Despite the rapidly expanding therapeutic options available in immunotherapy for patients with non-small cell lung cancer, there are still a number of drawbacks to treatment, explaining why not all patients respond to current treatment options.
Julie R. Brahmer, MD, MSc
Julie R. Brahmer, MD, MSc, offered a glimpse of what is to come in the treatment of non—small cell lung cancer (NSCLC) with immunotherapies after the standard PD-(L)1 and CTLA-4 checkpoint inhibitors, during a presentation at the 16th Annual Winter Lung Cancer Conference. She discussed some of the treatment options that could be entering the pipeline in lung cancer over the next 5 years.
Brahmer, the co-director of the Upper Aerodigestive Department in the Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins Medicine, explained that despite the rapidly expanding therapeutic options available in immunotherapy for patients with NSCLC there are still a number of drawbacks to treatment, explaining why not all patients respond to current treatment options.
She said that this could be due to heterogeneity as “not all tumors are the same, not even in the same patient,” and the lack of optimal biomarkers available to predict response and toxicities to immunotherapy. Also, many tumors relapse at some point for a number of reasons, such as alternative immune escape mechanisms, loss of neoantigens, and HLA mutations. “You have to be able to have the mechanism or machinery to present those abnormal proteins to the T cell, and that comes in the form of HLA mutations,” she mentioned.
Additional immunotherapeutic options being explored include chimeric antigen receptor (CAR) T-cell therapy, which has been approved for use in leukemia and lymphoma but is making its way into treating patients with solid tumors as well, oncolytic viruses, vaccines, and various antibody-drug conjugates.
The goal of many of these methods, Brahmer explained, revolves around finding methods to make noninflamed “cold” tumors that are resistant to immunotherapy inflamed, or “hot,” and hot tumors even more inflamed.
“Vaccines are designed to increase response against malignant cells by enlarging the pool of antigen-specific T cells. They require a selection of a particular antigen or protein. Really the goal is to induce an effector as well as memory T-cell response in the hopes to spare normal cells,” Brahmer said. “For a vaccine you’re looking at tumor antigens, you’re looking at different formulations. These vaccines are usually given with something called an adjuvant to really help use the proteins to mount a response, so you need to be able to stimulate the dendritic cells and other cells to be able to take out these antigens and really process them, and then how best to deliver them.”
She pointed to the CIMAvax-EGF vaccine which is being studied in patients with advanced NSCLC. The vaccine consists of a human recombinant EGF with the P64 protein as an adjuvant and is being investigated in several clinical trials. Additional clinical trials are looking at the GMCD401 vaccine with CCL-21, OBI-833, H1299 lysate vaccine, and MY-ESO-1 vaccine in patients with lung cancer.
The vaccines being tested in lung cancer today are nothing like previously seen vaccines, she noted. Previous vaccines focused on shared tumor antigens, such as with the MAGE-A3 vaccine, however this agent was not personalized enough. Newer vaccines instead have turned toward autologous tumor cells and neoantigen-specific vaccines for greater personalization, which Brahmer called “the holy grail” of vaccines.
She raised the NEO-PV-01 vaccine as one such vaccine in development that is being investigated in a clinical trial in combination with nivolumab (Opdivo) for patients with lung cancer, melanoma, and bladder cancer (NCT02897765). This agent builds on the fact that higher neoantigen loads, as in high mutational burden, are associated with improved clinical responses.1
“Theoretically, vaccines are best to give when there’s no residual disease, either after first-line therapy or after surgery, but most of these are going to require co-treatment with a checkpoint inhibitor, because that’s one of the reasons we think that the MAGE vaccine was not successful. You really need to take those breaks off of those T cells in order to make them react to the tumor antigen,” Brahmer said.
Other methods to active T cells to help them target tumors include formulations of interleukin (IL).
A phase I trial of pegilodecakin, a pegylated formulation of IL-10, in combination with an anti—PD-1 agent in patients with NSCLC was presented at the 2018 ASCO Annual Meeting. As a monotherapy, pegilodecakin induced a median progression-free survival (PFS) of 1.8 months in 9 patients with a median of 3 prior treatment regimen (range, 1-7) and a median survival (OS) of 15.4 months.2
When the pegylated interleukin was combined with nivolumab in 29 patients with a median of 2 prior therapies (range, 0-5), the objective response rate (ORR) was 41%, and both the median PFS and OS were not yet reached. And with pembrolizumab (Keytruda) added to pegilodecakin, the ORR was 40% in 5 patients with a median of 2 prior therapies (range, 0-5). The median PFS was 11 months and the median OS was 32.2 months.
“In the past we really had seen a lot of side effects with giving interleukins, and with this pegylated form, the side effects are actually really manageable,” Brahmer said. Grade 3/4 AEs among 29 evaluable patients treated with a combination of pegilodecakin and an anti—PD-1 therapy included thrombocytopenia and fatigue in 17% each, hypertriglyceridemia in 10%, maculopapular rash in 7%, and pneumonitis in 3.5%.
The combination is continuing to be investigated in 2 clinical trials, one looking at the regimen in the frontline (Cypress 1; NCT03382899) and a second in the second-line setting (Cypress 2; NCT03382912).
CAR T-cell therapies are also of interest in lung cancer but the issue in the past has been the lack of ideal tumor-specific antigens for solid tumors, where the immune-suppressive microenvironment and the risk of off-target toxicities can be difficult. However, she mentioned that the NCCN and the ASCO are working on a set of guidelines to manage toxicities associated with CAR T-cell treatment. Some “souped-up” CAR T-cell therapies are currently in development for solid tumors, such as second-generation mesothelin-targeted and DLL3 CAR T-cell therapies.
A BiTE, or a bispecific T-cell engager, has been previously effective in lymphoma and chronic leukemia, but is now moving to investigation in solid tumors. This immunotherapy has 2 antibodies that bring the T cells together with the particular antigen. Brahmer noted that a DLL3-specific BiTE is being investigated in small cell lung cancer (NCT03319940).
However, she noted that stability and drug distribution can be challenging with this antibody.
Other agents have looked to targeting the tumor microenvironment, such as with myeloid-derived suppressor cells (MDSCs) and metabolomics.
She explained that MDSCs are thought to be a significant part of the reason that patients with lung cancer do not respond to PD-(L)1 checkpoint inhibition. One such MDSC therapy in development is NC318, a Siglec-15—targeted antibody that is being investigated in a phase I/II trial (NCT03665285).
Researchers believe that by blocking arginase, which is immunosuppressive, it can result re-induce responses to immune checkpoint inhibition. The arginase inhibitor INCB001158 is currently being studied in a phase I/II trial as monotherapy and in combination with pembrolizumab in patients with advanced or metastatic solid tumors (NCT02903914).
Additionally, adenosine is interesting in this space as it may also induce responses in patients when it is inhibited. “Interestingly, adenosine may play a role in immunosuppression more in EGFR-mutant disease. It has been seen in EGFR-mutant patients, their tumors may overexpress CD73, which is part of this pathway, and by blocking this the hope is to re-induce a response to PD-1 or PD-L1,” Brahmer said.
Oleclumab, an adenosine inhibitor, is currently being investigated in a phase I/II trial of patients with EGFR-mutant NSCLC in a novel combination regimen (NCT03381274).
“There are multiple different mechanisms and very novel combinations, there are so many, but I think the question is how best can we direct patients. I think some of the future is in biomarker-driven trials. The goal is precision medicine,” she commented, pointing to HUDSON, Lung-MAP, and several other biomarker-driven precision medicine trials that are helping to match up patients to different immunotherapy options to help patients find greater benefit from immunotherapeutics.