Overall Response Rate, Progression-Free Survival, and Overall Survival With Targeted and Standard Therapies in Advanced Non–Small-Cell Lung Cancer: US Food and Drug Administration Trial-Level and Patient-Level Analyses

Blumenthal, Gideon M.; Karuri, Stella W.; Zhang, Hui; Zhang, Lijun; Khozin, Sean; Kazandjian, Dickran; Tang, Shenghui; Sridhara, Rajeshwari; Keegan, Patricia; Pazdur, Richard

doi:10.1200/jco.2014.59.0489

Cited by 181 publications

(188 citation statements)

References 48 publications

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“…At the time of ceritinib's approval, two randomized trials against standard therapy with the primary endpoint of PFS to confirm ceritinib's clinical benefit in patients with metastatic ALK-positive NSCLC were ongoing. Emerging evidence suggests a high correlation between ORR and PFS in metastatic NSCLC (24). Confirmation of these findings may qualify ORR as a validated endpoint for clinical benefit in metastatic NSCLC, especially for targeted agents that have a large magnitude of durable responses.…”

Section: Clinical Benefitmentioning

confidence: 77%

FDA Approval: Ceritinib for the Treatment of Metastatic Anaplastic Lymphoma Kinase–Positive Non–Small Cell Lung Cancer

Khozin

Blumenthal

Zhang

et al. 2015

Clinical Cancer Research

Self Cite

162

139

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On April 29, 2014, the FDA granted accelerated approval to ceritinib (ZYKADIA; Novartis Pharmaceuticals Corporation), a breakthrough therapy-designated drug, for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. The approval was based on a single-arm multicenter trial enrolling 163 patients with metastatic ALK-positive NSCLC who had disease progression on (91%) or intolerance to crizotinib. Patients received ceritinib at a starting dose of 750 mg orally once daily. The objective response rate (ORR) by a blinded independent review committee was 44% (95% CI, 36-52), and the median duration of response (DOR) was 7.1 months. The ORR by investigator assessment was similar. Safety was evaluated in 255 patients. The most common adverse reactions and laboratory abnormalities included diarrhea (86%), nausea (80%), increased alanine transaminase (80%), increased aspartate transaminase (75%), vomiting (60%), increased glucose (49%), and increased lipase (28%). Although 74% of patients required at least one dose reduction or interruption due to adverse reactions, the discontinuation rate due to adverse reactions was low (10%). With this safety profile, the benefit-risk analysis was considered favorable because of the clinically meaningful ORR and DOR.

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Section: Clinical Benefitmentioning

confidence: 77%

FDA Approval: Ceritinib for the Treatment of Metastatic Anaplastic Lymphoma Kinase–Positive Non–Small Cell Lung Cancer

Khozin

Blumenthal

Zhang

et al. 2015

Clinical Cancer Research

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162

139

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“…27,28), in which gefitinib demonstrated improvement in ORR and PFS compared with platinum-doublet chemotherapy. A recent meta-analysis by the FDA showed that in advanced NSCLC, a drug with a large magnitude of effect on ORR may likely result in a large improvement in PFS (29).…”

Section: Discussionmentioning

confidence: 99%

FDA Approval of Gefitinib for the Treatment of Patients with Metastatic EGFR Mutation–Positive Non–Small Cell Lung Cancer

Kazandjian

Blumenthal

Yuan

et al. 2016

Clinical Cancer Research

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183

130

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On July 13, 2015, the FDA approved gefitinib (Iressa; AstraZeneca UK Limited) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test. Concurrently, a labeling expansion of the therascreen EGFR RGQ PCR Kit (Qiagen) as a companion diagnostic test was approved. The approval was based on the results of a multicenter, single-arm, open-label clinical study of 106 treatment-na€ ve patients with metastatic EGFR mutation-positive NSCLC who received gefitinib, 250 mg daily, until disease progression or intolerable toxicity. The major efficacy outcome was RECIST v1.1 objective response rate (ORR). The blinded independent central review (BICR) ORR was 50% [95% confidence interval (CI), 41-59] with a median duration of response (DoR) of 6.0 months. Efficacy results were supported by a retrospective exploratory analysis of a subset of a randomized, multicenter, open-label trial on 1,217 patients with metastatic NSCLC. Of the patients randomized, 186 (15%) were retrospectively determined to be EGFR positive and evaluable for a BICR assessment. The HR for progression-free survival (PFS) was 0.54 (95% CI, 0.38-0.79), favoring gefitinib over platinum-doublet chemotherapy. The most common (20%) adverse reactions were skin reactions, increased aspartate and alanine aminotransferase, proteinuria, and diarrhea. Approximately 5% of patients discontinued treatment due to an adverse reaction. Given the safety profile and clinically meaningful ORR, DoR, and PFS, the benefit-risk analysis was deemed favorable for FDA approval.

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“…Although the goal of cancer treatment is to improve the quantity and quality of life,1 2 3 clinical trials designed to gain regulatory approval for new drugs often evaluate indirect or “surrogate” measures of drug efficacy. These endpoints show that an agent has biological activity, but they are not reliable surrogates for improved survival4 5 6 7 8 9 10 11 or quality of life4 6 11 12 13 in all settings, and two recent systematic reviews suggest that the strength of association between surrogates in cancer clinical trials and life extension is generally low 814 Moreover, there is growing concern that the benefits offered by many new treatments for cancer—often discussed and promoted as “breakthroughs”15 16 17 18—are marginal and might not be clinically meaningful to patients, despite rapidly escalating costs 19…”

Section: Introductionmentioning

confidence: 99%

Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13

Davis

Naci

Gurpinar

et al. 2017

BMJ

466

415

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Objective To determine the availability of data on overall survival and quality of life benefits of cancer drugs approved in Europe. Design Retrospective cohort study. Setting Publicly accessible regulatory and scientific reports on cancer approvals by the European Medicines Agency (EMA) from 2009 to 2013. Main outcome measures Pivotal and postmarketing trials of cancer drugs according to their design features (randomisation, crossover, blinding), comparators, and endpoints. Availability and magnitude of benefit on overall survival or quality of life determined at time of approval and after market entry. Validated European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) used to assess the clinical value of the reported gains in published studies of cancer drugs. Results From 2009 to 2013, the EMA approved the use of 48 cancer drugs for 68 indications. Of these, eight indications (12%) were approved on the basis of a single arm study. At the time of market approval, there was significant prolongation of survival in 24 of the 68 (35%). The magnitude of the benefit on overall survival ranged from 1.0 to 5.8 months (median 2.7 months). At the time of market approval, there was an improvement in quality of life in seven of 68 indications (10%). Out of 44 indications for which there was no evidence of a survival gain at the time of market authorisation, in the subsequent postmarketing period there was evidence for extension of life in three (7%) and reported benefit on quality of life in five (11%). Of the 68 cancer indications with EMA approval, and with a median of 5.4 years’ follow-up (minimum 3.3 years, maximum 8.1 years), only 35 (51%) had shown a significant improvement in survival or quality of life, while 33 (49%) remained uncertain. Of 23 indications associated with a survival benefit that could be scored with the ESMO-MCBS tool, the benefit was judged to be clinically meaningful in less than half (11/23, 48%). Conclusions This systematic evaluation of oncology approvals by the EMA in 2009-13 shows that most drugs entered the market without evidence of benefit on survival or quality of life. At a minimum of 3.3 years after market entry, there was still no conclusive evidence that these drugs either extended or improved life for most cancer indications. When there were survival gains over existing treatment options or placebo, they were often marginal.

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Overall Response Rate, Progression-Free Survival, and Overall Survival With Targeted and Standard Therapies in Advanced Non–Small-Cell Lung Cancer: US Food and Drug Administration Trial-Level and Patient-Level Analyses

Cited by 181 publications

References 48 publications

FDA Approval: Ceritinib for the Treatment of Metastatic Anaplastic Lymphoma Kinase–Positive Non–Small Cell Lung Cancer

FDA Approval: Ceritinib for the Treatment of Metastatic Anaplastic Lymphoma Kinase–Positive Non–Small Cell Lung Cancer

FDA Approval of Gefitinib for the Treatment of Patients with Metastatic EGFR Mutation–Positive Non–Small Cell Lung Cancer

Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13

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