog recaps from each of the five days of the conference, and be sure to check out all of our content on our Cancer Immunotherapy Month (#CIM18) page and follow us on Twitter for the latest updates throughout the rest of June!