Review
Review
Human Vaccines & Immunotherapeutics 10:11, 1–5; November 2014; © 2014 Landes Bioscience
Cancer vaccines
What do we need to measure in clinical trials? Alex Kudrin1,* Celltrion Inc; Incheon, South Korea
1
Cancer immunotherapy has seen a tremendous number of failures and only few recent regulatory successes. This review is dedicated to evaluate remaining challenges in capturing clinical response with cancer vaccines. Definition of disease progression in context of clinical rather image-specific criteria and interpretation of efficacy in relation to delayed effect of cancer vaccines should be taken into account in the design of future of immunotherapy trials.
Values of Cancer Immunotherapy The successful manipulation of a cancer-directed immune response has long been a battle ground for cancer immunologists, oncologists and patients themselves. The field of cancer immunotherapies has been littered with failures and there are estimates that more than 10 000 cancer patients were treated with these products in numerous unsuccessful clinical trials. However a glimmer of hope has arisen following FDA and EMA approval of sipuleucel-T (Provenge) for the treatment of castrate-resistant prostate cancer and ipilimumab (Yervoy) approval by FDA and EMA for patients with advanced melanoma. Cancer immunotherapy has always been an attractive strategy for treatment of cancer promising to restore own specific immunological responses against the tumor and providing with safe, tolerable, and long-lasting therapeutic regimen. Although traditional cytotoxic chemotherapy remains a treatment backbone for many malignancies, targeted therapies are now a component of treatment for many types of cancer. However targeted therapies can be employed in specific subgroups of patients and cancer immunotherapies may offer with options to deliver a broad clinical effectiveness across biomarker positive and negative patients. Growth in targeted therapies has reinvigorated interest in cancer immunotherapy because of the following potential advantages: (1) therapeutic vaccines employed as a monotherapy could deliver targeted immune-mediated effect on tumors; (2) the advantage of cancer vaccines compared with passive immunotherapy is that T-cell driven responses and memory associated with those could assist with immune response during disease recurrence; (3) combination regimens composed of vaccines *Correspondence to: Alex Kudrin; Email: [email protected] Submitted: 11/28/2013; Accepted: 12/19/2013; Published Online: 01/09/2014 http://dx.doi.org/10.4161/hv.27586
www.landesbioscience.com
and small molecule and / or biological anticancer agents could synergistically enhance the effect on tumor microenvironment, metastatic growth, and tissue remodelling; (4) effect on tumor “evasion” via immunological bypassing of accumulated tumor defects resulting in theoretical possibility of reduced failure of a backbone targeted therapy agent (e.g., anti-HER2 antibody); (5) sparing effect on the use of other chemotherapy agents that may translate in safety and cost benefits; (6) improvements in quality of life, tolerability, compliance, and patient reported outcome profiles; (7) there is a remote theoretical possibility that cancer immunotherapies may reduce long-term risk of secondary cancers in surviving patients; (8) there might be benefits in special populations such as pregnant women, children or at the very least immunotherapy could spare reproductive function in cancer survivors; (9) cancer vaccines could deliver clinical outcomes in chemotherapy-failures or biomarkers-negative patients (e.g., in HER2 triple negative breast cancer patients unable to receive trastuzumab; KRAS-mutants non-qualified for cetuximab or panitumumab and melanoma patients who do not carry V600E mutations and unable to qualify for vemurafenib; (10) cancer vaccines are less prone to genericisation and biosimilar rivalry. Overall, cancer vaccines could deliver a number of different therapeutic values which could be integrated by potential developers into target product profiles. However most of these values and benefits should be tested and explored in future clinical trials.
Sensing the Paradigm To sum up the knowledge around older and traditional yet unsuccessful cancer immunotherapy approaches, we can capitalize on the notion that “not enough of a good thing” is not the fundamental problem in tumor immunology and by trying to stimulate immune system using empirical approach of adding lacking cytokines, or delivering tumor-specific antigens will not succeed alone. New approaches should not be only aimed at trying to stimulate dysfunctional immune system or replace solitary lacking elements (such as cytokines or tumor antigens) but rather at eradicating or correcting dysfunctional elements of immune system. This paradigm will require sequential and combinatorial approaches and traditional antigen- or cell-based vaccination approaches will be considerably complemented by emerging technologies such as anti-PD1 antibodies, neoadjuvant and adjuvant radiotherapy, and photodynamic therapy etc.
Human Vaccines & Immunotherapeutics 1
©2014 Landes Bioscience. Do not distribute.
Keywords: cancer vaccines, endpoints, progression free survival, immune response, patient reported outcomes
Changing the Pipeline According to analyst report findings there are approximately 150 therapeutic cancer vaccines in phase 1–3 clinical development across 7 major markets. Approximately 70% of these products are standardized (“off-shelf”) vaccines. The remaining proportion is assigned to personalized vaccines. A disproportionately high number of candidates (almost 60%) is currently developed in prostate, breast, lung cancer, and melanoma. Such an imbalance can be explained by recent regulatory successes of Provenge (sipuleucel-T) in prostate cancer (US approval) and Yervoy (ipilimumab) in advanced melanoma (EU and US approvals) and possibly with greater available investment flow into these indications. In addition, the number of antigens discovered in these indications exceeded the number of antigens characterized in other types of tumors and this factor enabled to drive the innovation in these clinical indications. These findings illustrate that some indications with high unmet medical need are currently underrepresented in the pipeline. There is a gap in cancer vaccines for hematological, brain, thyroid, ovarian, pancreatic, and colorectal tumors.
Challenges in Clinical Development Concepts laid into FDA guidance have partially originated from the Cancer Vaccine Clinical Trial Working Group (CVCTWG).1 In this model, the first stage of development would be a proof-of-principle trial with the objective of evaluating the safety, dose and schedule, and the demonstration of biological activity, the later incorporating appropriate immune and molecular markers. The initial phase of clinical investigation may include as minimum as 20 patients in a homogenous, sensitive, and well-defined population and should be performed in an neo- or adjuvant setting without rapidly progressive disease in order to capture sufficient time for immune response to mature. According to Hoos et al.2 successful proof-of-principle trials support a more flexible, expeditious and focused clinical developmental process. Key recommendations on use of most sensitive, sufficiently lengthy, and homogenous clinical settings were reflected in FDA guidance. As opposed to CVCTWG recommendations, it is now apparent that an early POC study should be conducted in a controlled fashion allowing for more accurate assessment of immunological and clinical response and the time to its onset. Numerous cancer
2
vaccines failed in phase 3 studies were upstaged on the basis on erroneous evaluations of uncontrolled phase 2 studies. There is an ironic situation that some earlier failed trials might have resulted in elimination of cancer vaccine antigens which might have been mis-evaluated in trials of inappropriate design. The identification and validation of appropriate immunological biomarker is critical in development of cancer vaccines. Developers should consider cost-effectiveness, clinical utility, and clinical feasibility of the immunological biomarker or gene signature testing. If the test is cumbersome, requires specialized skills and labor, prohibitive in terms of cost to oncology health care and difficult to commercialize, it is likely that reimbursement bodies will displace these costs on developers or conclude on lack of cost-effectiveness. Poor technical feasibility of biomarker testing will most certainly reduce sales penetration and will require additional investment in training of health care practitioners and laboratory staff. During phase 3 planning, an adequate and pre-specified definition of progression and response are vital. Since cancer vaccines can cause tumor swelling, infiltration, and tumor fibrosis, some patient’s tumors may progress, increase their volume and give rise to new lesions (some possibly due to initial inflammation), which may be followed by a delayed response. As a consequence, a conventionally defined PFS may not be a suitable clinical endpoint in cancer vaccine studies.3,4 It is therefore recommended that the definition of progression should account for clinically relevant parameters such as patient’s performance status and / or global quality of life and not for volumetric or tumor-measurable criteria. However disease measurement should not be abandoned as long-term volumetric disease stabilization also should be considered as a measure of clinical activity.2,4 Continued treatment beyond progression under certain conditions can be summarized in blinded safety listings and monitored by independent data safety monitoring board (DSMB). The sponsor may need to plan regular DSMB safety reviews on e.g., 3–6-moly basis within the timeframe of expected delayed immune response (12–24 mo from the onset of vaccination). Studies with cancer immunotherapeutics can be irreversibly compromised by various confounding factors arising due to use of rescue medications, concomitant therapies and crossovers as a consequence of reported disease progression. Crossovers and concomitant therapies can abolish clinically and statistically significant differences in overall survival. Nevertheless, the advantage in PFS gain was still preserved but was not always sufficient from regulatory perspective. Crossovers can also contribute to reduced separation in OS. In the pivotal registration IMPACT trial with sipuleucel-T, control subjects who demonstrated objective disease progression were offered 3 infusions of an autologous cellular therapy produced from cells frozen at the time of control product generation. An exploratory analysis was performed to estimate how autologous therapy impacted the OS benefit of sipuleucel-T. It was found that postprogression treatment with sipuleucel-T may have extended the survival of control subjects in the IMPACT study. Adjusting for use of autologous rescue therapy resulted in an increase in median OS benefit with sipuleucel-T from 4.1 mo to 7.8 mo.5
Human Vaccines & Immunotherapeutics Volume 10 Issue 11
©2014 Landes Bioscience. Do not distribute.
It is reported that approximately 50 tumor antigens or antigen-targets are currently in different stages of development and they encompass not only membrane-bound but also intracellular targets. However with very high attrition rate reported in oncology, it is clear, that the number of currently studied tumor antigens is highly insufficient to ensure that there will a reasonable number of successful products in years to come. Therefore there is a considerable need for further tumor antigen discovery and their comprehensive validation.
www.landesbioscience.com
with MAGE3, Stimuvax, ipilimumab, and anti-PD1 therapies. The delayed response can risk the trial to become underpowered due to premature evaluation of OS, PFS and it most certainly question the utility of overall response evaluation in phase 1 and 2 immunotherapy studies. These 2 factors could account for many of previous clinical trial failures of cancer vaccine candidates. The most important recommendations out of these findings are as following: 1) The immune-related criteria of response should be implemented, used, and actively propagated to regulatory authorities as the most meaningful way of assessing the proof-of-concept related efficacy readouts with immunotherapy candidates 2) Adjusted PFS can be most appropriate clinical endpoint in some clinical settings with long survival horizon. 3) Definition of progression for the purpose of PFS censoring should be as objective as possible, standardized, and pre-specified. However in view of delayed volumetric effects of immunotherapy agents the definition of progression should be clinically driven rather than volume-driven. For example the worsening of Karnofski scores, ECOG status or specific Quality of Life parameters could represent criteria which are both clinically meaningful to prescribers and patients. 4) If volumetric progression criteria are employed, modified RECIST criteria should be used or a serial measurement with 3–6 mo interval employed. In accordance with Wolchok et al.4 immune-related response criteria ≥50% increase in tumor burden compared with nadir 2 consecutive measurements with 4 wk apart. However these criteria were derived from melanoma settings and this interval might be not sufficiently long to allow a delayed response to manifest in other oncology settings. In tumors with long survival duration, progression could be adjudicated as a continuous increase in target lesion size of >50% with serial measurements made with 3–6 mo interval. 5) Development of immunotherapies requires more sensitive imaging tools and sparse tumor biopsy in order to elucidate the time-dependent and treatment-dependent effects of immunotherapy on tumors and validate immune-related response criteria in numerous oncology settings. Therefore cancer immunotherapy requires validation of these new concepts in prospective randomized and observational studies in order to establish new endpoint structure and framework for future trials. From cancer vaccine perspective, more rational and risk-based evaluation of potential combination regimens is required. Since cancer vaccines are expected to provide with delayed response and impact on OS, a successful combination with product or regimen enabling earlier separation of OS curves and resulting in an improved efficacy profile and ultimately increasing the probability of success and reducing the trial duration and size. Rational selection of immunotherapy combination could be based on some new drug-screening platforms that quantitatively measure the effect of the combination on tumor-associated and systemic immune system and non-tumor cells (such as tumor stem and stromal cells). By using specific combinations of tumor and accessory cells, a screening assay can predict the relationship between targeted therapies and tumor microenvironment and isolate only those small molecule and / or biological
Human Vaccines & Immunotherapeutics 3
©2014 Landes Bioscience. Do not distribute.
These results suggest that crossover reduced the prominence of Sipuleucel T-driven favorable effect on OS. Given that cancer vaccines are unlikely to yield significant improvements in PFS, it is especially critical that the risk of crossovers and imbalanced use of concomitant therapies is minimised as much as possible through adequate protocol planning. From ethical perspective it is important that patients from placebo group will have access to the treatment which seems to show an improvement in clinical outcomes. However due to delayed effect of immunotherapeutics on PFS and long duration of studies required to demonstrate OS gains, the magnitude of the clinical benefit might not be so apparent. Therefore a careful consideration should be given to the crossover eligibility. The impact of any potential imbalances on OS/PFS evaluation should be elucidated using pre-specified statistical analyses and modeling. Investigators should be trained how to differentiate temporary worsening in disease vs. steady progression related deterioration. Sponsors should pre-define consistent characteristics constituting clinically relevant progression based on features agreed by patient and/or caregiver and treating physician. Whenever possible and feasible, a verification of underlying delayed immune response can be supported using tumor biopsy specimens and biomarker assays performed using peripheral blood samples. Correlation between immune assays and PFS/OS serve as one of the pivotal gate rules at the transition between phase 2 and phase 3. As described in FDA guidance, immunotherapy may induce novel patterns of antitumor response not captured by Response Evaluation Criteria in Solid Tumors (RECIST) or World Health Organization (WHO) criteria. Clinical protocols for investigation of cancer immunotherapies may utilize pre-specified adjusted response criteria for endpoints such as response rate or delayed PFS, which more comprehensively capture all response patterns.2 Increasingly some forms of cancer masquerade as chronic disease making overall survival (OS) an insurmountable clinical readout. With a relatively long life-span in malignancies such as ovarian, thyroid cancer and other tumors due to succession line of treatments with considerable impact on OS (breast, prostate, and renal cancer) new developers face a real challenge in running studies sufficiently long to capture OS benefits. Adjusted PFS (progression free survival) as a primary endpoint might be more appropriate in these settings. FDA has specifically stipulated that if PFS is used as a primary endpoint, the magnitude of PFS improvement must be substantial and it must outweigh the risk associated with the treatment.6 Based on time-to-progression (TTP) estimates from Provenge studies and other clinical experience with cancer vaccines, it is expected that cancer vaccines are unlikely to provide with TTP/PFS advantages because of the immunologically driven tumor swelling, remodeling, and / or infiltration observed in initial phases of treatment.7 It is expected that a delayed benefit may arise throughout the treatment, but the experience with PFS interpretation in different truncated phases of treatment is limited and did not go through sufficient regulatory scrutiny. Both FDA and EMA acknowledged in various oncology-related guidance documents that delayed clinical response is anticipated with cancer immunotherapies and such a phenomenon has been reported not only with Provenge but also
Regulatory Framework for Development of Cancer Vaccines EU regulatory requirements The most recent approval of cancer vaccine was EC decision on Provenge approval in June 2013. CHMP decision was made following long and complex review of quality and clinical data with Sipuleucel-T. One of the serious issues was lack of docetaxel use and potential imbalance between groups in the pivotal study in terms of background chemotherapy treatments. Nevertheless, the final outcome of the review was favorable. It is still remains unclear the pricing and reimbursement positioning around this product in cost-constrained EU. EMA guideline on evaluation of anti-cancer medicinal products in man (CHMP/EWP/433478/2010) mentions previously reported phenomenon of delayed immunological response with cancer vaccines. Patients may thus experience disease progression prior to the onset of biological activities or clinical effects. Discontinuation of active cancer immunotherapy in case of slow progression may not be appropriate. In these situations a detailed definition of “slow progressive disease” is expected in the study protocol.” It was indicated that OS primary endpoint will be preferred in confirmatory clinical studies. Possible toxicities like induction of autoimmune reactivity (cellular and humoral) and induction of tolerance should be carefully monitored during the clinical development. Currently there is no EMA specific guidance on clinical development of cancer vaccines. Scientific advice (SA) procedure should be sought during clinical development process and most certainly prior phase 3 study will commence. Global development program could be reviewed by EMA and FDA in so-called parallel SA procedures to simultaneously gauge the view from both agencies. Oncology is named as one of the area eligible for parallel SA route. If the request is submitted in a synchronised manner to the FDA and the EMA, similar procedural timelines allow for discussion before the final decision is reached by each agency. This exercise is not intended to provide a combined or joint advice from the 2 regulatory authorities, but is an opportunity for increased dialog. Each agency will provide their independent advice to the developer. FDA requirements on cancer vaccines For the approval of a Biologics License Application (BLA), it is critical that sufficient evidence of effectiveness is available
4
so that both the sponsor and the FDA can adequately complete the benefit/risk (B/R) assessment of the new molecular entity (NME) (21CFR 314.126). In addition, the product should be of acceptable safety (21CFR 314.126) and the product label would define an appropriate patient population and provide with an adequate information enabling safe and effective use of the product 21CFR 201). Section 505(d) of the FD&C Act, as well as Section 351 of the Public Health Service Act, indicate that new drugs and biologics should establish substantial evidence of clinical effectiveness through means of “adequate and well-controlled studies.” The base assumption is that since the term studies is plural, 2 or more controlled randomized clinical trials are required to establish efficacy. Specifically in oncology, there are many scenarios (and many past examples) where FDA rendered a single pivotal study sufficient for approval. The case for adequacy of a single study as well as a qualification for accelerated evaluation and approval should be made on the basis of advantages seen with the product in extending PFS and OS (as per phase 1–3 studies), gains observed in evaluation of patientreported outcomes and quality of life; and favorable effect on established surrogate and composite endpoints. With potential limitations and caveats in clinical data, sponsors might be prepared to seek a conditional approval route with ways to generate further clinical data supporting clinical benefits via post-approval commitments.9,10 Having reviewed a number of cancer vaccine products in different stages of development (around 124 IND submission),11 FDA has released a final guidance on clinical considerations for therapeutic cancer vaccines. The guidance does not cover adoptive immunotherapies or vaccines intended for prevention of cancers. Core messages from FDA guidance (2011) include the following: • Given relatively favorable safety profile with cancer immunotherapeutics and saturable dose-response curve, classical dose escalation studies are not appropriate for cancer vaccines and accelerated or continuous escalation regimens might be explored; • Exploratory phase 1–2 studies are extremely useful in evaluating cellular immunological responses, the pattern of ORR, dose-dependent relationships with surrogate outcome (e.g., skin test of delayed hypersensitivity reaction), and the rate of disease recurrence, isolating patient subgroups which benefit the most (e.g., HLA, NK, and immunological biomarkerstratified methodologies); • The type of schedule and route of administrations are particularly relevant for evaluation of the efficacy; • Throughout an entire development, immune response should be evaluated, validated, and correlated with any observed clinical outcomes. Therefore appropriate assays should be developed, validated, and bridged, if necessary; • Different disease settings might be pursued and development decisions should take into account the length of time required to establish delayed immune response and capture its effect on PFS/OS, with consequential considerations for resource burden in planning of an appropriate phase 3 study;
Human Vaccines & Immunotherapeutics Volume 10 Issue 11
©2014 Landes Bioscience. Do not distribute.
agents which could be favorably combined with cancer immunotherapies. Similarly, combinations of cancer vaccines, monoclonal antibodies, tyrosine kinase inhibitors, and other targeted therapies might be rationalised on the basis of their impact on T-regulatory (Tregs), myeloid-derived suppressor cells (MDSCs), natural killer (NK) cells, and kinetics of anti-tumor immune response.8 Newly emerging antibody technologies such as antibody-drug conjugates (ADCs) could be integrated with cancer vaccines into long-term combination regimens and provide with incremental gains in PFS/OS, improved quality of life, and enhanced safety and tolerability profile.
References 1. Hoos A, Parmiani G, Hege K, Sznol M, Loibner H, Eggermont A, Urba W, Blumenstein B, Sacks N, Keilholz U, et al.; Cancer Vaccine Clinical Trial Working Group. A clinical development paradigm for cancer vaccines and related biologics. J Immunother 2007; 30:1-15; PMID:17198079; http://dx.doi. org/10.1097/01.cji.0000211341.88835.ae 2. Hoos A, Eggermont AM, Janetzki S, Hodi FS, Ibrahim R, Anderson A, Humphrey R, Blumenstein B, Old L, Wolchok J. Improved endpoints for cancer immunotherapy trials. J Natl Cancer Inst 2010; 102:1388-97; PMID:20826737; http://dx.doi. org/10.1093/jnci/djq310 3. Di Lorenzo G, Buonerba C. Kidney cancer: Overall Survival is an unsuitable primary clinical endpoint. Nature Urology 2010; 7:367-8; http://dx.doi. org/10.1038/nrurol.2010.84 4. Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbé C, Maio M, Binder M, Bohnsack O, Nichol G, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 2009; 15:7412-20; PMID:19934295; http://dx.doi.org/10.1158/10780432.CCR-09-1624
www.landesbioscience.com
suitability of the subsequent BLA for accelerated approval or sufficiency of a single pivotal phase 3 study. Numerous interactions with the Agency can include EOP2 and post-phase 3 meetings as well as ad hoc meetings. Due to some differences in methodology of assessment and reported regulatory outcomes in the EU and US, some developers can opt for a parallel SA interaction which can be requested from both agencies in a synchronised manner. Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed. Disclaimer
The views expressed in this article are the personal views of the author and may not be understood, interpreted, or quoted as being made on behalf of, or reflecting the position of any companies or parties cited in this article.
5. Gomella L, Nabhan C, DeVries T, Whitmore J, Frohlich M. Estimating the overall survival benefit of sipuleucel-T in the IMPACT trial accounting for crossover treatment in control subjects with autologous immunotherapy generated from cryopreserved cell. J Urol 2012; 187:E278-9; http://dx.doi. org/10.1016/j.juro.2012.02.765 6. Schmidt C. Ovarian cancer treatments on the horizon. J Natl Cancer Inst 2011; 103:1284-5; PMID:21852261; http://dx.doi.org/10.1093/jnci/ djr343 7. Sonpavde G, Di Lorenzo G, Higano CS, Kantoff PW, Madan R, Shore ND. The role of sipuleucel-T in therapy for castration-resistant prostate cancer: a critical analysis of the literature. Eur Urol 2012; 61:63947; PMID:22036643; http://dx.doi.org/10.1016/j. eururo.2011.10.027 8. Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer 2012; 12:237-51; PMID:22437869; http://dx.doi.org/10.1038/nrc3237 9. Chabner BA. Early accelerated approval for highly targeted cancer drugs. N Engl J Med 2011; 364:10879; PMID:21428763; http://dx.doi.org/10.1056/ NEJMp1100548
10. Coutant D, Riggs D, Hoffman EV. Substantial Evidence: When Is a Single Trial Sufficient for Approval and Promotion? Drug Inf J 2011; 45:253-63 11. Witten C. FDA and Cancer Vaccine Development. 2008; Available from: http://www.fda.gov/downloads/biologicsbloodvaccines/newsevents/ workshopsmeetingsconferences/ucm102978.pdf Accessed on November 11th, 2013.
Human Vaccines & Immunotherapeutics 5
©2014 Landes Bioscience. Do not distribute.
• The choice of patient population should be as homogenous as possible. This is of particular significance in trials with autologous vaccines due to inherent feature of the product heterogeneity; • Clinical models used should be sufficiently sensitive to demonstrate clinical benefit; • Phase 2 studies should be conducted in controlled fashion to yield maximum of the information on “Go” and “No-Go” decisions; • Limitations with use of ORR and PFS due to immunotherapy-mediated effect on tumor swelling, cell infiltration, and remodelling. Alternative definitions of disease progression can be utilized if subjects still meet study-related eligibility criteria, do not show deterioration in performance scores or quality of life and there is no dose-limiting toxicity; • Use of biomarkers and development of combination therapies were discussed. Based on this guidance, cancer vaccine developers are expected to generate a substantial pre-phase 3 package to convince FDA on
Review
Human Vaccines & Immunotherapeutics 10:11, 1–5; November 2014; © 2014 Landes Bioscience
Cancer vaccines
What do we need to measure in clinical trials? Alex Kudrin1,* Celltrion Inc; Incheon, South Korea
1
Cancer immunotherapy has seen a tremendous number of failures and only few recent regulatory successes. This review is dedicated to evaluate remaining challenges in capturing clinical response with cancer vaccines. Definition of disease progression in context of clinical rather image-specific criteria and interpretation of efficacy in relation to delayed effect of cancer vaccines should be taken into account in the design of future of immunotherapy trials.
Values of Cancer Immunotherapy The successful manipulation of a cancer-directed immune response has long been a battle ground for cancer immunologists, oncologists and patients themselves. The field of cancer immunotherapies has been littered with failures and there are estimates that more than 10 000 cancer patients were treated with these products in numerous unsuccessful clinical trials. However a glimmer of hope has arisen following FDA and EMA approval of sipuleucel-T (Provenge) for the treatment of castrate-resistant prostate cancer and ipilimumab (Yervoy) approval by FDA and EMA for patients with advanced melanoma. Cancer immunotherapy has always been an attractive strategy for treatment of cancer promising to restore own specific immunological responses against the tumor and providing with safe, tolerable, and long-lasting therapeutic regimen. Although traditional cytotoxic chemotherapy remains a treatment backbone for many malignancies, targeted therapies are now a component of treatment for many types of cancer. However targeted therapies can be employed in specific subgroups of patients and cancer immunotherapies may offer with options to deliver a broad clinical effectiveness across biomarker positive and negative patients. Growth in targeted therapies has reinvigorated interest in cancer immunotherapy because of the following potential advantages: (1) therapeutic vaccines employed as a monotherapy could deliver targeted immune-mediated effect on tumors; (2) the advantage of cancer vaccines compared with passive immunotherapy is that T-cell driven responses and memory associated with those could assist with immune response during disease recurrence; (3) combination regimens composed of vaccines *Correspondence to: Alex Kudrin; Email: [email protected] Submitted: 11/28/2013; Accepted: 12/19/2013; Published Online: 01/09/2014 http://dx.doi.org/10.4161/hv.27586
www.landesbioscience.com
and small molecule and / or biological anticancer agents could synergistically enhance the effect on tumor microenvironment, metastatic growth, and tissue remodelling; (4) effect on tumor “evasion” via immunological bypassing of accumulated tumor defects resulting in theoretical possibility of reduced failure of a backbone targeted therapy agent (e.g., anti-HER2 antibody); (5) sparing effect on the use of other chemotherapy agents that may translate in safety and cost benefits; (6) improvements in quality of life, tolerability, compliance, and patient reported outcome profiles; (7) there is a remote theoretical possibility that cancer immunotherapies may reduce long-term risk of secondary cancers in surviving patients; (8) there might be benefits in special populations such as pregnant women, children or at the very least immunotherapy could spare reproductive function in cancer survivors; (9) cancer vaccines could deliver clinical outcomes in chemotherapy-failures or biomarkers-negative patients (e.g., in HER2 triple negative breast cancer patients unable to receive trastuzumab; KRAS-mutants non-qualified for cetuximab or panitumumab and melanoma patients who do not carry V600E mutations and unable to qualify for vemurafenib; (10) cancer vaccines are less prone to genericisation and biosimilar rivalry. Overall, cancer vaccines could deliver a number of different therapeutic values which could be integrated by potential developers into target product profiles. However most of these values and benefits should be tested and explored in future clinical trials.
Sensing the Paradigm To sum up the knowledge around older and traditional yet unsuccessful cancer immunotherapy approaches, we can capitalize on the notion that “not enough of a good thing” is not the fundamental problem in tumor immunology and by trying to stimulate immune system using empirical approach of adding lacking cytokines, or delivering tumor-specific antigens will not succeed alone. New approaches should not be only aimed at trying to stimulate dysfunctional immune system or replace solitary lacking elements (such as cytokines or tumor antigens) but rather at eradicating or correcting dysfunctional elements of immune system. This paradigm will require sequential and combinatorial approaches and traditional antigen- or cell-based vaccination approaches will be considerably complemented by emerging technologies such as anti-PD1 antibodies, neoadjuvant and adjuvant radiotherapy, and photodynamic therapy etc.
Human Vaccines & Immunotherapeutics 1
©2014 Landes Bioscience. Do not distribute.
Keywords: cancer vaccines, endpoints, progression free survival, immune response, patient reported outcomes
Changing the Pipeline According to analyst report findings there are approximately 150 therapeutic cancer vaccines in phase 1–3 clinical development across 7 major markets. Approximately 70% of these products are standardized (“off-shelf”) vaccines. The remaining proportion is assigned to personalized vaccines. A disproportionately high number of candidates (almost 60%) is currently developed in prostate, breast, lung cancer, and melanoma. Such an imbalance can be explained by recent regulatory successes of Provenge (sipuleucel-T) in prostate cancer (US approval) and Yervoy (ipilimumab) in advanced melanoma (EU and US approvals) and possibly with greater available investment flow into these indications. In addition, the number of antigens discovered in these indications exceeded the number of antigens characterized in other types of tumors and this factor enabled to drive the innovation in these clinical indications. These findings illustrate that some indications with high unmet medical need are currently underrepresented in the pipeline. There is a gap in cancer vaccines for hematological, brain, thyroid, ovarian, pancreatic, and colorectal tumors.
Challenges in Clinical Development Concepts laid into FDA guidance have partially originated from the Cancer Vaccine Clinical Trial Working Group (CVCTWG).1 In this model, the first stage of development would be a proof-of-principle trial with the objective of evaluating the safety, dose and schedule, and the demonstration of biological activity, the later incorporating appropriate immune and molecular markers. The initial phase of clinical investigation may include as minimum as 20 patients in a homogenous, sensitive, and well-defined population and should be performed in an neo- or adjuvant setting without rapidly progressive disease in order to capture sufficient time for immune response to mature. According to Hoos et al.2 successful proof-of-principle trials support a more flexible, expeditious and focused clinical developmental process. Key recommendations on use of most sensitive, sufficiently lengthy, and homogenous clinical settings were reflected in FDA guidance. As opposed to CVCTWG recommendations, it is now apparent that an early POC study should be conducted in a controlled fashion allowing for more accurate assessment of immunological and clinical response and the time to its onset. Numerous cancer
2
vaccines failed in phase 3 studies were upstaged on the basis on erroneous evaluations of uncontrolled phase 2 studies. There is an ironic situation that some earlier failed trials might have resulted in elimination of cancer vaccine antigens which might have been mis-evaluated in trials of inappropriate design. The identification and validation of appropriate immunological biomarker is critical in development of cancer vaccines. Developers should consider cost-effectiveness, clinical utility, and clinical feasibility of the immunological biomarker or gene signature testing. If the test is cumbersome, requires specialized skills and labor, prohibitive in terms of cost to oncology health care and difficult to commercialize, it is likely that reimbursement bodies will displace these costs on developers or conclude on lack of cost-effectiveness. Poor technical feasibility of biomarker testing will most certainly reduce sales penetration and will require additional investment in training of health care practitioners and laboratory staff. During phase 3 planning, an adequate and pre-specified definition of progression and response are vital. Since cancer vaccines can cause tumor swelling, infiltration, and tumor fibrosis, some patient’s tumors may progress, increase their volume and give rise to new lesions (some possibly due to initial inflammation), which may be followed by a delayed response. As a consequence, a conventionally defined PFS may not be a suitable clinical endpoint in cancer vaccine studies.3,4 It is therefore recommended that the definition of progression should account for clinically relevant parameters such as patient’s performance status and / or global quality of life and not for volumetric or tumor-measurable criteria. However disease measurement should not be abandoned as long-term volumetric disease stabilization also should be considered as a measure of clinical activity.2,4 Continued treatment beyond progression under certain conditions can be summarized in blinded safety listings and monitored by independent data safety monitoring board (DSMB). The sponsor may need to plan regular DSMB safety reviews on e.g., 3–6-moly basis within the timeframe of expected delayed immune response (12–24 mo from the onset of vaccination). Studies with cancer immunotherapeutics can be irreversibly compromised by various confounding factors arising due to use of rescue medications, concomitant therapies and crossovers as a consequence of reported disease progression. Crossovers and concomitant therapies can abolish clinically and statistically significant differences in overall survival. Nevertheless, the advantage in PFS gain was still preserved but was not always sufficient from regulatory perspective. Crossovers can also contribute to reduced separation in OS. In the pivotal registration IMPACT trial with sipuleucel-T, control subjects who demonstrated objective disease progression were offered 3 infusions of an autologous cellular therapy produced from cells frozen at the time of control product generation. An exploratory analysis was performed to estimate how autologous therapy impacted the OS benefit of sipuleucel-T. It was found that postprogression treatment with sipuleucel-T may have extended the survival of control subjects in the IMPACT study. Adjusting for use of autologous rescue therapy resulted in an increase in median OS benefit with sipuleucel-T from 4.1 mo to 7.8 mo.5
Human Vaccines & Immunotherapeutics Volume 10 Issue 11
©2014 Landes Bioscience. Do not distribute.
It is reported that approximately 50 tumor antigens or antigen-targets are currently in different stages of development and they encompass not only membrane-bound but also intracellular targets. However with very high attrition rate reported in oncology, it is clear, that the number of currently studied tumor antigens is highly insufficient to ensure that there will a reasonable number of successful products in years to come. Therefore there is a considerable need for further tumor antigen discovery and their comprehensive validation.
www.landesbioscience.com
with MAGE3, Stimuvax, ipilimumab, and anti-PD1 therapies. The delayed response can risk the trial to become underpowered due to premature evaluation of OS, PFS and it most certainly question the utility of overall response evaluation in phase 1 and 2 immunotherapy studies. These 2 factors could account for many of previous clinical trial failures of cancer vaccine candidates. The most important recommendations out of these findings are as following: 1) The immune-related criteria of response should be implemented, used, and actively propagated to regulatory authorities as the most meaningful way of assessing the proof-of-concept related efficacy readouts with immunotherapy candidates 2) Adjusted PFS can be most appropriate clinical endpoint in some clinical settings with long survival horizon. 3) Definition of progression for the purpose of PFS censoring should be as objective as possible, standardized, and pre-specified. However in view of delayed volumetric effects of immunotherapy agents the definition of progression should be clinically driven rather than volume-driven. For example the worsening of Karnofski scores, ECOG status or specific Quality of Life parameters could represent criteria which are both clinically meaningful to prescribers and patients. 4) If volumetric progression criteria are employed, modified RECIST criteria should be used or a serial measurement with 3–6 mo interval employed. In accordance with Wolchok et al.4 immune-related response criteria ≥50% increase in tumor burden compared with nadir 2 consecutive measurements with 4 wk apart. However these criteria were derived from melanoma settings and this interval might be not sufficiently long to allow a delayed response to manifest in other oncology settings. In tumors with long survival duration, progression could be adjudicated as a continuous increase in target lesion size of >50% with serial measurements made with 3–6 mo interval. 5) Development of immunotherapies requires more sensitive imaging tools and sparse tumor biopsy in order to elucidate the time-dependent and treatment-dependent effects of immunotherapy on tumors and validate immune-related response criteria in numerous oncology settings. Therefore cancer immunotherapy requires validation of these new concepts in prospective randomized and observational studies in order to establish new endpoint structure and framework for future trials. From cancer vaccine perspective, more rational and risk-based evaluation of potential combination regimens is required. Since cancer vaccines are expected to provide with delayed response and impact on OS, a successful combination with product or regimen enabling earlier separation of OS curves and resulting in an improved efficacy profile and ultimately increasing the probability of success and reducing the trial duration and size. Rational selection of immunotherapy combination could be based on some new drug-screening platforms that quantitatively measure the effect of the combination on tumor-associated and systemic immune system and non-tumor cells (such as tumor stem and stromal cells). By using specific combinations of tumor and accessory cells, a screening assay can predict the relationship between targeted therapies and tumor microenvironment and isolate only those small molecule and / or biological
Human Vaccines & Immunotherapeutics 3
©2014 Landes Bioscience. Do not distribute.
These results suggest that crossover reduced the prominence of Sipuleucel T-driven favorable effect on OS. Given that cancer vaccines are unlikely to yield significant improvements in PFS, it is especially critical that the risk of crossovers and imbalanced use of concomitant therapies is minimised as much as possible through adequate protocol planning. From ethical perspective it is important that patients from placebo group will have access to the treatment which seems to show an improvement in clinical outcomes. However due to delayed effect of immunotherapeutics on PFS and long duration of studies required to demonstrate OS gains, the magnitude of the clinical benefit might not be so apparent. Therefore a careful consideration should be given to the crossover eligibility. The impact of any potential imbalances on OS/PFS evaluation should be elucidated using pre-specified statistical analyses and modeling. Investigators should be trained how to differentiate temporary worsening in disease vs. steady progression related deterioration. Sponsors should pre-define consistent characteristics constituting clinically relevant progression based on features agreed by patient and/or caregiver and treating physician. Whenever possible and feasible, a verification of underlying delayed immune response can be supported using tumor biopsy specimens and biomarker assays performed using peripheral blood samples. Correlation between immune assays and PFS/OS serve as one of the pivotal gate rules at the transition between phase 2 and phase 3. As described in FDA guidance, immunotherapy may induce novel patterns of antitumor response not captured by Response Evaluation Criteria in Solid Tumors (RECIST) or World Health Organization (WHO) criteria. Clinical protocols for investigation of cancer immunotherapies may utilize pre-specified adjusted response criteria for endpoints such as response rate or delayed PFS, which more comprehensively capture all response patterns.2 Increasingly some forms of cancer masquerade as chronic disease making overall survival (OS) an insurmountable clinical readout. With a relatively long life-span in malignancies such as ovarian, thyroid cancer and other tumors due to succession line of treatments with considerable impact on OS (breast, prostate, and renal cancer) new developers face a real challenge in running studies sufficiently long to capture OS benefits. Adjusted PFS (progression free survival) as a primary endpoint might be more appropriate in these settings. FDA has specifically stipulated that if PFS is used as a primary endpoint, the magnitude of PFS improvement must be substantial and it must outweigh the risk associated with the treatment.6 Based on time-to-progression (TTP) estimates from Provenge studies and other clinical experience with cancer vaccines, it is expected that cancer vaccines are unlikely to provide with TTP/PFS advantages because of the immunologically driven tumor swelling, remodeling, and / or infiltration observed in initial phases of treatment.7 It is expected that a delayed benefit may arise throughout the treatment, but the experience with PFS interpretation in different truncated phases of treatment is limited and did not go through sufficient regulatory scrutiny. Both FDA and EMA acknowledged in various oncology-related guidance documents that delayed clinical response is anticipated with cancer immunotherapies and such a phenomenon has been reported not only with Provenge but also
Regulatory Framework for Development of Cancer Vaccines EU regulatory requirements The most recent approval of cancer vaccine was EC decision on Provenge approval in June 2013. CHMP decision was made following long and complex review of quality and clinical data with Sipuleucel-T. One of the serious issues was lack of docetaxel use and potential imbalance between groups in the pivotal study in terms of background chemotherapy treatments. Nevertheless, the final outcome of the review was favorable. It is still remains unclear the pricing and reimbursement positioning around this product in cost-constrained EU. EMA guideline on evaluation of anti-cancer medicinal products in man (CHMP/EWP/433478/2010) mentions previously reported phenomenon of delayed immunological response with cancer vaccines. Patients may thus experience disease progression prior to the onset of biological activities or clinical effects. Discontinuation of active cancer immunotherapy in case of slow progression may not be appropriate. In these situations a detailed definition of “slow progressive disease” is expected in the study protocol.” It was indicated that OS primary endpoint will be preferred in confirmatory clinical studies. Possible toxicities like induction of autoimmune reactivity (cellular and humoral) and induction of tolerance should be carefully monitored during the clinical development. Currently there is no EMA specific guidance on clinical development of cancer vaccines. Scientific advice (SA) procedure should be sought during clinical development process and most certainly prior phase 3 study will commence. Global development program could be reviewed by EMA and FDA in so-called parallel SA procedures to simultaneously gauge the view from both agencies. Oncology is named as one of the area eligible for parallel SA route. If the request is submitted in a synchronised manner to the FDA and the EMA, similar procedural timelines allow for discussion before the final decision is reached by each agency. This exercise is not intended to provide a combined or joint advice from the 2 regulatory authorities, but is an opportunity for increased dialog. Each agency will provide their independent advice to the developer. FDA requirements on cancer vaccines For the approval of a Biologics License Application (BLA), it is critical that sufficient evidence of effectiveness is available
4
so that both the sponsor and the FDA can adequately complete the benefit/risk (B/R) assessment of the new molecular entity (NME) (21CFR 314.126). In addition, the product should be of acceptable safety (21CFR 314.126) and the product label would define an appropriate patient population and provide with an adequate information enabling safe and effective use of the product 21CFR 201). Section 505(d) of the FD&C Act, as well as Section 351 of the Public Health Service Act, indicate that new drugs and biologics should establish substantial evidence of clinical effectiveness through means of “adequate and well-controlled studies.” The base assumption is that since the term studies is plural, 2 or more controlled randomized clinical trials are required to establish efficacy. Specifically in oncology, there are many scenarios (and many past examples) where FDA rendered a single pivotal study sufficient for approval. The case for adequacy of a single study as well as a qualification for accelerated evaluation and approval should be made on the basis of advantages seen with the product in extending PFS and OS (as per phase 1–3 studies), gains observed in evaluation of patientreported outcomes and quality of life; and favorable effect on established surrogate and composite endpoints. With potential limitations and caveats in clinical data, sponsors might be prepared to seek a conditional approval route with ways to generate further clinical data supporting clinical benefits via post-approval commitments.9,10 Having reviewed a number of cancer vaccine products in different stages of development (around 124 IND submission),11 FDA has released a final guidance on clinical considerations for therapeutic cancer vaccines. The guidance does not cover adoptive immunotherapies or vaccines intended for prevention of cancers. Core messages from FDA guidance (2011) include the following: • Given relatively favorable safety profile with cancer immunotherapeutics and saturable dose-response curve, classical dose escalation studies are not appropriate for cancer vaccines and accelerated or continuous escalation regimens might be explored; • Exploratory phase 1–2 studies are extremely useful in evaluating cellular immunological responses, the pattern of ORR, dose-dependent relationships with surrogate outcome (e.g., skin test of delayed hypersensitivity reaction), and the rate of disease recurrence, isolating patient subgroups which benefit the most (e.g., HLA, NK, and immunological biomarkerstratified methodologies); • The type of schedule and route of administrations are particularly relevant for evaluation of the efficacy; • Throughout an entire development, immune response should be evaluated, validated, and correlated with any observed clinical outcomes. Therefore appropriate assays should be developed, validated, and bridged, if necessary; • Different disease settings might be pursued and development decisions should take into account the length of time required to establish delayed immune response and capture its effect on PFS/OS, with consequential considerations for resource burden in planning of an appropriate phase 3 study;
Human Vaccines & Immunotherapeutics Volume 10 Issue 11
©2014 Landes Bioscience. Do not distribute.
agents which could be favorably combined with cancer immunotherapies. Similarly, combinations of cancer vaccines, monoclonal antibodies, tyrosine kinase inhibitors, and other targeted therapies might be rationalised on the basis of their impact on T-regulatory (Tregs), myeloid-derived suppressor cells (MDSCs), natural killer (NK) cells, and kinetics of anti-tumor immune response.8 Newly emerging antibody technologies such as antibody-drug conjugates (ADCs) could be integrated with cancer vaccines into long-term combination regimens and provide with incremental gains in PFS/OS, improved quality of life, and enhanced safety and tolerability profile.
References 1. Hoos A, Parmiani G, Hege K, Sznol M, Loibner H, Eggermont A, Urba W, Blumenstein B, Sacks N, Keilholz U, et al.; Cancer Vaccine Clinical Trial Working Group. A clinical development paradigm for cancer vaccines and related biologics. J Immunother 2007; 30:1-15; PMID:17198079; http://dx.doi. org/10.1097/01.cji.0000211341.88835.ae 2. Hoos A, Eggermont AM, Janetzki S, Hodi FS, Ibrahim R, Anderson A, Humphrey R, Blumenstein B, Old L, Wolchok J. Improved endpoints for cancer immunotherapy trials. J Natl Cancer Inst 2010; 102:1388-97; PMID:20826737; http://dx.doi. org/10.1093/jnci/djq310 3. Di Lorenzo G, Buonerba C. Kidney cancer: Overall Survival is an unsuitable primary clinical endpoint. Nature Urology 2010; 7:367-8; http://dx.doi. org/10.1038/nrurol.2010.84 4. Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbé C, Maio M, Binder M, Bohnsack O, Nichol G, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 2009; 15:7412-20; PMID:19934295; http://dx.doi.org/10.1158/10780432.CCR-09-1624
www.landesbioscience.com
suitability of the subsequent BLA for accelerated approval or sufficiency of a single pivotal phase 3 study. Numerous interactions with the Agency can include EOP2 and post-phase 3 meetings as well as ad hoc meetings. Due to some differences in methodology of assessment and reported regulatory outcomes in the EU and US, some developers can opt for a parallel SA interaction which can be requested from both agencies in a synchronised manner. Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed. Disclaimer
The views expressed in this article are the personal views of the author and may not be understood, interpreted, or quoted as being made on behalf of, or reflecting the position of any companies or parties cited in this article.
5. Gomella L, Nabhan C, DeVries T, Whitmore J, Frohlich M. Estimating the overall survival benefit of sipuleucel-T in the IMPACT trial accounting for crossover treatment in control subjects with autologous immunotherapy generated from cryopreserved cell. J Urol 2012; 187:E278-9; http://dx.doi. org/10.1016/j.juro.2012.02.765 6. Schmidt C. Ovarian cancer treatments on the horizon. J Natl Cancer Inst 2011; 103:1284-5; PMID:21852261; http://dx.doi.org/10.1093/jnci/ djr343 7. Sonpavde G, Di Lorenzo G, Higano CS, Kantoff PW, Madan R, Shore ND. The role of sipuleucel-T in therapy for castration-resistant prostate cancer: a critical analysis of the literature. Eur Urol 2012; 61:63947; PMID:22036643; http://dx.doi.org/10.1016/j. eururo.2011.10.027 8. Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer 2012; 12:237-51; PMID:22437869; http://dx.doi.org/10.1038/nrc3237 9. Chabner BA. Early accelerated approval for highly targeted cancer drugs. N Engl J Med 2011; 364:10879; PMID:21428763; http://dx.doi.org/10.1056/ NEJMp1100548
10. Coutant D, Riggs D, Hoffman EV. Substantial Evidence: When Is a Single Trial Sufficient for Approval and Promotion? Drug Inf J 2011; 45:253-63 11. Witten C. FDA and Cancer Vaccine Development. 2008; Available from: http://www.fda.gov/downloads/biologicsbloodvaccines/newsevents/ workshopsmeetingsconferences/ucm102978.pdf Accessed on November 11th, 2013.
Human Vaccines & Immunotherapeutics 5
©2014 Landes Bioscience. Do not distribute.
• The choice of patient population should be as homogenous as possible. This is of particular significance in trials with autologous vaccines due to inherent feature of the product heterogeneity; • Clinical models used should be sufficiently sensitive to demonstrate clinical benefit; • Phase 2 studies should be conducted in controlled fashion to yield maximum of the information on “Go” and “No-Go” decisions; • Limitations with use of ORR and PFS due to immunotherapy-mediated effect on tumor swelling, cell infiltration, and remodelling. Alternative definitions of disease progression can be utilized if subjects still meet study-related eligibility criteria, do not show deterioration in performance scores or quality of life and there is no dose-limiting toxicity; • Use of biomarkers and development of combination therapies were discussed. Based on this guidance, cancer vaccine developers are expected to generate a substantial pre-phase 3 package to convince FDA on
