Immunotherapy and Molecular Ways to Measure Response for Thoracic Cancers and Melanoma Featured at Annual Meeting of American Society of Clinical Oncology

06/10/2020

Johns Hopkins Kimmel Cancer Center thoracic cancer and cancer genomics experts reported promising new findings and studies in mesothelioma, lung cancer and melanoma at the annual meeting of the American Society of Clinical Oncology (ASCO), the world's leading professional organization for physicians and oncology professionals caring for cancer patients. Two of this year’s presenters include winners of ASCO Young Investigator and Merit Awards. The meeting was held virtually May 29–31.

Presentations included:

--Chemotherapy/Immunotherapy Combo for First-Line Treatment of Mesothelioma
A clinical study, called PrE0505, evaluated the efficacy of an immunotherapy-plus-chemotherapy combination for inoperable malignant pleural mesothelioma, a rare and aggressive cancer of the protective lining of the lungs, or pleura, often caused by exposure to asbestos. The study, presented by Patrick Forde, M.B.B.Ch., associate professor of oncology, director of the Kimmel Cancer Center’s thoracic cancer clinical research program and a Bloomberg~Kimmel Institute for Cancer Immunotherapy investigator, included 55 patients from 15 U.S. cancer centers who received the anti-PD-L1 immunotherapy drug durvalumab in combination with the anticancer chemotherapies cisplatin and pemetrexed as a first treatment.

Patients received six treatments of the combination therapy every three weeks followed by treatment with the immunotherapy durvalumab for up to one year in total. The chemo-immunotherapy combination improved overall survival from historical expected survival of 12 months with chemotherapy alone to 20.4 months with the chemo-immunotherapy combination. This is the first study to show survival exceeding 20 months for patients with inoperable mesothelioma. Treatment was well-tolerated overall with no unexpected side effects reported.

“Inflammation is key to the development of pleural mesothelioma and, as such, it represents a key target for immunotherapy. This, in addition to earlier studies that showed promising results using anti-PD-1 immunotherapy in previously treated cases, led us to study the combination,” says Forde. “Durvalumab plus standard chemotherapy delivered a promising median overall survival rate for patients with previously untreated inoperable malignant pleural mesothelioma, and we are in the process of starting a phase 3 study to confirm the benefit of this approach.” This study, known as DREAM3R, will begin accrual across the United States and Australia in late 2020.

The researchers, which included Julie Brahmer, M.D., professor of oncology and co-director of the upper aerodigestive department of the Bloomberg~Kimmel Institute for Cancer Immunotherapy, and Valsamo Anagnostou, M.D., Ph.D., assistant professor of oncology and director of the thoracic oncology biorepository at the Johns Hopkins University School of Medicine, studied tissue samples from 45 of the patients utilizing genomic, expression and immune cell repertoire analyses. PD-L1 expression and tumor mutation burden, which is a measure of the number of mutations carried by tumor cells, are both used as biomarkers, or indicators, of response to immunotherapy. However, neither were found to be associated with response for patients in the study. In-depth genomic, expression and functional analyses are ongoing to reveal the molecular mechanisms of therapeutic response and resistance.

Under the pathologist’s microscope, PD-L1 is seen as forming an armor around cancer cells that protects them from the immune system. Immunotherapies such as durvalumab, called checkpoint blockers, disrupt cancer cells’ ability to hijack PD-L1 signaling to avoid detection and destruction by immune cells.

Related poster presentations:

Joshua Reuss, M.D., fellow in oncology at the Johns Hopkins Kimmel Cancer Center, presented updates on an ongoing study called NeoMeso that evaluates the safety and benefit of using checkpoint blocker immunotherapy before surgery in patients with operable pleural mesothelioma as a way to improve dismal treatment outcomes. Currently, even using aggressive approaches of chemotherapy, surgery and radiation therapy, most patients relapse and die, Reuss says.

“Improving the mechanistic understanding of immune checkpoint blockade in metastatic pleural mesothelioma while concurrently optimizing the treatment strategy for limited-stage disease are two urgent, unmet needs,” he says.

Patients diagnosed with stage I-III pleural mesothelioma will receive three doses of the checkpoint blocker nivolumab leading up to surgery. Another arm of the study will evaluate a combination of two checkpoint blockers — nivolumab and ipilimumab. After surgery, some patients may also receive chemotherapy and/or radiation therapy. Patients will also be treated with up to one year of maintenance therapy with nivolumab.

Other members of the research team included Valsamo Anagnostou, M.D., Ph.D.; Kellie Smith, Ph.D.; Janis Taube, M.D., M.Sc.; Gary Rosner, Sc.D.; Khinh Ranh Voong, M.D., M.P.H.; Russell Hales, M.D.; Stephen Yang, M.D.; Richard Battafarano, M.D., Ph.D.; and Patrick Forde, M.B.B.Ch.

Jarushka Naidoo, M.B.B.Ch., a leader in the management of immunotherapy toxicities in lung cancer, presented findings on side effects for non-small cell lung cancer patients treated with the immunotherapy drug durvalumab.

--Crosstalk Among Tumor Cells and Immune Cells Interprets Response to Immunotherapy

There is a need for better biomarkers of response to immunotherapy. Researchers know that a complex cellular communication occurs among cancer cells and immune cells during treatment with immunotherapies called checkpoint blockers, and it could hold important information that can help identify cancers most likely to respond to immunotherapy. In research led by Valsamo Anagnostou, M.D., Ph.D., assistant professor of oncology, director of the thoracic oncology biorepository and a Bloomberg~Kimmel Institute for Cancer Immunotherapy investigator, researchers used machine learning tools, or artificial intelligence, and comprehensive studies of the genomes and transcriptome, or RNA produced by genes, of cancer cells and immune T cells to study this interplay. Their goal is development of an integrated molecular biomarker to help physicians identify patients most likely to respond to immunotherapy.

They analyzed biopsy samples from 64 patients with advanced melanoma who received the checkpoint blocker drug nivolumab alone or in combination with another checkpoint blocker called ipilimumab. Checkpoints serve as natural “go” and “stop” signals for the immune system, setting it in action and shutting it down. Cancer cells co-opt these checkpoints to hide from the immune system, and checkpoint blockers disrupt this activity, making cancers visible to the immune system.

High tumor mutation burden (the number of the gene mutations in a tumor) is an emerging biomarker used to predict response to immunotherapy and better clinical outcomes, but it has limitations and in this study did not fully explain clinical responses. High numbers of T cells in the tumor, which can search out and destroy cancer cells, shifts in the T cells population, and the presence of B cells, which produce antibodies to flag cancer cells as predators, were important predictors of clinical responses to immunotherapy with checkpoint blockers.

The researchers combined tumor genomic features with T- and B-cell features to generate a risk score to classify patients in high- and low-risk groups, with a high-risk score indicating those patients less likely to have a good response to checkpoint blocking drugs. The risk score outperformed existing biomarkers of response to immunotherapy — tumor mutation burden and PD-L1 expression in tumors.

“Integrative approaches that combine molecular features hold promise for predicting patients who will respond to immunotherapy with checkpoint blockade,” says Anagnostou. “Our findings highlight the multifaceted interactions between the tumor and the immune system and the importance of preexisting T- and B-cell immunity in driving clinical response.” Additional studies are ongoing.

Watch a video about these findings.

Other members of the research team included Daniel Bruhm, B.S., Noushin Niknafs, Ph.D.; James White, Ph.D.; Toni Ribas, M.D.; Suzanne Topalian, M.D.; Drew Pardoll, M.D., Ph.D.; and Victor Velculescu, M.D., Ph.D.

--Noninvasive Prediction of Response to Immunotherapy in Non-Small Cell Lung Cancer

First-line immunotherapy and combined immunotherapy/chemotherapy are approved treatments for patients with advanced non-small lung cancer, but interpretation of clinical responses by conventional imaging is challenging. In a poster presentation, Joe Murray, M.D., Ph.D., fellow in oncology and 2020 recipient of an ASCO Young Investigator Award and Merit Award, notes that liquid biopsies, which utilize noninvasive blood-based DNA analyses, can accurately and rapidly predict response to therapy.

The researchers are studying circulating tumor DNA (ctDNA) — cancer DNA shed into the bloodstream — to enhance their ability to measure clinical response. Tumor-derived circulating DNA was very carefully characterized by deep sequencing and by filtering out mutations in DNA shed from blood cells.

“We need accurate on-therapy response assessment to guide clinical decision-making,” says Murray, adding that imaging such as CT scans, the gold standard for monitoring response to treatment, may not always accurately capture immune responses.

In a study of 143 plasma samples and 24 white blood samples from 31 patients receiving immunotherapy for non-small cell lung cancer, ctDNA predicted clinical outcomes independent of PD-L1 status. In addition, responses were detected earlier via ctDNA and may be better for guiding on-therapy treatment decisions aimed at improving outcomes.

Other members of the research team included Kristen Marrone, M.D.; Jarushka Naidoo, M.B.B.Ch.; Benjamin Levy, M.D.; Christine Hann, M.D., Ph.D.; Josephine Feliciano, M.D.; David Ettinger, M.D.; Julie Brahmer, M.D.; Patrick Forde, M.B.B.Ch.; Victor Velculescu, M.D., Ph.D.; and Valsamo Anagnostou, M.D., Ph.D.

Erica Nakajima, M.D., fellow in oncology and 2020 ASCO Young Investigator Award recipient, reported in a poster presentation on CT and PET imaging features associated with major responses to immunotherapy before surgery in early-stage non-small cell lung cancer.

Other members of the research team included Patrick Forde, M.B.B.Ch., and Martin Pomper, M.D., Ph.D.