Advancing Progress in the Development of Combination Cancer Therapies with Immune Checkpoint Inhibitors Proceedings of a Workshop (2019) / Chapter Skim
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Proceedings of a Workshop
Proceedings of a Workshop
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One type of immunotherapy is an immune checkpoint inhibitor. Cells in the human body have proteins that regulate the immune system response to foreign invaders (e.g., cancer cells, microorganisms)
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Consequently, there is strong interest in combining checkpoint inhibitors with other cancer therapies to improve therapeutic effectiveness and patient outcomes. To examine the challenges and opportunities to develop combination cancer therapies that include immune checkpoint inhibitors, the National Cancer Policy Forum held a workshop, Advancing Progress in the Development of Combination Cancer Therapies with Immune Checkpoint Inhibitors.
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This Proceedings of a Workshop highlights a number of suggestions from individual participants regarding potential ways to improve the development of combination therapies using PD-1/PD-L1 immune checkpoint inhibitors. These suggestions are discussed throughout the proceedings and are summarized in Box 1.
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• Develop a comprehensive database of clinical trials testing dif ferent combination strategies with immune checkpoint inhibitors, and include information on trial outcomes and biospecimens col lected as part of the trial protocols. (Herbst)
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• Use master protocol trial designs to more efficiently evaluate combination therapies using immune checkpoint inhibitors. (Herbst, Ibrahim, Tarhini)
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Each bubble lists the number of active clinical trials that are testing drugs against the listed target. SOURCES: Ibrahim presentation, July 16, 2018; Tang et al., 2018c.
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. The Impact of Immune Checkpoint Inhibitors on Cancer Treatment A number of workshop participants described the striking effect that immune checkpoint inhibitor therapy has had on cancer care.
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Community-based oncologists, as well as other clinicians who care for patients with cancer, need to be aware of the potential adverse effects that patients might experience with immune checkpoint inhibitor therapies, as well as how to best intervene to mitigate these effects. Roy Herbst, Ensign Professor of Medicine, chief of medical oncology, and director of the thoracic oncology research program at the Yale Cancer Center, said the advent of immune checkpoint inhibitors has ushered in a new era in lung cancer treatment (Herbst et al., 2018; Kazandjian et al., 2016)
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NOTE: ALK = anaplastic lymphoma kinase, EGFR = endothelial growth factor receptor, TKI = tyrosine kinase inhibitor, VEGF = vascular endothelial growth factor. 9 SOURCES: Abernethy presentation, July 17, 2018; Flatiron Health.
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Herbst added that investigators are evaluating combination therapy strategies in lung cancer, including combinations with targeted therapies, other checkpoint inhibitors, and chemotherapy. For example, he noted that the KEYNOTE 189 clinical trial showed that pembrolizumab combined with chemo herapy increased overall survival and progression-free survival t in patients with metastatic NSCLC compared with chemotherapy plus placebo (Gandhi et al., 2018)
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Primary resistance occurs when there is no initial response to immune checkpoint inhibitor therapy; with acquired resistance, there is an initial response to therapy, but then a patient relapses or no longer experiences a response (Kim et al., 2018)
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Jaffee said investigators are seeking to accomplish three primary goals by testing combination therapies: • Enhancing efficacy of a single immune checkpoint inhibitor in an inflamed tumor; • Increasing response to immunotherapy among patients with cold tumors; and • Achieving higher response rates and more durable responses among patients who respond to immune checkpoint inhibitor therapies. Chen noted that selecting potential combination strategies with immune checkpoint inhibitors is quite challenging because these drugs are broadly active, with complex biological effects on orthogonal signaling pathways.
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. Rupalla said that the checkpoint inhibitors nivolumab and pilimumab -- both approved as monotherapies -- each have independent i anticancer activity (Brahmer et al., 2010; Hamid and Carvajal, 2013; Topalian et al., 2012; Wang et al., 2014)
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Dan Theodorescu, director of the Samuel Oschin Comprehensive C ancer Center, added that functional genomics and preclinical models can also be leveraged to identify potential drugs to enhance the activity of immune checkpoint inhibitors (Tu et al., 2019)
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. Chen noted that thus far, the biggest successes with combinations using immune checkpoint inhibitors have been with combinations of agents that have independent action.
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Prioritization and Redundancy A recurring theme at the workshop was the sheer quantity of research on immune checkpoint inhibitor therapies, and the implications for advancing progress in developing effective therapeutic approaches for patients with ancer. Herbst noted that cancer immunotherapy develop c ment has been described as a conundrum: Too many experimental drugs are being evaluated in too many clinical trials, and not enough patients are 11 T-cell exhaustion is a condition that can prevent optimal control of infections or tumors due to dysfunctional T-cell performance (Wherry, 2011)
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is also assessing a VEGFR inhibitor in combination with an immune checkpoint inhibitor. Modelng and simulation indicated that the combination of i avelumab ( D-L1 inhibitor)
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Dansey said the vast number of clinical trials with immune checkpoint inhibitors sounds daunting, but he noted that most of these trials are small, investigator-initiated signal-finding studies with 20 to 40 patients. Dansey said, We can all understand why there is so much enthusiasm.
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Richard Pazdur, director of the FDA Oncology Center of Excellence, said FDA has encouraged industry sponsors to use a common control arm, due in part to the experience with clinical trials investigating immune checkpoint inhibitor combinations in renal cell cancer. Boshoff and others said that in the past 3 years, more than 2,000 patients with renal cell cancer have participated in different clinical trials, all with the same control arm therapy (unitinib)
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. She encouraged the drug development community to submit cross-labeling applications, noting that this could help address some of the redundancy in immune checkpoint inhibitor development.
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for melanoma (for adjuvant and metastatic indications) , non-small cell lung cancer (NSCLC)
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This approval was based on clinical trial data on overall response rate, with progression-free survival as a second ary endpoint. McKee noted there is a post-marketing requirement to provide overall survival results from a randomized controlled trial in the same setting.
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. BIOMARKERS IN DEVELOPMENT OR IN USE FOR IMMUNE CHECKPOINT INHIBITOR THERAPIES Several workshop speakers discussed the role of biomarkers in advancing the development of combination therapies with immune checkpoint inhibitors.
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Types of Biomarker Tests Several speakers discussed biomarker tests that are in development or in use for immune checkpoint inhibitor therapies, including • Immunohistochemistry • Genomics • Expression signatures • Multiplex fluorescence • Circulating biomarkers • Assessment of the microbiome Lisa Butterfield, professor of medicine, surgery, immunology, and clinical and translational science at the University of Pittsburgh Hillman Cancer Center, said that biomarkers -- for prediction, prognosis, and elucidation of mechanisms of action -- are still largely exploratory, but validation, both analytical and clinical, is ongoing. Jaffee said investigators are leveraging rapidly developing technologies for biomarker discovery, including multiplex immunohistochemistry, mass cytometry, T-cell receptor sequencing, and immunoPET (positron emission tomography)
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. 14 The FDA definition of a companion diagnostic is "a medical device, often an in vitro device, which provides information that is essential for the safe and effective use of a corresponding drug or biological product"; see https://www.fda.gov/medicaldevices/ productsandmedicalprocedures/invitrodiagnostics/ucm407297.htm (accessed April 25, 2019)
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. In support of this hypothesis, one study found a significant correlation between TMB and the objective response rates to immune checkpoint inhibitor therapy in an analysis of 27 tumor types (Yarchoan et al., 2017)
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. Rizvi added that some of the emerging research suggests that individuals with both low PD-L1 expression and low TMB may not respond well to immune checkpoint inhibitor therapy.
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They also developed an algorithm to identify immune evasion, using single-cell RNA sequencing data from tumor samples of patients whose cancers were resistant to immune checkpoint inhibitor therapy. Even though these signatures were derived in different ways, Izar noted that they demonstrated overlap that was highly statistically significant, and termed this overlap "the resistance program." Investigators validated the predictive value of this resistance program for progression-free survival and overall response in an independent cohort of patients with melanoma who received PD-1 inhibitor therapy (Izar et al., 2018; Jerby-Arnon et al., 2018)
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Multiplex Fluorescence Multiplex fluorescence is a method that characterizes multiple proteins of a patient's tumor and the tumor microenvironment using immuno histochemistry with fluorescence tagging. Rimm noted that multiplex fluorescence was used to demonstrate that patients who responded to immune checkpoint inhibitor therapy had preexisting tumor-infiltrating CD8 T-cells (Tumeh et al., 2014)
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We think there is an inherent genetic sensitivity for the PD-1 blockade, but clearly there are both responders to PD-1 blockade in Hodgkin's ymphoma, l and patients who either don't respond or progress following initial responses, so it becomes very important to also understand biomarkers for response and resistance. To characterize the tumor microenvironment of cHL and better understand the mechanisms of action of resistance to immune checkpoint inhibitor therapy, Shipp's lab used multiplex immunofluorescence, digital image analysis, and mass cytometry (Cader et al., 2018; Carey et al., 2017)
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Matson and colleagues found that increased prevalence of eight microbial species, including Bifidobacterium longum, was associated with improved response to immune checkpoint inhibitor therapy, but two bacterial species were associated with non-responsiveness. Routy and colleagues found that increased prevalence of Akkermansia muciniphila was associated with improved response to immune checkpoint inhibitor therapy, and that exposure to antibiotics was associated with reduced responsiveness to therapy.
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biomarkers for combinations yet, even though arguably that's when we need them the most." He added that biomarker research often follows clinical trials, and there is less incentive to incorporate biomarkers in the design of early-phase studies because "no one wants to eliminate patients who might respond." Rimm suggested devising new strategies for incorporating biomarkers in Phase II and III studies. Defining Thresholds for Biomarker Results Ronald Kline, medical officer with the Center for Medicare & Medicaid Innovation at the Centers for Medicare & Medicaid Services, noted that biomarkers are rarely dichotomous variables; consequently, investigators need to define thresholds for positive or negative biomarker results.
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. Lemery said the supplemental BLA for pembrolizumab in patients with MSI-H cancers was approved in 2017 based on objective response rates and durability of responses across 14 tumor types.
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Availability of Biospecimens for Biomarker Discovery and Development Butterfield said variability in the quality of biospecimens available for study hinders the development of useful biomarkers for immune checkpoint inhibitor therapies -- many biospecimens have not been collected, processed, and stored under standardized conditions, and are thus not useful for biomarker development. She pointed to an editorial from Nature Biotechnology stating (No sample left behind, 2015)
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Butterfield also suggested several opportunities to improve the measurement of immune biomarkers in clinical trials of combination therapies: 19 See https://www.sitcancer.org/research/biomarkers (accessed April 22, 2019)
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, urged researchers to examine the patient experience in clinical trials for combination therapies with immune checkpoint inhibitors. "We really haven't talked about how our patients are living with their cancer and living with the treatments that we're giving them," House said.
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Herbst also suggested that clinical trials should be designed with the community center in mind and seek input from the leaders in community cancer care at the stage of trial design to ensure that the trials can be done outside of an academic center. 21 See https://www.asco.org/research-progress/clinical-trials/clinical-trial-eligibility-criteria (accessed April 23, 2019)
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Dosing, Sequencing Administration, and Treatment Duration for Combinations Another challenge when designing clinical trials for combination therapies is determining the appropriate dose, sequencing of therapies, and treatment durations. Chen noted that with single-agent cancer therapies, determining optimal dosing and treatment duration is already quite challenging.
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Trial Designs to Promote Efficiency Several speakers discussed opportunities to improve the efficiency of clinical trials assessing combinations with immune checkpoint inhibitors, including different types of master protocols and clinical trials with shared controlled arms. Tarhini noted that the ever-expanding array of immune therapies in cancer creates a need for greater efficiency in clinical trials.
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Patients with the disease are screened for the presence of particular biomarkers and assigned to a stratum on the basis of the biomarker test results. As mentioned earlier, one example of an umbrella clinical trial is Lung-MAP (Lung Cancer Master Protocol)
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fying meaningful short-term study endpoints that may enable the adaptive designs often used with master protocols can also be more complex with combinations involving immune checkpoint inhibitors. Tarhini suggested that the NCI-sponsored National Clinical Trials Network (NCTN)
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Ibrahim noted that master protocols could also introduce some standardization across ongoing studies, as well as reduce redundancies, especially in regard to small, investigator-initiated studies. Shared or External Control Arms As noted earlier, many trials involving immune checkpoint inhibitors are using the same comparator treatment, which is creating redundancy.
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The FDA Oncology Center of Excellence is conducting Project: Switch,24 which is assessing: • Whether well-matched external control arms, based on prior clinical trials, can be used to make inferences regarding the effect of a new drug; or • Whether an external control arm could be used in place of a control arm in ongoing randomized controlled trials for patients with rare cancers, poor prognoses, and few treatment options. 24 See https://www.fda.gov/NewsEvents/Speeches/ucm629942.htm (accessed April 24, 2019)
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For example, Flatiron Health's real-world dataset illustrating the shift in the standard of care for lung cancer over time can inform the development of new clinical trials for immune checkpoint 25 See https://projectdatasphere.org/projectdatasphere/html/home (accessed May 1, 2019)
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. Researchers found that this real-world cohort had shorter overall survival compared with clinical trial results, and suggested that this difference may be due to the narrow eligibility criteria of these clinical trials (Khozin et al., 2018b)
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One example of an industry-driven collaboration is the Clinicogenomic Database, assembled by Foundation Medicine and Flatiron Health, to combine patients' clinical data with their genomic sequencing data (Agarwala et al., 2018; Singal et al., 2019)
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WRAP-UP Dansey reflected that this workshop convened experts with diverse perspectives to consider solutions to ongoing challenges in the development of combination cancer therapies with immune checkpoint inhibitors. The state of the science is changing rapidly, and workshop speakers emphasized 31 See https://www.focr.org/sites/default/files/pdf/RWE_FINAL%207.6.18.pdf (accessed April 30, 2019)
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48 FIGURE 3 Process to link clinical data from Flatiron Health to genomic data from Foundation Medicine. NOTE: FH = Flatiron Health; FMI = Foundation Medicine; ID = identification; SFTP = Secure File Transfer Protocol.
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He noted the importance of biomarker research -- both in refining and standardizing current biomarkers, as well as in the identification, development, and validation of new biomarkers -- to better select patients who might benefit from immune checkpoint inhibitor therapy and to prioritize combination strategies for evaluation in clinical trials. To conduct this research, he stressed the critical importance of collecting, processing, and storing biospecimens under standardized conditions.
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2019. 24-month overall survival from KEYNOTE-021 cohort G: Pemetrexed and carboplatin with or without pembrolizumab as first-line therapy for advanced nonsquamous non-small cell lung cancer.
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2017. First-line nivolumab in stage IV or recurrent non–small-cell lung cancer.
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2018. Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer.
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2018. The biology and management of non-small cell lung cancer.
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2018b. Real-world outcomes of patients with metastatic non-small cell lung cancer treated with programmed cell death protein 1 inhibitors in the year following U.S.
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with unresectable or metastatic melanoma: Results of the phase 3 ECHO-301/KEYNOTE-252 study. Journal of Clinical Oncology 2018 ASCO Annual Meeting 36(Suppl, Abstr 108)
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2018. Myocarditis associated with immune checkpoint inhibitors: An expert consensus on data gaps and a call to action.
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-1 and anti– programmed death-ligand 1 (PD-L1) blockade in patients with non–small-cell lung cancer profiled with targeted next-generation sequencing.
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2018c. The clinical trial landscape for PD1/PDL1 immune checkpoint inhibitors.
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as a predictive biomarker for atezolizumab (atezo) in 1L non-small cell lung cancer (NSCLC)
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2017. Master protocols to study multiple therapies, multiple diseases, or both.
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