- •Fifty drugs (55%) approved for a genomic indication had a study evaluating OS benefit.
- •Twenty-two randomised studies (24%) demonstrated an improvement in OS.
- •The median improvement in OS for drugs with a genomic indication was 4.7 months.
Drug approvals for genome-informed indications have been increasing in recent years, but it is unknown how many of them have demonstrated an improvement in overall survival (OS). We assessed the frequency of approved genome-informed drugs demonstrating improvements in OS and progression-free survival (PFS) and whether the frequencies differed by cancer type.
Materials and methods
We searched all Food and Drug Administration approvals from 2006 to 2020, and for each drug that was approved for a genomic indication, we then searched on PubMed for randomised studies examining OS or PFS.
We found 53 drugs approved for 92 unique indications from 2006 to 2020. We found that 50 drugs (55%) approved for a genomic indication had a randomised study evaluating OS benefit, and of those, only 22 demonstrated an improvement in OS. Similarly, 52 drugs (57%) evaluated PFS benefit, and 51 of these studies demonstrated an improvement in PFS. Drugs approved for BRAF V600 melanoma demonstrated an improvement in OS more often than drugs approved for ALK non–small cell lung cancer. The median improvement in OS was 4.7 months (range 1.5 months–49.1 months).
Although there is widespread enthusiasm for this class of agents, and many demonstrate impressive response rates, further trials or post-marketing studies are needed to ascertain the impact on survival and quality of life, the magnitude of these gains, and the cost-effectiveness of these agents.
Two-thirds of oncology drugs are approved based on surrogate markers such as overall response rate (ORR) or progression-free survival (PFS) [
]. However, only one in seven oncology drugs that are approved on a surrogate outcome is later shown to improve overall survival (OS) in extended follow-up, post-marketing, or subsequent studies [
- Kim C.
- Prasad V.
Strength of validation for surrogate end points used in the US food and drug administration's approval of oncology drugs.
Mayo Clin Proc. May 10, 2016; https://doi.org/10.1016/j.mayocp.2016.02.012
- Kim C.
- Prasad V.
Cancer drugs approved on the basis of a surrogate end point and subsequent overall survival: an analysis of 5 years of US food and drug administration approvals.
JAMA Intern Med. Dec 2015; 175: 1992-1994https://doi.org/10.1001/jamainternmed.2015.5868
Approvals for genome-informed indications, which are often based on ORR, have been increasing in recent years. Currently, 13.6% of US cancer patients are eligible for genome targeted drugs and 7% of cancer patients may respond [
]. However, it is unknown what percentage of these drugs have proven OS gains for these indications and what the magnitude of those differences are. In this study, we sought to determine the percentage of drugs approved for a targeted indication that have studies reporting on OS and PFS and whether this varies by cancer type.
- Haslam A.
- Kim M.S.
- Prasad V.
Updated estimates of eligibility for and response to genome-targeted oncology drugs among US cancer patients, 2006-2020.
Ann Oncol. Apr 13, 2021; https://doi.org/10.1016/j.annonc.2021.04.003
We searched the Food and Drug Administration (FDA) website to find all oncology drugs approved for a genetically targeted indication for advanced, metastatic, or unresectable cancers (January 2006 through December 2020). We then extracted data regarding the indication, ORR, and date of approval. For each approved drug, we searched PubMed for articles reporting on randomised clinical studies that tested whether the approved drug improved OS, PFS, or ORR, compared with standard of care for each approved indication. The search terms included the study drug, the tumour type, and the genetic indication, filtering by ‘clinical trials’. In some cases where there were a lot of search results produced, we used the Boolean operator of ‘not’ to remove studies that were not relevant to our study (e.g. adjuvant if the drug was approved first line). We searched for studies published through May 25, 2021.
For each study, we extracted data relating to the efficacy for both the intervention and control groups in the study (e.g. median times of PFS and OS, hazard ratios, ORR, P values, and/or confidence intervals). We then classified each drug as having a randomised controlled trial that reported on these outcomes, and if so, whether the results were positive or negative/null for each outcome type (OS, PFS, or overall ORR).
We then calculated frequencies for each outcome by trial result positivity. We did this for all cancers combined and for four cancers with the most frequent drug approvals. For drugs that demonstrated OS improvement and reported median OS, we calculated the median OS improvement. All analyses were done using Excel and R software, version 3.6.1. In accordance with 45 CFR §46.102(f), this study was not submitted for institutional review board approval because it involved publicly available data and did not involve individual patient data.
During the time interval 2006–2020, we found 53 drugs approved for 92 unique indications. Genetic indications with the most approvals include drugs targeting the Philadelphia chromosome (PH)+ (14 approvals), EGFR (12 approvals), HER2 (10 approvals), ALK (8 approvals), and BRAF V600 (9 approvals). Cancer types with the most drug/indication approvals were non–small cell lung cancer (NSCLC; 23 approvals), breast (12 approvals), chronic myeloid leukaemia (10 approvals), colorectal (8 approvals), and melanoma (7 approvals). Fifty-eight (63%) approvals were regular, and 34 (37%) were accelerated. There were 18 approvals in 2020, 8 in 2019, 14 in 2018, and 11 in 2017. The remaining 41 approvals were made in 2016 or before, with 16 of them being accelerated.
As presented in Fig. 1, 50 drugs (55%) approved for a genomic indication had a randomised study evaluating OS benefit; 52 drugs (57%) evaluated PFS benefit. These results, stratified by haematologic versus solid tumour indications, are presented in Fig. 1.
The percentage of drugs/indications with positive study results was 24% for OS (n = 22) and 55% for PFS (n = 51). The percentage of drugs with negative or null study results was 30% for OS (n = 28) and 1% for PFS (n = 1).
These results vary by cancer type, with NSCLC drugs having a low percentage of studies reporting positive results for OS (n = 3; 12% of studies for NSCLC drugs) and melanoma drugs having a higher percentage of studies confirming OS benefit (n = 5; 71% of studies for melanoma drugs; data not shown). Table 1 shows the drugs/indications for which we found a study showing improved OS.
Table 1Drugs that are FDA approved for a genomic indication that have shown to improve overall survival.
|Drug||Date of approval||Cancer type||Genomic target||Median overall survival times (intervention versus control)|
|Gilteritinib||11/28/18||AML||FLT3||9.3 versus 5.6 months|
|Midostaurin||4/28/17||AML||FLT3||74.7 versus 25.6 months|
|Trastuzumab||9/25/1998||Breast||HER2||25.4 versus 20.3 months|
|Tucatinib in combination with trastuzumab and capecitabine||4/17/20||Breast||HER2||21.9 versus 17.4 months|
|Pertuzumab||6/8/12||Breast||HER2||56.5 versus 40.8 months|
|Ado-trastuzumab emtansine||2/22/13||Breast||HER2||30.9 versus 25.1 months|
|Ibrutinib||7/28/14||CLL||17p||90% versus 81% at 12 months|
|Nilotinib||6/17/10||CML||Ph+||98.5% versus 95.2% at 3 years|
|Encorafenib in combination with cetuximab||4/8/20||CRC||BRAF V600E||8.4 versus 5.4 months|
|Cetuximab in combination with FOLFIRI||7/9/12||CRC (1st line)||EGFR (KRAS)||23.5 versus 20.0 months|
|Cetuximab||2/1/04||CRC (later line)||EGFR (KRAS)||6.1 versus 4.6 months|
|Panitumumab||9/27/06||CRC||KRAS||10.0 versus 7.4 months|
|Trastuzumab||10/20/10||Gastric||HER2||13.8 versus 11.1 months|
|Imatinib||12/19/08||GIST||GIST||92% versus 82% at 5 year|
|Encorafenib and binimetinib||6/27/18||Melanoma||BRAF V600 E or K||33.6 versus 16.9 months|
|Cobimetinib in combination with vemurafenib||11/10/15||Melanoma||BRAF V600 E or K||22.3 versus 17.4 months|
|Trametinib and dabrafenib||1/10/14||Melanoma||BRAF V600 E or K||25.1 versus 18.7 months|
|Trametinib||5/29/13||Melanoma||BRAF V600 E or K||81% versus 67% at 6 months|
|Vemurafenib||8/17/11||Melanoma||BRAF V600E||13.6 versus 9.7 months|
|Dacomitinib||9/27/2018||NSCLC||EGFR 19/21||34.1 versus 26.8 months|
|Osimertinib||4/19/18||NSCLC||EGFR 19/21||38.6 versus 31.8 months|
|Nivolumab||10/9/15||NSCLC||EGFR or ALK||12.0 versus 9.6 months|
FDA = Food and Drug Administration; AML = acute myeloid leukemia; CLL = chronic lymphocytic leukemia; CML = chronic myeloid leukemia; CRC = colorectal cancer; GIST = gastrointestinal stromal tumour; NSCLC = non-small cell lung cancer.
For drugs that were shown to improve OS and reported median OS times (n = 17), the median improvement in OS was 4.7 months. The improvement ranged from 1.5 months for EGFR relapsed/refractory colorectal cancer to 49.1 months for FLT3 acute myeloid leukaemia. More than half (59%) of the approvals that demonstrated an improvement in OS were for BRAF V600 melanoma and EGFR NSCLC or colorectal cancer.
We found 34 drugs/indications that failed to improve OS, RR, or PFS, 15 drugs/indications improved all three of these outcomes, 18 drugs/indications had an improvement in PFS only, three had an improvement in ORR only, two had an improvement in OS only, 15 improved both PFS and ORR, three improved OS and PFS, and two improved OS and ORR (Supplemental Table). Of the drugs that had no data on OS, 16 (38%) drug approvals were for haematologic indications.
Fig. 2 shows the percentage of drugs demonstrating an improvement in OS in oncology drugs approved for a genetic indication, by cancer type and genetic target, for the more common cancer types. The number and percentage of studies finding an improvement in OS varied by tumour type and genetic indication. We found that for the seven drugs approved for BRAF V600 melanoma, five (71%) improved OS, and all eight (100%) of the drugs approved for ALK NSCLC failed to show an improvement in OS. Of the three drugs approved for MSI/MMR colorectal cancer, none (0%) had studies reporting on OS.
We found that only about half of oncology drugs FDA approved for a genomic indication had studies reporting on OS, and only about one-fifth of them demonstrated an improvement in OS. Our results are slightly lower than another study that report that 32% of drugs approved for an oncology indication had studies showing an improvement in OS in either pre- or post-marketing studies [
]. With a focused effort on increasing earlier treatment options for cancer patients, surrogate markers such as PFS or ORR, which are thought to bring drugs to market faster, are being increasingly used in drug approvals. However, to justify the high cost of these drugs, an improvement in OS should also be demonstrated. Here, we show that most approved targeted drugs have yet to show OS benefit.
- Zettler M.
- Basch E.
- Nabhan C.
Surrogate end points and patient-reported outcomes for novel oncology drugs approved between 2011 and 2017.
JAMA Oncol. Jul 3, 2019; 5: 1358-1359https://doi.org/10.1001/jamaoncol.2019.1760
We found that drugs approved for a genomic indication, which improved OS, did so by a median of 4.7 months, which is slightly more than other studies that have evaluated all cancer drugs approved between 2003 and 2013 [
] and metastatic cancers approved between 2002 and 2014 [
- Salas-Vega S.
- Iliopoulos O.
- Mossialos E.
Assessment of overall survival, quality of life, and safety benefits associated with new cancer medicines.
JAMA Oncol. Mar 1, 2017; 3: 382-390https://doi.org/10.1001/jamaoncol.2016.4166
- Fojo T.
- Mailankody S.
- Lo A.
Unintended consequences of expensive cancer therapeutics—the pursuit of marginal indications and a me-too mentality that stifles innovation and creativity: the John Conley Lecture.
JAMA Otolaryngol Head Neck Surg. 2014; 12: 1225-1236
]. This is not unexpected given that previous observational studies have shown that for certain cancers, patients treated with targeted therapies have better OS than patients treated without targeted therapies [
- Vaishampayan U.
- Vankayala H.
- Vigneau F.D.
- Quarshie W.
- Dickow B.
- Chalasani S.
- et al.
The effect of targeted therapy on overall survival in advanced renal cancer: a study of the national surveillance epidemiology and end results registry database.
Clin Genitourin Cancer. Apr 2014; 12: 124-129https://doi.org/10.1016/j.clgc.2013.09.007
]. A concern for targeted drugs is that trial-level data overestimates OS because participants who are less likely to participate in clinical trials are also less likely to have an improved OS in real-world data [
- Li P.
- Jahnke J.
- Pettit A.R.
- Wong Y.-N.
- Doshi J.A.
Comparative survival associated with use of targeted vs nontargeted therapy in medicare patients with metastatic renal cell carcinoma.
JAMA Netw Open. 2019; 2 (e195806–e195806)https://doi.org/10.1001/jamanetworkopen.2019.5806
- Nabi J.T.
New cancer therapies are great—but are they helping everyone?.
One of the limitations to our analysis is that we only used PubMed to find articles demonstrating an improvement in outcomes. We may have found more studies finding improvement in these outcomes had we used other search engines. However, increasing the number of studies examining a given outcome also increases the likelihood of finding benefit, real or not. A second limitation is that some data were immature, and the final results for these studies may be different from the preliminary data. In these instances, we used the immature findings because that is all we had available. Consequently, our results apply to current knowledge and may not be generalisable to future findings.
About half of FDA-approved drugs for a genome-informed oncology indication have had studies evaluating OS benefit. Only about one-fifth of drugs for these indications have had randomised studies reporting positive OS outcomes, whereas over half of drugs have been shown to improve PFS. Although there is widespread enthusiasm for this class of agents, and many demonstrate impressive response rates [
], further trials or post-marketing studies are needed to ascertain the impact on survival and quality of life, the magnitude of these gains, and the cost-effectiveness of these agents.
- Marquart J.
- Chen E.Y.
- Prasad V.
Estimation of the percentage of US patients with cancer who benefit from genome-driven oncology.
JAMA Oncol. Aug 1, 2018; 4: 1093-1098https://doi.org/10.1001/jamaoncol.2018.1660
V.P., A.H., and M.S.K. conceptualised study design. A.H. and M.S.K. reviewed and abstracted data. V.P. reviewed and confirmed abstracted data. A.H. wrote the first draft of the article. All authors reviewed and revised subsequent and finalised draft of the article.
This study was funded by Arnold Ventures.
Conflict of interest statement
V.P. received research funding from Arnold Ventures, royalties from Johns Hopkins Press and Medscape, and honoraria from Grand Rounds/lectures from universities, medical centres, non-profits, and professional societies; is a consultant at UnitedHealthcare; and received speaking fees from Evicore. (Other) Plenary Session podcast has Patreon backers. All other authors have no financial nor non-financial conflicts of interest to report.
Appendix A. Supplementary data
The following is the Supplementary data to this article:
- Multimedia component 1
- Strength of validation for surrogate end points used in the US food and drug administration's approval of oncology drugs.Mayo Clin Proc. May 10, 2016; https://doi.org/10.1016/j.mayocp.2016.02.012
- Cancer drugs approved on the basis of a surrogate end point and subsequent overall survival: an analysis of 5 years of US food and drug administration approvals.JAMA Intern Med. Dec 2015; 175: 1992-1994https://doi.org/10.1001/jamainternmed.2015.5868
- Updated estimates of eligibility for and response to genome-targeted oncology drugs among US cancer patients, 2006-2020.Ann Oncol. Apr 13, 2021; https://doi.org/10.1016/j.annonc.2021.04.003
- Surrogate end points and patient-reported outcomes for novel oncology drugs approved between 2011 and 2017.JAMA Oncol. Jul 3, 2019; 5: 1358-1359https://doi.org/10.1001/jamaoncol.2019.1760
- Assessment of overall survival, quality of life, and safety benefits associated with new cancer medicines.JAMA Oncol. Mar 1, 2017; 3: 382-390https://doi.org/10.1001/jamaoncol.2016.4166
- Unintended consequences of expensive cancer therapeutics—the pursuit of marginal indications and a me-too mentality that stifles innovation and creativity: the John Conley Lecture.JAMA Otolaryngol Head Neck Surg. 2014; 12: 1225-1236
- The effect of targeted therapy on overall survival in advanced renal cancer: a study of the national surveillance epidemiology and end results registry database.Clin Genitourin Cancer. Apr 2014; 12: 124-129https://doi.org/10.1016/j.clgc.2013.09.007
- Comparative survival associated with use of targeted vs nontargeted therapy in medicare patients with metastatic renal cell carcinoma.JAMA Netw Open. 2019; 2 (e195806–e195806)https://doi.org/10.1001/jamanetworkopen.2019.5806
- New cancer therapies are great—but are they helping everyone?.2019
- Estimation of the percentage of US patients with cancer who benefit from genome-driven oncology.JAMA Oncol. Aug 1, 2018; 4: 1093-1098https://doi.org/10.1001/jamaoncol.2018.1660
Published online: November 21, 2021
Accepted: October 21, 2021
Received in revised form: October 13, 2021
Received: September 14, 2021
© 2021 The Authors. Published by Elsevier Ltd.
User licenseCreative Commons Attribution – NonCommercial – NoDerivs (CC BY-NC-ND 4.0) |
How you can reuse
Elsevier's open access license policy
Creative Commons Attribution – NonCommercial – NoDerivs (CC BY-NC-ND 4.0)
For non-commercial purposes:
- Read, print & download
- Redistribute or republish the final article
- Text & data mine
- Translate the article (private use only, not for distribution)
- Reuse portions or extracts from the article in other works
- Sell or re-use for commercial purposes
- Distribute translations or adaptations of the article
Elsevier's open access license policy