Conference Update

Immune checkpoint inhibitors are adopted at a much quicker pace in real-world practice

12 months ago, OP Editor

It sometimes takes more than a decade to adopt new evidence from clinical trials into real-world practice. The delay may be detrimental to the patients, as it limits access to novel therapies that is potentially efficacious and life-saving. With the rapid approval of anti-programmed cell death protein 1 (PD-1) antibodies that brought both excitement and questions in cancer research, a team of researchers investigated on how long it takes for real-world patients to benefit from the new therapy.1 The results showed that clinicians are very responsive to new evidence regarding the immune checkpoint inhibitors, but caution should be taken as the evidence may not be representative to real-world patients, which can be compensated with post-approval studies using real-world data.1 The findings were released at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting and published in JAMA Oncology.1

A new drug takes 17 years to reach patients

For a new drug that is newly discovered to become widely used by the public, there are multiple steps before the research is translated into practice and become beneficial at the bedside. Conventionally, the process of drug development can be extremely time-consuming as it involves procedures such as grant awards, ethical approvals, phase I-III trials, pre-market approvals, post-market surveillance and so forth, with an estimate of 17 years to turn 14% of the original researches to the benefit of patient care.2-4 This traditional way of viewing translational research perhaps has been changed with the advent of breakthrough therapies.

Rapid approval for novel therapies by the US Food and Drug Administration (FDA)

Between the period of 2001 and 2010, the FDA approved 225 applications for novel therapeutic agents, of which the time for first review completion was significantly shorter than those approved by the European Medicines Agency (EMA) and Health Canada, with 303 days being the median length of time.5

The brisk approval process has contributed to the advancements in cancer research and drug development in recent years. The 2017 report by the American Association for Cancer Research (AACR) stated that between August 1, 2016 and July 31, 2017, there were 17 anticancer therapeutics approved by the FDA, with some of them being immune checkpoint inhibitors.6

By July 31, 2017, the FDA has approved six checkpoint inhibitors, some of which are indicated for multiple types of cancer, with one medication approved for as many as seven indications.6 Indeed, there is an increasing enthusiasm to speed-up the progress in the cancer therapy field, particularly with the implementation of government policies aiming to further accelerate the pace of drug development.7,8

However, the rapid approval for therapies does not necessarily translate to a rapid adoption in clinical practice. Using tamoxifen as an example – a breast cancer therapy shown to be highly effective, the medication took over 10 years to reach the eligible patients,9 suggesting that patients may have to wait for many years before receiving benefits from new treatments.

Concerns over the generalizability of trial evidence

Besides, the rapid approvals by FDA suggest that the evidence used in the review process were mostly preliminary results from clinical trials.10,11 The level of evidence has posed questions on the adequacy of data to support the approval decision.

Other than the study design, the studied population in the pivotal trials that lead to FDA approvals also caused some concerns, as several studies have shown that these patients were often younger, resulting in the underrepresentation of the elderly population.12-16 This finding is particularly relevant with checkpoint inhibitors because they exert their anti-tumor effect through effector T-cells, which may be affected by an age-related decline known as immunosenescence.17

Although many studies have already suggested that the efficacy of checkpoint inhibitors are unaffected by age,17-19 the concerns over the effect of age on anti-PD-1 remain unresolved with some studies questioning the small numbers of older participants in the clinical trials.20,21 With the concerns over the generalizability of trial evidence regarding patient age, there is uncertainty whether this will influence the adoption rate of these therapies.

The adoption rate of anti-PD-1 agent in real-world practice was high

In order to fill these knowledge gaps, Dr. Jeremy O’Connor, Postdoctoral Fellow at the Yale University School of Medicine and his research team conducted a retrospective cohort study to find out the answer of two questions: 1) how fast the real-world practice adopts anti-PD-1 agents, and 2) how much different is the age of patients treated in pivotal trials and patients in real-world practice.1,22

The research team gathered electronic health record data (EHR) from the Flatiron Health longitudinal EHR database, a cloud-based EHR platform that allowed the integration of real-world evidence from a large, geographically diverse cohort of patients with melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma (RCC). The EHR data were combined with an unstructured source (e.g. practitioner notes) to create a dataset that included demographic data (e.g. age) and clinical data (e.g. cancer type, disease stage, PD-L1 expressivity) that were statistically analyzed.1

A total of 3,089 patients (555 with melanoma, 2,159 with NSCLC, and 375 with RCC) were identified to be eligible for anti-PD-1 treatment (nivolumab and pembrolizumab) between January 1, 2011 and August 31, 2016.1 The results showed that the adoption rate was quick, with over 60% of the eligible patients receiving anti-PD-1 treatment within four months of FDA approval (Figure 1).1 At the end of the study period, the adoption rate reached 79.1% in melanoma patients, 65.6% in NSCLC patients, and 71.2% in RCC patients.1



Real-world patients are older than patients in pivotal trials

Another key finding in this study was the age differences in the real-world practice patients and pivotal trials participants. In the real-world practice, more patients received anti-PD-1 treatment were 65 years or older (ranging from 60.6% to 63.9%) or 75 years or older (ranging from 27.7% to 36.7%) than those in the pivotal trial (65 years or older, ranging from 31.7% to 41.0%; 75 years or older, ranging from 8.3% to 11.7%), which was statistically significant for all comparisons (Tables 1 and 2).1





Although the patients in real-world practice were significantly older than the pivotal trial patients, the proportional uptake of anti-PD-1 agents was similar across the three age groups (less than 65 years, 65 years to 74 years, and 75 years or older).1 The similar pattern across the age groups suggested that the clinical adoption of anti-PD-1 agents is unlikely to be associated with patient age.1

Post-approval studies are imperative for confirming the benefit and risk of novel therapies

The findings suggest that physicians are now reacting rapidly to new evidence of the anti-PD-1 antibodies, and they are willing to incorporate them into practice at a rate that is much faster as compared to the adoption rate of tamoxifen.1 “This is great news for patients who have had rapid access to drugs that are safe and effective in certain contexts,” commented Dr. O’Connor in an interview.23

However, there are also concerns with the findings, as the patients in clinical practice tended to be substantially older than patients in the pivotal trials, making it difficult to predict treatment outcome because the evidence may not fully represent patients in real-world practice.1

Even though recent studies have already confirmed that immune checkpoint inhibitors are effective,24,25 the authors stressed on the importance of integrating real-world evidence (via EHR or big data) to reinforce findings from pivotal trials and to allow better assessment.26,27

The authors also suggested in the interview that the healthcare field should move away from conceptualizing FDA approval as a singular stamp of approval for widespread clinical use.23 It is important for clinicians to consider the pivotal evidence as the drug is still in development, as it might be difficult to see a therapeutic agent change from “experimental” to “proven standard of care” overnight.23

“It is essential that we think of FDA approval as one step in the continuing evaluation of whether new drugs are indeed beneficial in the larger population,” said Prof. Cary Gross of the Yale University School of Medicine.28

Making a move to increase the generalizability of evidence to older patients

Meanwhile, the FDA is also taking steps to improve the conduct of research to support treatments used in older patients. The American Society of Clinical Oncology (ASCO) reviewed a report by the Institute of Medicine,29 and made actionable recommendations for improving research in older adults with cancer.30-32

The recommendations include: 1) increasing the FDA’s authority to incentivize and require research to involve older patients with cancer, 2) leverage research designs and infrastructure for generating evidence on older adults with cancer, and 3) use journal policies to improve researchers’ reporting on the age distribution and health risk profiles of research participants.31

Getting approvals faster without undermining safety

“This finding indicates that clinical practice can change promptly and substantially when novel cancer therapeutics first enter the market—in opposition to traditional teaching, which holds that clinicians are slow to respond to new evidence,” the authors concluded.

Both benefits and concerns are coming with this phenomenon, however, conducting post-approval studies with real-world data can allow the FDA to review the risk and benefit more comprehensively, and ultimately bring an efficacious and safe treatment to the patients.


  1. O’Connor JM, Fessele KL, Steiner J, et al. Speed of Adoption of Immune Checkpoint Inhibitors of Programmed Cell Death 1 Protein and Comparison of Patient Ages in Clinical Practice vs Pivotal Clinical Trials. JAMA Oncol. 2018:e180798-e180798.
  2. Morris ZS, Wooding S, Grant J. The answer is 17 years, what is the question: understanding time lags in translational research. J R Soc Med. 2011;104(12):510-520.
  3. Green LW. Making research relevant: if it is an evidence-based practice, where’s the practice-based evidence? Fam Pract. 2008;25(suppl_1):i20-i24.
  4. Balas EA, Boren SA. Managing clinical knowledge for health care improvement. Yearb Med Inform. 2000;(1):65-70.
  5. Downing NS, Aminawung JA, Shah ND, et al. Regulatory review of novel therapeutics—comparison of three regulatory agencies. N Engl J Med. 2012;366(24):2284-2293.
  6. American Association for Cancer Research. 2017. Cancer Progress Report 2017 (Accessed June 21, 2018, at
  7. Avorn J, Kesselheim AS. The 21st Century Cures Act—will it take us back in time? N Engl J Med. 2015;372(26):2473-2475.
  8. Singer DS, Jacks T, Jaffee E. A US “Cancer Moonshot” to accelerate cancer research. Science. 2016;353(6304):1105-1106.
  9. Mariotto A, Feuer EJ, Harlan LC, et al. Trends in use of adjuvant multi-agent chemotherapy and tamoxifen for breast cancer in the United States: 1975–1999. J Natl Cancer Inst. 2002;94(21):1626-1634.
  10. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non–small-cell lung cancer. N Engl J Med. 2015;372(21):2018-2028.
  11. Rizvi NA, Mazières J, Planchard D, et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015;16(3):257-265.
  12. Hutchins LF, Unger JM, Crowley JJ, et al. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med. 1999;341(27):2061-2067.
  13. Murthy VH, Krumholz HM, Gross CP. Participation in cancer clinical trials: race-, sex-, and age-based disparities. JAMA. 2004;291(22):2720-2726.
  14. Talarico L, Chen G, Pazdur R. Enrollment of elderly patients in clinical trials for cancer drug registration: a 7-year experience by the US Food and Drug Administration. J Clin Oncol. 2004;22(22):4626-4631.
  15. Mitchell AP, Harrison MR, Walker MS, et al. Clinical trial participants with metastatic renal cell carcinoma differ from patients treated in real-world practice. J Oncol Pract. 2015;11(6):491-497.
  16. Downing NS, Shah ND, Neiman JH, et al. Participation of the elderly, women, and minorities in pivotal trials supporting 2011–2013 US Food and Drug Administration approvals. Trials. 2016;17(1):199.
  17. Nishijima TF, Muss HB, Shachar SS, et al. Comparison of efficacy of immune checkpoint inhibitors (ICIs) between younger and older patients: a systematic review and meta-analysis. Cancer Treat Rev. 2016;45:30-37.
  18. Betof AS, Nipp RD, Giobbie‐Hurder A, et al. Impact of age on outcomes with immunotherapy for patients with melanoma. Oncologist. 2017;22(8):963-971.
  19. Johnpulle RA, Conry RM, Sosman JA, et al. Responses to immune checkpoint inhibitors in nonagenarians. Oncoimmunology. 2016;5(11):e1234572.
  20. Daste A, Domblides C, Gross-goupil M, et al. Immune checkpoint inhibitors and elderly people: A review. Eur J Cancer. 2017;82:155-166.
  21. Elias R, Morales J, Presley C. Checkpoint Inhibitors for non-small cell lung cancer among older adults. Curr Oncol Rep. 2017;19(9):62.
  22. Adoption of Anti–PD-1 Agents Into Clinical Practice and Age Differences in Practice vs Pivotal Clinical Trials. The ASCO Post. 2018 (Accessed June 21, 2018, at
  23. Checkpoint Inhibitors Rapidly Being Incorporated Into Routine Cancer Care. 2018 (Accessed June 22, 2018, at
  24. Hodi FS, Chesney J, Pavlick AC, et al. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016;17(11):1558-1568.
  25. Brahmer J, Horn L, Jackman D, et al. Five-year follow-up from the CA209-003 study of nivolumab in previously treated advanced non-small cell lung cancer (NSCLC): Clinical characteristics of long-term survivors. American Association for Cancer Research (AACR) Annual Meeting 2017; Washington D.C., US. April 1-5, 2017. Abstract CT077.
  26. Khozin S, Blumenthal GM, Pazdur R. Real-world Data for Clinical Evidence Generation in Oncology. J Natl Cancer Inst. 2017;109(11).
  27. Khozin S, Abernethy AP, Nussbaum NC, et al. Characteristics of Real‐World Metastatic Non‐Small Cell Lung Cancer Patients Treated with Nivolumab and Pembrolizumab During the Year Following Approval. Oncologist. 2018;23(3):328-336.
  28. New cancer immunotherapy drugs rapidly reach patients after approval. YaleNews. 2018 (Accessed June 22, 2018, at
  29. Levit LA, Balogh E, Nass SJ, et al. Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis. Washington (DC): National Academies Press (US); 2013 Dec.
  30. Progress Through Collaboration: ASCO and FDA’s Efforts to Improve the Evidence Base for Treating Older Adults With Cancer. ASCO Daily News. 2018 (Accessed June 25, 2018, at
  31. Hurria A, Levit LA, Dale W, et al. Improving the evidence base for treating older adults with cancer: American Society of Clinical Oncology statement. J Clin Oncol. 2015;33(32):3826-3833.
  32. Presentations and Discussion Questions for FDA-ASCO Public Workshop: Geriatric Oncology. US FDA News & Events. 2018 (Accessed June 25, 2018, at


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