Immune-related response criteria

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The immune-related response criteria (irRC) is a set of published rules that define when tumors in cancer patients improve ("respond"), stay the same ("stabilize"), or worsen ("progress") during treatment, where the compound being evaluated is an immuno-oncology drug. Immuno-oncology, part of the broader field of cancer immunotherapy, involves agents which harness the body's own immune system to fight cancer. Traditionally, patient responses to new cancer treatments have been evaluated using two sets of criteria, the WHO criteria and the response evaluation criteria in solid tumors (RECIST). The immune-related response criteria, first published in 2009, [1] arose out of observations that immuno-oncology drugs would fail in clinical trials that measured responses using the WHO or RECIST Criteria, because these criteria could not account for the time gap in many patients between initial treatment and the apparent action of the immune system to reduce the tumor burden.

Contents

Background

Part of the process of determining the effectiveness of anti-cancer agents in clinical trials involves measuring the amount of tumor shrinkage such agents can generate. The WHO Criteria, developed in the 1970s by the International Union Against Cancer and the World Health Organization, represented the first generally agreed specific criteria for the codification of tumor response evaluation. These criteria were first published in 1981. [2] The RECIST criteria, first published in 2000, [3] revised the WHO criteria primarily to clarify differences that remained between research groups. Under RECIST tumour size was measured unidimensionally rather than bidimensionally, fewer lesions were measured, and the definition of 'progression' was changed so that it was no longer based on the isolated increase of a single lesion. RECIST also adopted a different shrinkage threshold for definitions of tumour response and progression. For the WHO Criteria it had been >50% tumour shrinkage for a Partial Response and >25% tumour increase for Progressive Disease. For RECIST it was >30% shrinkage for a Partial Response and >20% increase for Progressive Disease. One outcome of all these revisions was that more patients who would have been considered 'progressors' under the old criteria became 'responders' or 'stable' under the new criteria. [4] RECIST and its successor, RECIST 1.1 from 2009, [5] is now the standard measurement protocol for measuring response in cancer trials.

The key driver in the development of the irRC was the observation that, in studies of various cancer therapies derived from the immune system such as cytokines and monoclonal antibodies, the looked-for Complete and Partial Responses as well as Stable Disease only occurred after an increase in tumor burden that the conventional RECIST Criteria would have dubbed 'Progressive Disease'. Basically, RECIST failed to take account of the delay between dosing and an observed anti-tumour T cell response, so that otherwise 'successful' drugs - that is, drugs which ultimately prolonged life - failed in clinical trials. [6] This led various researchers and drug developers interested in cancer immunotherapy such as Axel Hoos at Bristol-Myers Squibb (BMS) to start discussing whether a new set of response criteria ought to be developed specifically for immmuno-oncology drugs. Their ideas, first flagged in a key 2007 paper in the Journal of Immunotherapy, [1] evolved into the immune-related response criteria (irRC), which was published in late 2009 in the journal Clinical Cancer Research . [1]

The criteria

The developers of the irRC based their criteria on the WHO Criteria but modified it:

Evidence of usefulness

The initial evidence cited by the creators of the irRC that their criteria were useful lay in the two Phase II melanoma trials described in the Clinical Cancer Research paper. The drug being trialled was a monoclonal antibody called ipilimumab, then under development at BMS with Axel Hoos as the medical lead. The drug targeted an immune checkpoint called CTLA-4, known as a key negative regulator of T cell activity. By blocking CTLA-4, ipilimumab was designed to potentiate antitumor T-cell responses. In the Phase IIs, which encompassed 227 treated patients and evaluated patients using the irRC, around 10% of these patients would have been deemed to have Progressive Disease by the WHO Criteria but actually experienced irPRs or irSDs, consistent with a response to ipilimumab.

The Phase III clinical failure of Pfizer's tremelimumab anti-CTLA-4 monoclonal antibody, which competed with ipilimumab, provided the first large-scale evidence of the utility of the irRC. The Pfizer study used conventional response criteria, and an early interim analysis found no survival advantage for the treated patients, leading to the termination of the trial in April 2008. [7] [8] However within a year of this development, Pfizer's investigators were beginning to notice a separation of survival curves between treatment and control groups. [9] Tremelimumab's competitor, ipilimumab, which was trialled in Phase III using the irRC, went on to gain FDA approval in 2011, indicated for unresectable stage III or IV melanoma, after a 676-patient study that compared ipilimumab plus an experimental vaccine called gp100 with the vaccine alone. The median overall survival for the ipilimumab+vaccine group was 10 months versus only 6.4 months for the vaccine. [10] Marketed as Yervoy, ipilimumab subsequently became a blockbuster for BMS.

Key people

The 2009 paper which described the new irRC had twelve authors, all associated with the ipilimumab clinical trials used as examples - Jedd Wolchok of Memorial Sloan Kettering Cancer Center, Axel Hoos and Rachel Humphrey of Bristol-Myers Squibb, Steven O'Day and Omid Hamid of the Angeles Clinic in Santa Monica, Ca., Jeffrey Weber of the University of South Florida, Celeste Lebbé of Hôpital Saint-Louis in Paris, Michele Maio of University Hospital of Siena, Michael Binder of Medical University of Vienna, Oliver Bohnsack of a Berlin-based clinical informatics firm called Perceptive Informatics, Geoffrey Nichol of the antibody engineering company Medarex (which had originally developed ipilimumab) and Stephen Hodi of the Dana–Farber Cancer Institute in Boston.

Related Research Articles

Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies. Immunotherapy is under preliminary research for its potential to treat various forms of cancer.

<span class="mw-page-title-main">Melanoma</span> Cancer originating in melanocytes

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Response evaluation criteria in solid tumors (RECIST) is a set of published rules that define when tumors in cancer patients improve ("respond"), stay the same ("stabilize"), or worsen ("progress") during treatment. The criteria were published in February 2000 by an international collaboration including the European Organisation for Research and Treatment of Cancer (EORTC), National Cancer Institute of the United States, and the National Cancer Institute of Canada Clinical Trials Group. Today, the majority of clinical trials evaluating cancer treatments for objective response in solid tumors use RECIST. These criteria were developed and published in February 2000, and subsequently updated in 2009.

<span class="mw-page-title-main">Ipilimumab</span> Pharmaceutical drug

Ipilimumab, sold under the brand name Yervoy, is a monoclonal antibody medication that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.

<span class="mw-page-title-main">Tremelimumab</span> Monoclonal antibody

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References

  1. 1 2 3 Hoos A, Parmiani G, Hege K, Sznol M, Loibner H, Eggermont A, Urba W, Blumenstein B, Sacks N, Keilholz U, Nichol G (January 2007). "A clinical development paradigm for cancer vaccines and related biologics". J. Immunother. 30 (1): 1–15. doi: 10.1097/01.cji.0000211341.88835.ae . PMID   17198079.
  2. ↑ Miller AB, Hoogstraten B, Staquet M, Winkler A (January 1981). "Reporting results of cancer treatment". Cancer. 47 (1): 207–14. doi: 10.1002/1097-0142(19810101)47:1<207::aid-cncr2820470134>3.0.co;2-6 . PMID   7459811.
  3. ↑ Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (February 2000). "New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada". J. Natl. Cancer Inst. 92 (3): 205–16. doi:10.1093/jnci/92.3.205. PMID   10655437.
  4. ↑ Trillet-Lenoir V, Freyer G, Kaemmerlen P, Fond A, Pellet O, Lombard-Bohas C, et al. (November 2002). "Assessment of tumour response to chemotherapy for metastatic colorectal cancer: accuracy of the RECIST criteria". Br J Radiol. 75 (899): 903–8. doi:10.1259/bjr.75.899.750903. PMID   12466256.
  5. ↑ Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (January 2009). "New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)". Eur. J. Cancer. 45 (2): 228–47. doi:10.1016/j.ejca.2008.10.026. PMID   19097774. S2CID   8748071.
  6. ↑ Hoos A, Britten C (May 2012). "The immuno-oncology framework: Enabling a new era of cancer therapy". Oncoimmunology. 1 (3): 334–339. doi:10.4161/onci.19268. PMC   3382871 . PMID   22737609.
  7. ↑ "Pfizer Announces Discontinuation of Phase III Clinical Trial for Patients with Advanced Melanoma". Pfizer.com. 1 April 2008. Retrieved 5 December 2015.
  8. ↑ Ribas A, Hauschild A, Kefford R, Punt CJ, Haanen JB, Marmol M, Garbe C, Gomez-Navarro J, Pavlov D, Marsha M (2008). "Phase III, open-label, randomized, comparative study of tremelimumab (CP-675,206) and chemotherapy (temozolomide [TMZ] or dacarbazine [DTIC]) in patients with advanced melanoma". Journal of Clinical Oncology. 26 (15_suppl): LBA9011. doi:10.1200/jco.2008.26.15_suppl.lba9011. ISSN   0732-183X.
  9. ↑ Marshall MA, Ribas A, Huang B (2010). "Evaluation of baseline serum C-reactive protein (CRP) and benefit from tremelimumab compared to chemotherapy in first-line melanoma". Journal of Clinical Oncology. 28 (15_suppl): 2609. doi:10.1200/jco.2010.28.15_suppl.2609. ISSN   0732-183X.
  10. ↑ Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. (August 2010). "Improved survival with ipilimumab in patients with metastatic melanoma". N. Engl. J. Med. 363 (8): 711–23. doi:10.1056/NEJMoa1003466. PMC   3549297 . PMID   20525992.
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