Policy Issues in the Clinical Development and Use of Immunotherapy for Cancer Treatment Proceedings of a Workshop (2016) / Chapter Skim
Currently Skimming:
Proceedings of a Workshop
Proceedings of a Workshop
Pages 1-102
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 1... ...
Clinical trials are currently evaluat 1 The planning committee's role was limited to planning the workshop. The Proceedings of a Workshop has been prepared by the rapporteurs as a factual account of what occurred at the workshop.
|
From page 2... ...
. t For example, adverse events with immunotherapy treatment are quite different from those experienced with other types of cancer therapy.
|
From page 3... ...
• Drug development challenges for immunotherapies, including a lack of preclinical animal models and assays; difficulty in selecting appropriate clinical trial endpoints, predicting effective doses, and anticipating, understanding, and mitigating toxicities; scarcity of validated biomarkers to identify patient populations who would benefit from immunotherapies; and the complexities of testing combination immunotherapies. • New opportunities for collaboration and information exchange for advancing the field, including data aggregation and sharing elec tronic health records (EHRs)
|
From page 4... ...
• onsider alternatives to preclinical testing in animal models, C given the limitations of these models in assessing immunothera pies. (Fox, Heslop, Singh)
|
From page 5... ...
• onsider novel regulatory paradigms and adaptive clinical trials C to improve immunotherapy development. (Ibrahim, Kaufman)
|
From page 6... ...
Addressing Adverse Effects and Improving Patient, Clinician, and Payer Education • etter inform patients about cancer immunotherapies, especially B the need to report and address side effects early, as well as the potential for pseudo-progression that can occur while taking immunotherapies for cancer. (Ibrahim, Schwartzberg, Wolchok)
|
From page 7... ...
• tandardize how adverse events in immunotherapy are defined, S and consider novel terminology for characterizing immune related adverse events in clinical trials. (Ibrahim)
|
From page 8... ...
Center for Cancer Research; Malcolm Brenner, professor at the Center for Gene Therapy at Baylor College of Medicine; Naiyer Rizvi, director of thoracic oncology and director of immunotherapeutics at Columbia University Medical Center; and Steven Rosenberg, chief of the surgery branch at the NCI -- discussed the current state of the science for immunotherapy in oncology. They said that tumor cells often express proteins that are not expressed under normal physiological conditions, and that these abnormal proteins (antigens)
|
From page 9... ...
In addition to activating an immune response, the immune system also has mechanisms to curb or suppress immune responses. This prevents the production of cytotoxic T-cells once an infection or tumor has been cleared, and can help prevent an overblown immune response that can result in an autoimmune reaction that kills normal tissues.
|
From page 10... ...
"That is just part of the normal biology that occurs when you have an immune response. You cannot have unchecked T-cell activation" (see Figure 2)
|
From page 11... ...
Only the cancer cells with excessive production of immune suppressing factors or a lack of immune stimulating factors will survive and repopulate a tumor. Rizvi said that "there is not just one pathway of immune escape, but multiple pathways, which is why single-agent immunotherapy only works in a subset of patients with cancer." CANCER IMMUNOTHERAPIES Harnessing the current knowledge of immune response to tumors, researchers have developed a number of new immunotherapies for cancer, including immune modulating drugs that release the brakes on the immune system, vaccines that stimulate an antitumor immune response, and cellbased therapies that use a patient's own T-cells, said Rizvi, Berzofsky, and Rosenberg.
|
From page 12... ...
. Rizvi reported that a pooled analysis of clinical trials of ipilimumab in 1,800 patients with advanced melanoma found nearly 20 percent of the treated patients were still alive 10 years later, suggesting an unusually durable response for a subgroup of patients (Schadendorf et al., 2015)
|
From page 13... ...
"Most cancer antigens are expressed inside the cell and cannot be seen by antibodies," Berzofsky said, making a T-cell-mediated vaccine more universally applicable. Berzofsky added that T-cells have many advantages as antitumor agents, including their ability to travel through multiple tissues, rapidly increase in number, and recruit other immune responses.
|
From page 14... ...
Berzofsky added that common mutations in the RAS or p53 gene could be used in the development of a cancer vaccine by creating neoantigens that are recognized by T-cells and evoke an antitumor T-cell mediated immune response (Smith et al., 1997) .3 In one study, patients with cancer underwent genetic analysis for mutations in RAS and p53.
|
From page 15... ...
. Autophagosomes can elicit a strong antitumor T-cell response, Fox said, and added that more than 100 antigens commonly overexpressed in human cancers were present in the off-the-shelf autophagosome vaccine currently in clinical trials (Page et al., 2016)
|
From page 16... ...
activated," R osenberg said. A patient's immune cells are depleted prior to reinfusion of the cells in order to avoid suppression of the immune response.
|
From page 17... ...
"There are no predictions necessary because everything is a direct measurement of the ability of a mutation to be an active antigen," Rosenberg said. "This is a blueprint for how one might develop an immunotherapy for virtually any cancer." Proof-of- rinciple testing in 25 patients whose tumors responded p to adoptive cell transfer immunotherapy found that each patient harbored unique tumor antigens randomly scattered throughout their genome that were not shared by other patients.
|
From page 18... ...
Nonetheless, he said that some biotechnology companies have expressed interest in personalized cell-based immunotherapy because they see the potential for its application to a wide variety of cancer types. One participant asked what the impediments to clinical trials evaluating personalized adoptive T-cell transfer therapy are.
|
From page 19... ...
Cancer vaccines that have tried to target these shared relatively weak antigens have also not been effective in cancer treatment, because they are not targeting the unique mutation in that patient's tumor," he said. A fourth participant questioned whether patients are more likely to respond to personalized adoptive cell transfer therapy if they have more mutations that can elicit an antitumor T-cell response.
|
From page 20... ...
"These cells are both personalized, because every dose comes from a specific patient, and they are precise because they specifically target a protein on the tumor." Porter described the development of a CAR T-cell therapy directed against the CD19 receptor on B-cells, a class of immune cells responsible for producing antibodies. The CD19 receptor is expressed by most B-cell malignancies, and Porter said that research has found that antibodies against CD19 inhibit tumor cell growth.
|
From page 21... ...
Furthermore, the solid tumor microenvironment contains cytokines, regulatory immune cells, and other factors that "render the environment very hostile to any immune response that might develop," Brenner said. 4 Cytokine release syndrome occurs when patients experience inflammatory symptoms that result from rapid and large release of cytokines into the bloodstream.
|
From page 22... ...
might potently t activate antitumor T-cells by promoting tumor cell death and the release of multiple tumor antigens. These antitumor effects could potentially be enhanced through inhibition of immune suppression by treatment with checkpoint inhibitors, such as anti-CTLA-4 or anti-PD1 compounds, or other immune response regulators.
|
From page 23... ...
Data also showed that the combination of nivolumab and ipilimumab caused a 58 percent response rate for melanoma patients with metastatic melanoma; FDA has since approved that combination therapy for that patient population, Rizvi added. Response rates were 72 percent in patients with melanoma who tested positive for upregulation of PD-L1 in tumors and blood (Larkin et al., 2015)
|
From page 24... ...
, added, "When we are regulating products that are designed for a single person, we just have to develop new paradigms." He said that given the high response rates seen in personalized cell-based immunotherapies for cancer, "we have to develop a way forward, an approach to this that will facilitate these products being available." In particular, Bross suggested changes to the business model for cancer immunotherapies, which some people do not view as economically feasible without some federal funding of preclinical and clinical development. Brenner added that the complexity of these treatments "means you cannot follow the standard drug development pathway from preclinical [studies to]
|
From page 25... ...
Preclinical Challenges for Immunotherapy Animal models for preclinical testing are an essential component of cancer therapy development. Whitney Helms, supervisory pharmacologist at FDA's Office of Hematology and Oncology Products, said that FDA often requires testing in two animal species for drugs and one animal species for biologics prior to the initiation of clinical trials evaluating novel cancer therapies.
|
From page 26... ...
.5 She said that immune modulator drugs that are currently being assessed in human clinical trials (e.g., drugs that modulate CTLA-4, PD-1, PDL-1, OX40, LAG3, 4-1BB, and GITR) have all been developed based on data from mouse models (Budhu et al., 2014; Pardoll, 2012)
|
From page 27... ...
Because immunotherapy requires a functional immune system, immunedeficient mice models are not sufficient to evaluate hypotheses related to immunotherapies. Other syngeneic mouse models exist, in which tumor cell lines developed from the same strain are implanted into immune competent mice (for example, the B16 melanoma and ID8 ovarian cell lines in C57/BL6 mice)
|
From page 28... ...
Fox described experiments designed to provoke an immune response in mouse models by genetically engineering the B16 melanoma tumor cell line to express receptors for several interleukins, interferon gamma, granulocyte-macrophage colony-stimulating factor (GM-CSF) , and a number of other cytokines.
|
From page 29... ...
were treated with an antitumor vaccine, only the first group of mice was protected from developing tumors. Because different mouse models have often generated conflicting findings, Snyder said "the evaluation of any intervention in several models is critical." Angela Thomas, clinical trials chair of the Biological and Vaccines Expert Advisory Group at the UK National Health Service (NHS)
|
From page 30... ...
. Because of these species-unique differences in MHC, Singh said there are no relevant toxicity-predicting animal models for the protein fragments that fit within the HLA clefts of human immune cells (or HLA-restricted peptides)
|
From page 31... ...
For example, Heslop said that lack of appropriate animal models to evaluate the toxicity of an Epstein-Barr virus–specific T-cell therapy to prevent or treat patients with Epstein-Barr virus–related lymphoproliferative disease after receiving a bone marrow transplant led to FDA placing a hold on the clinical trial, due to concerns about cross-reactivity damaging normal healthy tissue (Heslop et al., 2010)
|
From page 32... ...
. Protein arrays to evaluate immune response in mouse models would also be useful, said Fox, but unfortunately do not yet exist.
|
From page 33... ...
Evidence Requirements and Considerations for First-in-Human Trials Several presenters suggested that because of the limitations of pre clinical animal models and tests for cancer immunotherapies -- especially
|
From page 34... ...
The trial was also redesigned as an antigen-escalation study, in which the first group of patients received only one antigen and the second group received two antigens, until all five antigens were provided to patients. Heslop also suggested that investigators consider options in advance to reduce clinical risk if adverse events occur, such as having the ability to ablate cells (e.g., with steroids)
|
From page 35... ...
should be considered," Helms said, adding that checkpoint inhibitors would fall into the class of biopharmaceuticals for which a MABEL would be appropriate. Determining a MABEL relies heavily on a variety of pharmacology studies rather than the traditional toxicology models, she said.
|
From page 36... ...
Because animal models cannot often recapitulate human immune responses and side effects, he asked if FDA would consider skipping preclinical toxicology analyses for cancer immunomodulators in which there is either abundant proof-ofprinciple studies using the candidate or related agents or in vitro studies of the candidate agent that indicate a mechanism of action. Helms said, "The point of an animal toxicology study is not just to look for exaggerated pharmacology, which obviously we are not seeing so far with some of the immuno odulators, but to address the worry that you are going to miss m something.
|
From page 37... ...
Singh also suggested that clinical dose escalation studies may not be helpful in determining toxicities of cancer immunotherapies, and instead suggested assessing off-target toxicity in the preclinical setting. Clinical Trial Design Considerations A number of workshop participants discussed issues and challenges in the design of clinical trials for immunotherapies in cancer, including • Inability to identify which subsets of patients are most likely to respond to specific immunotherapies.
|
From page 38... ...
Several workshop participants discussed the use of elevated PD-L1 expressed in tumors as an indicator for anti-PD-1/PD-L1 therapy. Rizvi said a review of checkpoint inhibitors found that elevated expression of PD-L1 on tumors correlated with greater likelihood of responding to anti-PD-L1 or antiPD-1 therapies (Sunshine and Taube, 2015)
|
From page 39... ...
Another proposed biomarker for identifying which patients are likely to respond to cancer immunotherapies is the mutation load of their tumors. Melanoma, lung, bladder, and other cancers that tend to have high rates of mutation (or mutation loads)
|
From page 40... ...
Reprinted with permission from Macmillan Publishers Ltd. Figure 4 that mutation load combined with original source replaced from PD-L1 expression levels were especially vector editable robust in predicting benefit to anti-PD1 treatment in patients with lung cancer; 10 of the 11 patients (or 90 percent)
|
From page 41... ...
. However, she said that this is a prognostic signal and not a validated biomarker ready to be used for prediction of patient response as part of the enrollment criteria for patients in clinical trials.
|
From page 42... ...
a lot of different types of samples for unspecified future research to identify the biomarkers we need," B utterfield said. She added that many tumor specimens collected in clinical trials are likely to be nonviable because they have not been prepared in the manner necessary to conduct functional assays, such as the ones needed for the personalized cancer immunotherapy that Rosenberg described.
|
From page 43... ...
, and that requires really good communication with the community to enable evidence gathering. It requires not just physician engagement, but patient engagement and using some of the tools that are being developed in the informatics space that allow patients to interact with their data and with other patients and with the companies and academic centers running clinical trials," he said.
|
From page 44... ...
In addition, overall response rates have been inconsistent from one cancer type to another, with melanoma patients tending to have greater responses than patients with non-small cell lung cancer, for example. The effectiveness of cancer therapies is often assessed using the Response Evaluation Criteria In Solid Tumors (RECIST)
|
From page 45... ...
"This makes the data from clinical trials really complex unless you use overall survival or landmark survival as an endpoint," Wolchok said. After conducting an analysis of Phase II trials of ipilimumab in melanoma patients, Wolchok found that 10 to 20 percent of patients showed tumor progression on their first set of scans, but subsequently showed a response without any additional therapy, which led to the development of immune-related response criteria as an alternative to RECIST (Wolchok et al., 2009)
|
From page 46... ...
since treatment start or the appearance of one or more new lesions Stable disease (SD) Neither sufficient Not meeting criteria for CR or shrinkage to qualify as PR PR, in absence of PD nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since treatment start NOTE: BOR = best overall response; CR = complete response; LD = longest diameter; PD = progressive disease; PR = partial response; RECIST = Response Evaluation Criteria In Solid Tumors; SD = stable disease.
|
From page 47... ...
imaging might also provide a better mechanistic understanding of immune cell trafficking to tumors that could provide additional support for immune response criteria. "Once we can put a bit more data behind the observations, this will come more easily," Wolchok said.
|
From page 48... ...
That is where we can see a higher rate of dis ordance c between potential response and enlargement of lesions on imaging," W olchok said. He suggested that patients in clinical trials be offered the possibility of continuing on an immunotherapy beyond the point when progression is detected by imaging, as long as their performance status is maintained, but added "we are all learning about this together." Ibrahim said the FDA guidance document for vaccine development acknowledges the need for new response criteria and suggests that the studies with immunotherapies should have an exploratory endpoint that tries to characterize the immune response rate observed.
|
From page 49... ...
Simon said a literature review of a large number of vaccine clinical trials found that grade 3 or 4 toxicities were exceedingly low -- generally less than 1 percent of patients or less than a tenth of 1 percent of vaccine administrations. In those patients who did experience grade 3 or 4 toxicities, there was little evidence that it was dose related, Simon added (Rahma et al., 2014)
|
From page 50... ...
There are also manufacturing challenges, such as ensuring identity comparability and sterility of products that can affect the statistical interpretation of clinical trials, Bross said. But perhaps the ultimate challenge, he suggested, is "How are we supposed to regulate a product that is different for every patient?
|
From page 51... ...
"One statistician calculated the possibility of putting together all of these in combination and calculated it would take 300 years to clinically test them," Khleif said. "What are the clinical trial designs that would be necessary to move this field further so we could do it in 10 or 15 years rather than waiting 300 years?
|
From page 52... ...
Clinical trials of combination cancer immunotherapies are complex because investigators need to consider which agents to combine and how to sequence these agents to maximize efficacy and minimize toxicity, several speakers said. When the immune stimulant OX40 was given concurrently with anti-PD1 treatment in mice, the animals did not survive as long as they did when given OX40 alone, Fox said.
|
From page 53... ...
He also recommended defining upfront the duration of therapy in clinical trials, independently of progression of disease for the treatment arm containing the immunotherapy, to overcome the challenge of pseudoprogression in analyses. For example, clinical endpoints for Phase IIb trials could be response status after 6 months of treatment, and the clinical endpoints for Phase III studies could be overall survival, he said.
|
From page 54... ...
Simon showed several examples of study designs for Phase II clinical trials of combination therapies. One is to first treat patients with a single immunotherapy, and then for those patients who do not respond, investigators could provide an additional immune modulator.
|
From page 55... ...
Bruce Chabner, director of clinical research at the Cancer Center at Massachusetts General Hospital, noted that small discovery Phase II studies and even Phase I s tudies have led to accelerated approvals of individual checkpoint inhibitors because they generated such high response rates and durable responses. "It all depends on whether you can select patients appropriately for the trial and have a very high response rate," Chabner said, adding that discovery trials for combination therapies could quickly become trials used to garner drug approvals if the right combinations go to the right patients.
|
From page 56... ...
To personalize the vaccine, researchers conduct an analysis of each patient's tumor antigens and assess whether any of 71 pre anufactured m peptide fragments that are commonly found in glioblastoma are prevalent in the patient's tumor and stimulate an immune response. They also use next-generation sequencing to identify neoantigens specific to each patient's tumor.
|
From page 57... ...
Porter said that in the pilot clinical trial of CAR T-cell therapy, they did not start with a traditional Phase I dose escalation study "because this is a living drug and while we knew a reasonable dose to start with from some animal model studies, we did not really think a traditional Phase I study was appropriate." However, the researchers conducted a follow-up study -- essentially a randomized Phase II dose-optimization trial -- that tested two dose levels, both of which had induced complete remissions in the pilot trial. Most new immunotherapies for cancer have entered the market via the accelerated approval pathway based on objective response rates, Sridhara said (see Box 2 for a summary of the different FDA approval pathways and designations and Box 3 for an overview of European regulation of drugs and biologics)
|
From page 58... ...
• reakthrough therapy designation is for drugs or iologics B b intended to treat a serious or life-threatening disease or con dition when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies. The designation enables FDA to provide intensive guidance on an efficient drug development program, begin ning as early as Phase I clinical trials.
|
From page 59... ...
The safety data for all those indications were then pooled, "giving a lot of information about these immunotherapies in a very controlled and careful way," Thomas said. She added that there was concern that EAMS might impair recruitment to Phase III clinical trials, but that has not been documented, with most drugs already under evaluation in Phase III trials when they enter EAMS.
|
From page 60... ...
a treatment will provide and how much that will cost. Drugs that cost more than $30,000 per QALY are not likely to be recommended, Thomas said, although she added that a higher limit is often acceptable if there is a life expectancy of less than 2 years without treatment and the drug will prolong a person's life for more than 3 months, as is true for many cancer treatments.
|
From page 61... ...
A patient's health information can be stored in a variety of places: community health care settings, academic and government medical centers, registries of clinical trials, omics-based databases such as The Cancer Genome Atlas, as well as in patient-powered databases like PatientsLikeMe9 and PCORnet.10 "Today there is so much data out there that you could use. What people can now do with all these data is getting more impressive and interesting every day," Perakslis said.
|
From page 62... ...
62 POLICY ISSUES FOR CANCER IMMUNOTHERAPY Demographics Outside Structured Unstructured Practice Diagnosis Data Data Hospitals Visits Labs Labs Physician Notes Electronic Health Radiology Reports e Prescribing Record Pathology Reports Discharge Notes De identification of all data Data processing Aggregated EHR data FIGURE 6 Electronic health records (EHRs) include a variety of structured and unstructured data sources that need to be combined and structured for analysis.
|
From page 63... ...
She and her colleagues used a claims database that compiled information from more than 115 million patients and more than 100 payers to compare the 1-year costs of hematopoietic cell transplantation (HCT) or chemotherapy treatment in patients with acute myeloid leukemia.
|
From page 64... ...
Being up to date is critical given the rapidly changing landscape of cancer immunotherapies, she said. For example, nationwide PD-L1 checkpoint inhibitors made up only about 1 percent of all treatments for patients with non-small cell lung cancer in November 2014.
|
From page 65... ...
Figure 7 SOURCES: Abernethy presentation, February 29, 2016; Flatiron Health. vector, editable cians and patients about the effectiveness and costs of different cancer therapies, Newcomer said.
|
From page 66... ...
For example, if a patient received CAR T-cell therapy at one institution after another immunotherapy failed at a different institution, and then went on to have a bone marrow trans
|
From page 67... ...
Precompetitive Collaboration Several speakers said precompetitive collaboration among industry, academia, patients, payers, and clinicians will be needed to improve the development and implementation of cancer immunotherapies in clinical practice. Brenner called for a culture of collaboration and transparency among academic institutions and pharmaceutical firms.
|
From page 68... ...
." But he said that complex immunotherapies often require longer academic involvement, which makes it more likely that new agents may "end up in the valley of death," in which academic funding has been depleted but industry funding that has yet to emerge. To prevent this funding cliff, Brenner described the mission of the Center for Cell and Gene Therapy, which conducts basic and translational research necessary for a cell therapy to advance into Phase II clinical trials.
|
From page 69... ...
Recognizing all these challenges, before any of the anti-PD-1/PD-L1 agents or assays received FDA approval, the leadership of the pharmaceutical and diagnostic companies explored the potential for precompetitive collaboration and formed a consortium called Blueprint, which was facilitated by the American Association for Cancer Research. The consortium enlisted what Averbuch called "an independent honest broker," the International Association for the Study of Lung Cancer, to compare the analytical performance of the different diagnostic assays and pave the way for postmarket standardization.
|
From page 70... ...
70 TABLE 2 Summary of Published Findings for PD-L1 Immunohistochemistry in Therapeutic Trials Positive ORR % ORR % Definition of N Positive Predictive IHC pos.
|
From page 71... ...
a Expression in tumor cells unless otherwise stated. b The 31% figure is for all tumors.
|
From page 72... ...
It was always about the patient. That is what kept everybody together." CLINICAL IMPLEMENTATION Many workshop presenters and discussants said there are a number of challenges in implementing cancer immunotherapies in clinical practice, including scaling up complex cell-based therapies, detecting and managing adverse side effects that are often non-specific, and educating clinicians and patients on what responses to expect from immunotherapies, which can differ markedly from standard cancer treatments.
|
From page 73... ...
Once Novartis was satisfied that it had adequately duplicated the cell therapy, it started manufacturing the T-cell products for use in clinical practice and conducted a review of its process capabilities. Factors of particular concern when scaling up production include having better control of and streamlining the process by improving unit operations, and having better product characterization.
|
From page 74... ...
Novartis was able to generate a T-cell expansion rate within a tighter range, but comparable to that seen at the University of Pennsylvania, Dudley reported, and the pharmaceutical company is currently conducting a global Phase II trial of the CAR T-cell therapy in patients with acute lymphocytic leukemia. "We started by making one product at a time, treating a couple patients a month.
|
From page 75... ...
targeting Adult and pediatric ALL, Therapeutics CD19, NHL, AML, NSCLC TCR targeting Wilms tumor protein-1 Cardio3 CARs targeting NKp30; NKG2D; Range of hematological Biosciences B7H6 malignancies and solid tumors Cellular CARs targeting CD19, CD20, Range of hematological Biomedicine CD30, and EGFR malignancies and solid Group (China) tumors CARsgen CARs targeting GPC-3 Hepatocellular carcinoma Celgene/Bluebird CAR (autologous)
|
From page 76... ...
CD19, TCR, MAGE-A4 Bellicum CAR (autologous) targeting CD19 Potential hematological Pharmaceuticals with a proprietary safety switch malignancies and solid to mute unwanted adverse events, tumors such as cytokine release syndrome Cellular CAR (autologous)
|
From page 77... ...
ALL = acute lymphoblastic leukemia; AML = adult acute myeloid leukemia; B7H6 = B7 homolog 6; CAR = chimeric antigen receptor; CD = cluster of differentiation; EGFR = epidermal growth factor receptor; GPC-3 = glypican-3; MM = multiple myeloma; NHL = non-Hodgkin's lymphoma; NK= natural killer; NKG2D = NK group 2, member D; NKp30 = NK cell p30-related protein; NSCLC = non-small cell lung cancer; TCR = T-cell receptor; TIL = tumor infiltrating lymphocytes. SOURCES: Porter presentation, February 29, 2016; adapted from June et al., 2015.
|
From page 78... ...
. Adverse events in the skin following anti-CTLA-4 therapies usually are seen early, whereas adverse events involving the liver or endocrine system have more of a delayed onset.
|
From page 79... ...
Low-grade events are usually managed with treatments aimed at relieving symptoms or with topical agents, but if the condition persists or worsens, patients are usually prescribed systemic corticosteroids, he said. Education and vigilance are key to managing adverse events in patients who receive cancer immunotherapies because the earlier the recognition of the inflammation and its treatment, the less likely the patient will develop serious complications, Ibrahim said.
|
From page 80... ...
While investigators involved in clinical trials of immunotherapies know how to identify and manage adverse events, this "might not be the case once the drugs get marketed or investigators who have less experience start treating patients with these agents," Ibrahim said. He added that clinical trials occur in closely monitored environments and there are very strict criteria about when to stop treatment when adverse events occur, unlike in community oncology settings.
|
From page 81... ...
Schwartzberg said the ability to manage patients' adverse events varies according to the size of the practice providing cancer immunotherapies. Small- to medium-sized community practices, which provide approximately 80 percent of cancer care in the United States, may have challenges addressing the side effects of immunotherapies, given that many may be reported by patients during the weekend when practice clinicians are not available.
|
From page 82... ...
. Educating Clinicians, Patients, and Payers Schwartzberg described the rapid progress seen in immunotherapies for cancer, with nine approvals of five different drugs or drug combinations within the course of 1 year: • March 2015: Nivolumab approved for squamous cell cancers fol lowing platinum-based therapy • September 2015: Nivolumab and ipilimumab approved for BRAF V600 wild type metastatic melanoma • October 2015: Pembrolizumab approved for PD-L1 positive non small cell lung cancer following platinum-based therapy (compan ion diagnostic)
|
From page 83... ...
to provide information about cancer BOX 4 Immunotherapy Information and Education for Patients Informing patients about cancer immunotherapies is particu larly important, several participants said. Gwen Darien, executive vice president for Patient Advocacy at the National Patient Advocate Foundation, described the results of a survey of cancer patients within the Cancer Support Community Cancer Experience Registry.
|
From page 84... ...
The potential for pseudo-progression with immunotherapy treatment is another important area of education, Schwartzberg said. He added that this is especially for patients with lung cancer, who typically have imaging scans every 6 to 9 weeks while receiving standard treatment and may not understand why the imaging inter vals are longer for immunotherapies, he said.
|
From page 85... ...
The two organizations are offering a clinical immuno-oncology symposium in 2017.11 Wolchok added that the Cancer Research Institute is working collaboratively with the Oncology Nursing Society to develop educational programs and materials for nurses and patients about cancer immunotherapies. There also is a policy working group convened by Friends of Cancer Research with a cancer immunotherapy education initiative.
|
From page 86... ...
And that is really where the value is," said Krug. At the same time, there are concerns about the high costs of cancer immunotherapies -- both currently approved therapies, as well as the expected high costs of future cell- and vaccine-based therapies, and combination therapies.
|
From page 87... ...
They have better response rates, but if your argument is that when we see prolonged survival then we can charge more, why are you charging so much more for new drugs before the evidence is there? " Ramsey added that although it is expensive to develop drugs, the cost of developing drugs is not going up commensurate with the price increases seen in cancer therapies.
|
From page 88... ...
But unfortunately, clinicians are not reimbursed for taking more time to explain cancer immunotherapies to their patients, said Patricia Ganz, distinguished professor at the University of California, Los Angeles, School of Medicine. "One of the big challenges is that our payment models do not allow clinicians and patients to have the time to communicate about this.
|
From page 89... ...
, there was very little emphasis placed on overall survival whereas now we're placing more and more emphasis on that," Rollins said Although CMS makes some National Coverage Decisions, CMS will often leave these decisions up to the discretion of Medicare contractors through a Local Coverage Decision, or sometimes will enable Coverage with Evidence Development (CED)
|
From page 90... ...
When making its coverage determinations, CMS reviews the medical literature and considers data from various sources. There is a preference for systematic reviews and meta-analyses of random ized clinical trials.
|
From page 91... ...
0.75 0.83 Cure proportion (percent) 6 21 NOTE: Mean overall survival of cured patients was greater than mean overall survival of uncured patients, and 15 percent more patients were cured by ipilimumab than gp100 (glycoprotein 100)
|
From page 92... ...
Greg Rossi, oncology business unit director at AstraZeneca, suggested that traditionally when cancer patients achieve a life expectancy similar to that of their age- and gender-matched peers, they are considered to have a durable response, if not a cure. Outcomes-Based Pricing and Bundled Models Rossi suggested use of value-based pricing of cancer immunotherapies for each indication and use of outcomes-based agreements with drug sponsors.
|
From page 93... ...
But because both the response and treatment duration will be unknown for many cancer immunotherapies, Rossi said calculating their value is difficult. "How do we understand what we are getting for the money we are spending?
|
From page 94... ...
Krug agreed and said that the Immuno-Oncology- ntegrated I Community Oncology Network, a network of community cancer centers, is currently collaborating with BMS so more community cancer centers are incorporated into clinical trials and novel treatments can be made available to more patients. Effort is also being made to make eligibility criteria for clinical trials broader so more patients can be enrolled, and to simplify and streamline the clinical trial process so data can be collected more quickly, Krug said.
|
From page 95... ...
Clinical Cancer Research 17(10)
|
From page 96... ...
2005. Immunization with mutant p53- and k-RAS-derived peptides in cancer patients: Immune response and clinical outcome.
|
From page 97... ...
2014. Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: A randomized clinical trial.
|
From page 98... ...
2008. Efficient cross presentation depends on autophagy in tumor cells.
|
From page 99... ...
2014. Is the "3+3" dose-escalation Phase I clinical trial design suitable for therapeutic cancer vaccine development?
|
From page 100... ...
2015. Pooled analysis of long-term survival data from Phase II and Phase III trials of ipilimumab in unresectable or metastatic melanoma.
|
From page 101... ...
2011. Tumor-derived autophagosome vaccine: Induction of cross-protective immune responses against short-lived proteins through a p62-dependent mechanism.
|
From page 102... ...
Clinical Cancer Research 15(23)
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.