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The FDA Oncology Center of Excellence recently launched a crowdsourcing pilot to request ideas from the scientific community for research questions that FDA could address with pooled analyses of clinical trial data submitted to the agency for regulatory purposes. This effort builds on FDA's track record of publishing pooled analyses to explore scientific questions that cannot be addressed in a single trial due to limited sample size. The research crowdsourcing pilot tested a new approach for obtaining external input on regulatory science activities, because FDA is generally unable to share patient-level data outside of the agency due to federal disclosure laws and regulations protecting different types of data submitted in regulatory applications. We received 29 submissions over the 28-day crowdsourcing campaign, including one research idea that we are exploring for possible follow-up. Based on our experience with this pilot, we learned that crowdsourcing is a promising new approach to gather external input and feedback. We identified opportunities to build understanding in the external oncology community about the types of data typically included in regulatory applications and expand the dissemination of published FDA pooled analyses to help inform future drug development and clinical practice.

This review highlights strategies to integrate dose optimization into premarketing drug development and discusses the underlying statistical principles. Poor dose optimization can have negative consequences for patients, most commonly because of toxicity, including poor quality of life, reduced effectiveness because of inability of patients to stay on current therapy or receive subsequent therapy because of toxicities, and difficulty in developing combination regimens. We reviewed US Food and Drug Administration initial approvals (2019-2021) of small molecules and antibody-drug conjugates for oncologic indications to determine the proportion with a recommended dosage at the maximum tolerated dose or the maximal administered dose, to characterize the use of randomized evaluations of multiple dosages in dose selection, to describe the frequency of dose modifications at the recommended dosage, and to identify case examples that highlight key principles for premarket dose optimization during drug development. Herein, we highlight major principles for dose optimization and review examples of recent US Food and Drug Administration approvals that illustrate how investigation of dose- and exposure-response relationships and use of randomized dose trials can support dose optimization. Although there has been some progress, dose optimization through randomized dose evaluation in oncology trials is not routinely conducted. Dose optimization is essential to ensure that patients receive therapies which maximize efficacy while minimizing toxicity.

Summary of Crowdsourcing Submissions Received

Pooled analyses of oncology clinical trial data 2018-2021

Grouped terms used in safety analyses

On March 29, 2018, the FDA granted accelerated approval for blinatumomab (Blincyto; Amgen, Inc.) for the treatment of adults and children with B-cell precursor acute lymphoblastic leukemia (BCP ALL) in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%. Blinatumomab is a CD3xCD19 bispecific antibody approved previously for the treatment of relapsed or refractory BCP ALL. The basis for this accelerated approval was a single-arm trial. For the 86 patients in first and second complete remission with MRD ≥ 0.1%, conversion to MRD < 0.01% was achieved after one cycle of blinatumomab by 85.2% [95% confidence interval (CI): 73.8%, 93.0%] and 72.0% (95% CI: 50.6%, 87.9%), respectively, and the estimated median hematologic relapse-free survivals (RFS) were 35.2 months (95% CI: 0.4–53.5) and 12.3 months (95% CI: 0.7–42.3), respectively. Hematologic RFS was considered substantial independent of whether patients underwent subsequent allogeneic stem cell transplantation. The safety profile for blinatumomab was established in prior studies, and no new safety signals were observed in the new population. Cytokine release syndrome and neurotoxicity remain significant risks. The FDA is requiring confirmation of clinical benefit in a randomized trial.

RFS by baseline MRD level from Study 20120148

Supplementary Tables S1-S3

Grade >/= 3 AR

Literature review - efficacy by log-group MRD

Supplementary Figure 1. Detailed flow diagram for ascertainment of DS cases.

Purpose: Both objective response rate (ORR) and progression-free survival as defined by RECIST are weakly associated with overall survival (OS) in trials evaluating immunotherapy drug products. We proposed a novel intermediate response endpoint (IME) for evaluating immunotherapies.Experimental Design: We defined IME response as having no nontarget lesion progression, no new lesion appearance, and reaching a target lesion response determined by baseline tumor burden, tumor reduction depth, and tumor change dynamics within one year after randomization. Database used consisted of data from randomized active-controlled immunotherapy trials. Criterion for IME was developed on the basis of patient-level data from a training dataset, and further evaluated using an independent testing dataset. A patient-level responder analysis comparing OS between patients with and without an IME response was conducted using combined data. Association between trial-level OS hazard ratio (HR) and IME odds ratio (OR) was analyzed using a weighted linear regression model.Results: A total of 5,806 patients from 9 randomized studies were included in the database. At patient level, patients with IME response had improved OS compared with nonresponders (HR = 0.09). At trial level, association between OS and IME was moderate (R2 = 0.68).Conclusions: The IME was moderately associated with OS, and the association appeared to be stronger than the association observed between RECIST-defined ORR and OS. However, the analyses conducted in this research are exploratory and further evaluation is needed before using this endpoint in future studies. Clin Cancer Res; 24(10); 2262–7. ©2017 AACR.

Supplementary Figure 2. Relative risk of DS for frequently co-mutated genes.

Supplementary Tables S1-S7

Key baseline demographic and characteristics; Hazard ratio from Cox model

The FDA Oncology Center of Excellence (OCE) is a leader within the agency in scientific outreach activities and regulatory science research. On the basis of analysis of scientific workshops, internal meetings, and publications, the OCE identified nine scientific priority areas and one cross-cutting area of high interest for collaboration with external researchers. This article describes the process for identifying these scientific interest areas and highlights funded and unfunded opportunities for external researchers to work with FDA staff on critical regulatory science challenges.

Purpose:Differentiation syndrome (DS) is a serious adverse reaction of isocitrate dehydrogenase (IDH) inhibitors ivosidenib and enasidenib in patients with (IDH)1- and IDH2-mutated acute myeloid leukemia (AML), respectively.Experimental Design:During FDA review of marketing applications for ivosidenib and enasidenib, data from pivotal trials were queried to identify cases of DS in patients with relapsed or refractory (R/R) AML. One hundred seventy-nine patients with R/R AML received ivosidenib and 214 received enasidenib. Adverse events, labs, and vital signs in the first 90 days of treatment were screened per diagnostic criteria, and narratives were reviewed to adjudicate DS cases.Results:We identified 72 of 179 (40%) potential cases for ivosidenib and 86 of 214 (40%) for enasidenib; 34 of 179 (19%) and 41 of 214 (19%) were adjudicated as DS. Leukocytosis was present in 79% and 61% of cases, respectively. Median (range) time to onset was 20 (1–78) and 19 (1–86) days. Grade ≥ 3 adverse reactions occurred in 68% and 66%; 6% and 5% were fatal. Univariate analyses suggested baseline bone marrow blasts ≥ 48% and peripheral blood blasts ≥ 25% and 15% for ivosidenib and enasidenib, respectively, were associated with increased risk of DS. Complete remission (CR) + CR with partial hematologic recovery rates were lower in patients with versus without DS [ivosidenib 18% (95% confidence interval, 7%–35%) vs. 36% (28%–45%); enasidenib 18% (7%–33%) vs. 25% (18%–32%)].Conclusions:DS is a common and potentially fatal adverse reaction of IDH inhibitors, and use of standardized diagnostic criteria may aid in earlier diagnosis and treatment.See related commentary by Zeidner, p. 4174

Literature review - efficacy by binary MRD outcome

Supplementary Tables

Supplementary Figure 3. Blood count trajectory for patients with or without DS.

The FDA has approved three androgen receptor inhibitors—enzalutamide, apalutamide, and darolutamide—for the treatment of patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). These approvals were all based on randomized, double blind, placebo-controlled trials demonstrating large improvements in metastasis-free survival (MFS) and internally consistent evidence of benefit seen across secondary endpoints. In this article, we summarize the FDA regulatory history of MFS and we describe the design, conduct, and results of the three pivotal trials supporting these important treatment options for patients with nmCRPC.

PURPOSE To explore trial-level and patient-level associations between response (complete remission [CR] and CR + CR with incomplete hematologic [CRi] or platelet [CRp] recovery), event-free survival (EFS), and overall survival (OS) in newly diagnosed acute myeloid leukemia (AML) trials of intensive chemotherapy. METHODS We identified data from eight randomized, active-controlled trials of intensive chemotherapy submitted to the US Food and Drug Administration for treatment of newly diagnosed AML (N = 4,482). Associations between trial-level odds ratios (ORs) for CR and CR + CRi or CRp, and hazard ratios (HRs) for EFS and OS were analyzed using weighted linear regression models. We performed patient-level responder analyses to compare OS by response using pooled data from all studies. RESULTS In trial-level analyses, association between HR for OS and OR for CR was moderate (R2 = 0.49; 95% CI, 0.05 to 0.86), as was the association with OR for CR + CRi or CRp (R2 = 0.48; 95% CI, 0.05 to 0.99). For OS versus EFS, a strong association was observed (R2 = 0.87; 95% CI, 0.47 to 0.98) when EFS definitions were harmonized across trials using raw data. In the patient-level responder analyses, patients who achieved CR had better OS compared with CRi or CRp responders (0.73; 95% CI, 0.64 to 0.84) and nonresponders (HR, 0.33; 95% CI, 0.31 to 0.37). CONCLUSION On a trial level, there is a moderate association between OS and CR rate. A strong association between EFS and OS was observed. However, CIs were wide, and results became moderate using alternative definitions for EFS. Patient-level analyses showed CR responders have better OS compared with CRi or CRp responders and nonresponders. A therapy in newly diagnosed AML with benefit in EFS or substantial benefit in CR rate would be likely to have an OS effect.

Summary Background Cyclin-dependent kinase 4/6 inhibitors (CDKIs) are oral targeted agents approved for use in combination with endocrine therapy as first-line or second-line treatment of patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer. We previously reported the pooled analyses of progression-free survival in patients in specific clinicopathological subgroups, all of whom received consistent benefit from the addition of a CDKI to hormonal therapy. Here, we report the pooled overall survival results in patients treated with a CDKI and fulvestrant. Methods In this exploratory analysis, we pooled individual patient data from three phase 3 randomised trials of CDKI or placebo in combination with fulvestrant in patients with breast cancer submitted to the US Food and Drug Administration and approved before Aug 1, 2020, in support of marketing applications. All analysed patients were aged at least 18 years, had an Eastern Cooperative Oncology Group performance status of 0–1, had hormone receptor-positive, HER2-negative advanced or metastatic breast cancer, and received at least one dose of CDKI or placebo in combination with fulvestrant. The median overall survival was estimated using Kaplan-Meier methods, and hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression models. Patients were analysed collectively, by number of previous lines of systemic endocrine therapy in any disease setting (first-line or endocrine naive vs second-line and later), and in various clinicopathological subgroups of interest. The estimated median overall survival was not reported by group when the pooled population included patients treated across lines of therapy because of potential patient heterogeneity. All results presented are considered exploratory and hypothesis generating. Findings Across the three pooled trials, 1960 patients were randomly assigned between Oct 7, 2013, and June 10, 2016 (12 patients were not treated and 1296 [66%] patients were randomly assigned to CDKI and 652 [33%] to placebo). In all treated patients (n=1948), the estimated HR for overall survival was 0·77 (95% CI 0·68–0·88), with a median follow-up of 43·7 months (IQR 37·8–47·7) and deaths in 935 (48%) of the 1948 patients. The difference in estimated median overall survival was 7·1 months, favouring CDKIs. In patients who received CDKIs or placebo in combination with fulvestrant as first-line systemic endocrine therapy (two trials; n=396), the estimated HR for overall survival was 0·74 (95% CI 0·52–1·07), with a median follow-up of 39·4 months (IQR 37·0–42·2). 123 (31%) of these patients died. The difference in estimated median overall survival could not be calculated because median overall survival was not estimable (95% CI 50·9–not estimable) in the CDKI group and was 45·7 months (95% CI 41·7–not estimable) in the placebo group. In patients who received CDKIs or placebo in combination with fulvestrant as second-line or later systemic endocrine therapy (three trials; n=1552), the estimated HR for overall survival was 0·77 (95% CI 0·67–0·89), with a median follow-up of 45·1 months (95% CI 39·2–48·5). 812 (52%) of these patients died. The difference in estimated median overall survival was 7·0 months, favouring CDKIs. Interpretation The addition of CDKIs to fulvestrant resulted in a consistent overall survival benefit in all pooled patients and within most clinicopathological subgroups of interest. These findings support the existing standard of care of CDKIs plus fulvestrant for the treatment of patients with hormone receptor-positive, HER2-negative, advanced breast cancer. Funding None.

This article summarizes the discussions from the American Statistical Association (ASA) Biopharmaceutical (BIOP) Section Open Forum that took place on December 10, 2020 and was organized by the ASA BIOP Statistical Methods in Oncology Scientific Working Group, in coordination with the U.S. FDA Oncology Center of Excellence. Diverse stakeholders including experts from international regulatory agencies, academicians, and representatives of the pharmaceutical industry engaged in a discussion on the use of nonconcurrent control in Master Protocols for oncology trials. While the use of nonconcurrent control with the concurrent control may increase the power of detecting the therapeutic difference between a treatment and the control, the panelists had diverse opinion on the statistical approaches for modeling nonconcurrent and concurrent controls. Some were more concerned about the temporality of the nonconcurrent control and bias introduced by different confounders related to time, for example, changes in standard of care, changes in patient population, changes in recruiting strategies, changes in assessment of endpoints. Nevertheless, in some situations such as when the recruitment is extremely challenging for a rare disease, the panelists concluded that the use of a nonconcurrent control can be justified.

Subgroup analyses are assessments of treatment effects based on certain patient characteristics out of the total study population and are important for interpretation of pivotal oncology trials. However, appropriate use of subgroup analyses results for regulatory decision-making and product labeling is challenging. Typically, drugs approved by the FDA are indicated for use in the total patient population studied; however, there are examples of restriction to a subgroup of patients despite positive study results in the entire study population and also extension of an indication to the entire study population despite positive results appearing primarily in one or more subgroups. In this article, we summarize key issues related to subgroup analyses in the benefit–risk assessment of cancer drugs and provide case examples to illustrate approaches that the FDA Oncology Center of Excellence has taken when considering the appropriate patient population for cancer drug approval. In general, if a subgroup is of interest, the subgroup analysis should be hypothesis-driven and have adequate sample size to demonstrate evidence of a treatment effect. In addition to statistical efficacy considerations, the decision on what subgroups to include in labeling relies on the pathophysiology of the disease, mechanistic justification, safety data, and external information available. The oncology drug review takes the totality of the data into consideration during the decision-making process to ensure the indication granted and product labeling appropriately reflect the scientific evidence to support patient population for whom the drug is safe and effective.

Unblinded trials are common in oncology, but patient knowledge of treatment assignment may bias response to questionnaires. We sought to ascertain the extent of possible bias arising from patient knowledge of treatment assignment.This is a retrospective analysis of data from 2 randomized trials in multiple myeloma, 1 double-blind and 1 open label. We compared changes in patient reports of symptoms, function, and health status from prerandomization (screening) to baseline (pretreatment but postrandomization) across control and investigational arms in the 2 trials. Changes from prerandomization scores at ~2 and 6 months on treatment were evaluated only across control arms to avoid comparisons between 2 different experimental drugs. All scores were on 0- to 100-point scales. Inverse probability weighting, entropy balancing, and multiple imputation using propensity score splines were used to compare score changes across similar groups of patients.Minimal changes from screening were seen at baseline in all arms. In the control arm, mean changes of7 points were seen for all domains at 2 and 6 months. The effect of unblinding at 6 months in social function was a decline of less than 6 points (weighting: -3.09; 95% confidence interval -8.41 to 2.23; balancing: -4.55; 95% confidence interval -9.86 to 0.76; imputation: -5.34; 95% confidence interval -10.64 to -0.04).In this analysis, we did not find evidence to suggest that there was a meaningful differential effect on how patients reported their symptoms, function or health status after knowing their treatment assignment.

The FDA Oncology Center of Excellence (OCE) is a leader within the agency in scientific outreach activities and regulatory science research. On the basis of analysis of scientific workshops, internal meetings, and publications, the OCE identified nine scientific priority areas and one cross-cutting area of high interest for collaboration with external researchers. This article describes the process for identifying these scientific interest areas and highlights funded and unfunded opportunities for external researchers to work with FDA staff on critical regulatory science challenges.

The development and review of combination drug regimens in oncology may present unique challenges to investigators and regulators. For regulatory approval of combination regimens, it is necessary to demonstrate the contribution of effect of each monotherapy to the overall combination. Alternative approaches to traditional designs may be needed to accelerate oncology drug development, for example, when combinations are substantially superior to available therapy, to reduce exposure to less effective therapies, and for drugs that are inactive as single agents and that in combination potentiate activity of another drug. These approaches include demonstration of activity in smaller randomized trials and/or monotherapy trials conducted in a similar disease setting. This article will discuss alternative approaches used in the development of approved drugs in combination, based on examples of recent approvals of combination regimens in renal cell carcinoma.

Background Although the Adjuvant Paclitaxel and Trastuzumab (APT) trial has been adopted clinically, single-arm trials have limitations, and interest remains whether these patients with small node-negative human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC) would benefit from more intensive chemotherapy. This analysis explored whether external controls can contextualize single-arm studies to add to clinical decision making in the use of de-escalated therapy in patients with low-risk HER2-positive EBC. Patients and methods Patient-level data from five randomized trials supporting drug approval in adjuvant HER2-positive EBC were pooled, and patients with low-risk EBC were selected (n = 1770). Patients treated concurrently with trastuzumab and either anthracycline/cyclophosphamide/taxane/trastuzumab (ACTH) or taxane/carboplatin/trastuzumab (TCH; n = 1366) were matched (1:1) to patients treated with paclitaxel and trastuzumab (TH) in the APT trial (n = 406) using propensity scores. Patients treated with anthracycline/cyclophosphamide/taxane (ACT; n = 374) were also matched (1:1) to those treated with TH. Propensity scores were estimated using covariates of age, tumor stage, estrogen receptor status, progesterone receptor status, and histological grade. Results After matching, the estimated probabilities of invasive disease-free survival (iDFS) at 3 and 5 years were 98.6% and 96.5% in the TH arm, and 96.6% and 92.9% in the ACTH/TCH arm, respectively. The estimated probabilities of overall survival (OS) at 3 and 5 years were 99.7% and 99.3% in the TH arm, and 99.0% and 97.4% in the ACTH/TCH arm, respectively. Comparing the TH arm with the ACT arm in the matched sample, the estimated difference in iDFS was 7.5% (TH 98.8% and ACT 91.3%) at 3 years and 12.6% (TH 96.1% and ACT 83.5%) at 5 years. The estimated difference in OS was 2.6% (TH 100% and ACT 97.4%) at 3 years, and 5.3% (TH 99.3% and ACT 94.0%) at 5 years. Conclusions Our analyses suggest that patients' outcomes in both arms were in general similar, thus providing additional reassurance regarding de-escalation of therapy.

Purpose: Differentiation syndrome (DS) is a serious adverse reaction of isocitrate dehydrogenase (IDH) inhibitors ivosidenib and enasidenib in patients with (IDH)1- and IDH2-mutated acute myeloid leukemia (AML), respectively. Experimental Design: During FDA review of marketing applications for ivosidenib and enasidenib, data from pivotal trials were queried to identify cases of DS in patients with relapsed or refractory (R/R) AML. One hundred seventy-nine patients with R/R AML received ivosidenib and 214 received enasidenib. Adverse events, labs, and vital signs in the first 90 days of treatment were screened per diagnostic criteria, and narratives were reviewed to adjudicate DS cases. Results: We identified 72 of 179 (40%) potential cases for ivosidenib and 86 of 214 (40%) for enasidenib; 34 of 179 (19%) and 41 of 214 (19%) were adjudicated as DS. Leukocytosis was present in 79% and 61% of cases, respectively. Median (range) time to onset was 20 (1–78) and 19 (1–86) days. Grade ≥ 3 adverse reactions occurred in 68% and 66%; 6% and 5% were fatal. Univariate analyses suggested baseline bone marrow blasts ≥ 48% and peripheral blood blasts ≥ 25% and 15% for ivosidenib and enasidenib, respectively, were associated with increased risk of DS. Complete remission (CR) + CR with partial hematologic recovery rates were lower in patients with versus without DS [ivosidenib 18% (95% confidence interval, 7%–35%) vs. 36% (28%–45%); enasidenib 18% (7%–33%) vs. 25% (18%–32%)]. Conclusions: DS is a common and potentially fatal adverse reaction of IDH inhibitors, and use of standardized diagnostic criteria may aid in earlier diagnosis and treatment. See related commentary by Zeidner, p. 4174

On March 8, 2019, the FDA granted accelerated approval to atezolizumab in combination with paclitaxel protein-bound for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 [PD-L1 stained tumor-infiltrating immune cells (IC) of any intensity covering ≥1% of the tumor area], as determined by an FDA-approved test. Approval was based on data from IMpassion130, which randomized patients to receive atezolizumab or placebo in combination with paclitaxel protein-bound. Investigator-assessed progression-free survival (PFS) in the intent-to-treat (ITT) and PD-L1–positive populations were coprimary endpoints. After 13-month median follow-up, the estimated median PFS in the PD-L1–positive population was 7.4 months in the atezolizumab arm and 4.8 months in the placebo arm [HR = 0.60; 95% confidence interval (CI), 0.48–0.77]. Overall survival (OS) results were immature with 43% deaths in the ITT population, representing 59% of the OS events required to perform the final OS analysis. Adverse reactions occurring in ≥20% of patients receiving atezolizumab with paclitaxel protein-bound were alopecia, peripheral neuropathies, fatigue, nausea, diarrhea, anemia, constipation, cough, headache, neutropenia, vomiting, and decreased appetite. Accelerated approval was appropriate taking into account the unmet medical need along with the immaturity of the OS results and potential for PFS in the PD-L1–expressing population to predict clinical benefit.

On April 4, 2019, the FDA approved a supplemental new drug application for palbociclib (IBRANCE), to expand the approved indications in women with hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer (MBC) in combination with an aromatase inhibitor or fulvestrant, to include men. Palbociclib was first approved in 2015 for use in combination with letrozole for the treatment of estrogen receptor–positive, HER2-negative advanced breast cancer as initial endocrine-based therapy in postmenopausal women and subsequently in 2016 in combination with fulvestrant in women with HR-positive, HER2-negative advanced breast cancer with disease progression following endocrine therapy. The current approval was primarily based on the results of the PALOMA-2 and PALOMA-3 trials and, supported by real-world data from electronic health records and insurance claims. To support the safety evaluation in male patients, data from two phase I studies with palbociclib and safety information from the global safety database, were also reviewed. This article summarizes FDA decision-making and data supporting the approval of palbociclib for the treatment of male patients with HR-positive, HER2-negative advanced or MBC.

Background: The Adjuvant Paclitaxel and Trastuzumab (APT) trial was a single-arm trial in patients with small node-negative HER2-positive early breast cancer (EBC). Although the regimen used in the APT trial has been adopted clinically, single-arm trials have limitations, and interest remains if these patients, particularly those with T1c or T2 disease would benefit from more intensive chemotherapy. Methods: Patient-level data from five randomized trials (BCIRG 006, NSABP-B31, HERA, N-9831, and APHINITY) submitted to FDA to support drug approval in adjuvant HER2-positive EBC were pooled (n=19087). Patients treated concurrently with trastuzumab and either anthracycline/cyclophosphamide/taxane (ACTH) (n=932), or taxane/carboplatin (TCH) (n=434), were matched (1:1) to patients treated with paclitaxel and trastuzumab (TH) in the APT trial (n=406) using propensity scores. Patients treated with anthracycline/cyclophosphamide/taxane (ACT) (n=374) were also matched (1:1) to those treated with TH on the APT trial. Propensity score models included age, tumor size (Tim/T1a, T1b, T1c, T2), grade, and hormone receptor status. Invasive disease-free survival (iDFS) and overall survival (OS) were compared between patients treated with ACTH or TCH and patients treated with TH from the APT trial, and between patients treated with ACT and TH. Results: After matching, 305 patients were included from the APT trial and 305 patients from the trastuzumab containing external control (ACTH or TCH). One hundred and sixty-nine patients from the APT trial were also matched to 169 patients from the ACT external control. The propensity score matching adequately balanced the patients’ baseline age and disease characteristics (Table 1). The iDFS and OS results are shown in Table 2. Similar results were observed when comparing patients who received ACTH versus TH, and comparing patients who received TCH versus TH. Similar results were also seen in trastuzumab-based treatment subgroups based on tumor size. Conclusions: External controls can be useful to contextualize single arm studies. These exploratory analyses further support the use of de-escalated therapy in patients with low-risk HER2-positive EBC. Table 1: Demographics and Disease CharacteristicsAPT (TH) N = 305External Control (ACTH/TCH) N = 305Std. Mean Diff (%)Age (Yrs), Mean (Std)54.6 (10.7)54.7 (9.8)1.1Primary Tumor Size (cm), Mean (Std)1.3 (0.6)1.4 (0.6)19.7Tumor Stage, n (%)T1ami16 (5.3)11 (3.6)-8.0T1b93 (30.5)95 (31.2)1.4T1c162 (53.1)166 (54.4)2.6T234 (11.2)33 (10.8)-1.1Grade, n (%)G119 (6.2)20 (6.6)1.3G2107 (35.1)95 (31.2)-8.4G3179 (58.7)190 (62.3)7.4ER+, n (%)198 (64.9)200 (65.6)1.4PR+, n (%)158 (51.8)157 (51.5)-0.7HR+, n (%)204 (66.9)202 (66.2)-1.4 APT (TH) N = 169External Control (ACT) N = 169Std. Mean Diff (%)Age (Yrs), Mean (Std)51.9 (10)52.5 (8.9)6.7Tumor Size (cm), Mean (Std)1.5 (0.6)1.6 (0.6)24.3Tumor Stage, n (%)T1ami6 (3.6)6 (3.6)0T1b30 (17.8)25 (14.8)-8.0T1c103 (61.0)109 (64.5)7.4T230 (17.8)29 (17.2)-1.6Grade, n (%)G13 (1.8)3 (1.8)0G252 (30.8)52 (30.8)0G3114 (67.5)114 (67.5)0ER+, n (%)100 (59.2)93 (55.0)-8.4PR+, n (%)81 (47.9)79 (46.8)-2.4HR+, n (%)103 (61.0)100 (59.2)-3.6 Table 2: iDFS and OSAPT (TH) (%)External Control (ACTH/TCH) (%)iDFS3 yrs98.6 (96.4, 99.5)96.6% (93.7, 98.1)5 yrs96.5 (93.6, 98.1)92.9% (88.2, 95.8)OS3 yrs99.7 (97.6, 100.0)99.0% (96.9, 99.7)5 yrs99.3 (97.2%, 99.8)97.4 (94.5, 98.7)APT (TH) (%)External Control (ACT) (%)iDFS3 yrs98.8 (95.3, 99.7)91.3 (85.7, 94.7)5 yrs96.1 (91.5, 98.2)83.5 (76.5, 88.6)OS3 yrs100 (NA, NA)97.4 (93.3, 99.0)5 yrs99.3 (95.3, 99.9)94.0 (88.8, 96.8) Citation Format: Laleh Amiri-Kordestani, Diqiong Xie, Erik Bloomquist, Shenghui Tang, Richard Pazdur, Rajeshwari Sridhara, Sara M Tolaney, Eric P Winer, Julia A Beaver. An FDA analysis of survival outcomes comparing adjuvant paclitaxel and trastuzumab trial (APT) to an external control from historical clinical trials [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD4-08.

Summary Background Cyclin-dependent kinase 4/6 inhibitors (CDKIs) are indicated with endocrine therapy as first-line or second-line treatment for hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer. We aimed to investigate the benefit of adding CDKIs to endocrine therapy in patients whose tumours might have differing degrees of endocrine sensitivity. Methods We pooled individual patient data from all phase 3 randomised breast cancer trials of CDKIs plus endocrine therapy submitted to the US Food and Drug Administration before Jan 1, 2019, in support of marketing applications. Our pooled analysis included all randomly assigned patients in these trials who received at least one dose of CDKI or placebo with endocrine therapy (an aromatase inhibitor [letrozole or anastrazole] or fulvestrant). We did prespecified subgroup analyses in patients with progesterone receptor-negative disease; patients with a disease-free interval of 12 months or less; patients with de-novo metastases, lobular histology, and bone-only disease; patients with visceral metastases; and patients aged up to 40 years. Patients who were not treated, who received tamoxifen as endocrine therapy, or who were treated with an aromatase inhibitor but who had received previous chemotherapy in the metastatic setting (not first-line) were excluded from our pooled analyses. All studies had a primary endpoint of investigator-assessed progression-free survival, defined as time from date of randomisation to the initial date of documented cancer progression or death, whichever occurred first. Median progression-free survival was estimated with Kaplan-Meier methods. Hazard ratios (HR) with 95% CIs for progression-free survival were estimated by means of Cox regression models. Findings The seven studies meeting this study's inclusion criteria were done between Feb 22, 2013, and Nov 3, 2017, with a median duration of follow-up of 19·7 months (IQR 15·9–25·9). 4200 patients were included in the pooled analysis, of whom 1320 received an aromatase inhibitor plus a CDKI, 932 received placebo plus an aromatase inhibitor, 1296 received fulvestrant plus a CDKI, and 652 received fulvestrant plus placebo. Across all seven pooled trials, the difference in estimated median progression-free survival was 8·8 months in favour of CDKI plus endocrine therapy over placebo plus endocrine therapy (range across the trials 6·8–13·3 months; HR 0·59, 95% CI 0·54–0·64). Progression-free survival results favoured the CDKI group in all prespecified clinicopathological subgroups analysed, with similar HRs to that for the broader intended-use population. In first-line aromatase inhibitor-treated patients (n=2252), the median progression-free survival in the CDKI plus aromatase inhibitor group was 28·0 months (95% CI 25·3–29·1) versus 14·9 months (14·0–16·7) in the placebo plus aromatase inhibitor group (difference 13·1 months; range across the trials 13·0–13·3 months; HR 0·55, 95% CI 0·49–0·62). In first-line fulvestrant-treated patients (n=396), the median progression-free survival was 18·6 months (95% CI 14·8–23·5) in the placebo plus fulvestrant group and not estimable (22·4 to not estimable) in the CDKI plus fulvestrant group (difference not estimable; HR 0·58, 95% CI 0·42–0·80). In the patients treated with fulvestrant in the second-line setting and beyond (n=1552), the difference in estimated median progression-free survival between the CDKI plus fulvestrant group and the placebo plus fulvestrant group was 6·9 months in favour of the CDKI group (range across the trials 5·5–7·3 months; HR 0·56, 95% CI 0·49–0·64). Interpretation Since the addition of CDKI to endocrine therapy seemed to benefit all clinicopathological subgroups of interest in this pooled analysis, further research is needed to identify patient subgroups for whom endocrine therapy alone might be appropriate for first-line or second-line treatment of hormone receptor-positive, HER2-negative metastatic breast cancer. Funding None.

PURPOSE Many older women will be treated with a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor and an aromatase inhibitor (AI), given US Food and Drug Administration approval of three agents in this class. The current pooled analysis examines the efficacy and safety of this combination in older women. PATIENTS AND METHODS We pooled data from three randomized controlled studies (N = 1,827) of different CDK4/6 inhibitors in combination with an AI for initial treatment of postmenopausal women with hormone receptor–positive, human epidermal growth factor receptor 2–negative metastatic breast cancer. The effect of age on progression-free survival was evaluated using Kaplan-Meier estimates and a Cox proportional hazards regression model. RESULTS For patients age 75 years or older (n = 198) who were treated with a CDK4/6 inhibitor and an AI, hazard ratio was 0.49 (95% CI, 0.31 to 0.76) with an estimated median progression-free survival of 31.1 months (95% CI, 20.2 months to not reached) versus 13.7 months (95% CI, 10.9 months to 24.9 months) for those treated with an AI. Incidence of grade 3 to 4 adverse events was 88.8% in patients age 75 years and older and 73.4% in patients younger than age 75 years. Patients age 75 years or older reported a decline in quality-of-life measures using the EQ-5D regardless of treatment with AI alone or with the addition of a CDK4/6 inhibitor. CONCLUSION There was similar efficacy with a CDK4/6 inhibitor in combination with an AI compared with AI alone for first-line treatment of hormone receptor–positive, human epidermal growth factor receptor 2–negative metastatic breast cancer in older women compared with younger patients. Patients older than age 75 years experienced higher rates of toxicity, dose modifications, and a decrease from baseline in quality-of-life measures.

With the advent of patient-focused drug development, the US Food and Drug Administration (FDA) has redoubled its efforts to review patient-reported outcome (PRO) data in cancer trials submitted as part of a drug's marketing application. This Review aims to characterise the statistical analysis of PRO data from pivotal lung cancer trials submitted to support FDA drug approval between January, 2008, and December, 2017. For each trial and PRO instrument identified, we evaluated prespecified PRO concepts, statistical analysis, missing data and sensitivity analysis, instrument completion, and clinical relevance. Of the 37 pivotal lung cancer trials used to support FDA drug approval, 25 (68%) trials included PRO measures. The most common prespecified PRO concepts were cough, dyspnoea, and chest pain. At the trial level, the most common statistical analyses were descriptive (24 trials [96%]), followed by time-to-event analyses (19 trials [76%]), longitudinal analyses (12 trials [48%]), and basic inferential tests or general linear models (10 trials [40%]). Our findings indicate a wide variation in the analytic techniques and data presentation methods used, with very few trials reporting clear PRO research objectives and sensitivity analyses for PRO results. Our work further supports the need for focused research objectives to justify and to guide the analytic strategy of PROs to facilitate the interpretation of patient experience.

On December 20, 2017, the FDA granted regular approval to pertuzumab in combination with trastuzumab and chemotherapy for the adjuvant treatment of patients with HER2-positive early breast cancer (EBC) at high risk of recurrence. Approval was based on data from the APHINITY trial, which randomized patients to receive pertuzumab or placebo in combination with trastuzumab and chemotherapy. After 45.4-month median follow-up, the proportion of invasive disease-free survival (IDFS) events in the intent-to-treat population was 7.1% (n = 171) in the pertuzumab arm and 8.7% (n = 210) for placebo [hazard ratio (HR), 0.82; 95% confidence interval (CI), 0.67–1.00; P = 0.047]. The proportion of IDFS events in patients with hormone receptor–negative disease was 8.2% (n = 71) and 10.6% (n = 91) in the pertuzumab and placebo arms, respectively (HR, 0.76; 95% CI, 0.56–1.04). The proportion of IDFS events for patients with node-positive disease was 9.2% (n = 139) and 12.1% (n = 181) in the pertuzumab and placebo arms, respectively (HR, 0.77; 95% CI, 0.62–0.96). Adverse reactions in ≥30% of patients receiving pertuzumab were diarrhea, nausea, alopecia, fatigue, peripheral neuropathy, and vomiting. From a regulatory standpoint, the benefits of the addition of pertuzumab to adjuvant treatment outweighed the risks for patients with EBC at high risk of recurrence.

BACKGROUND: The primary endpoint in many registration trials is progression-free survival (PFS), defined as the time from randomization until objective tumor progression or death. In the clinical setting, however, PFS can be difficult to measure and explain, especially in patient-friendly language. For real-world evidence (RWE) based studies, time to treatment discontinuation (TTD), defined as time from randomization to discontinuation of the investigational study drug, may be a more practical endpoint. We hypothesize TTD will correlate with PFS and analyzed registration trials from recently FDA approved cyclin dependent kinase 4/6 inhibitors (CDKIs) to test this hypothesis. TTD was defined as time from randomization to discontinuation of the CDKI. METHODS: We pooled data from five phase III randomized, controlled, registration trials of CDKIs with an aromatase inhibitor (AI) in the first-line or fulvestrant in the second-line setting. The CDKI discontinuation dates used to calculate TTD were derived from the patient-level datasets. We calculated patient-level correlation between TTD and PFS. We also summarized median TTD and PFS as well as the number of TTD and PFS events. RESULTS: A total of 3017 patients were included in the pooled analysis (n=1899 treated with CDKI, n=1118 with placebo). The median PFS and TTD and the number of events are shown in Table 1. The patient-level Spearman correlation coefficient of TTD and PFS ranged from 0.87-0.95. The trial-level association was approximately R2=0.23. Table 1:Primary ResultsTreatment ArmNPFS EventsTTD EventsMedian PFS, in mo (95% CI)Median TTD, in mo (95% CI)Spearman Correlation CoefficientCDKI1899873138320.7 (19.2-22.2)14.3 (13.6-14.9)0.87Placebo111871488311.7 (11.0-13.6)11.0 (9.7-12.0)0.95 CONCLUSION: Patient-level pooled cross-trial analysis show a relationship between TTD and PFS in registration trials of CDKIs. In all trials, the difference in time between median TTD and median PFS appeared greater in the CDKI arm than the placebo arm. This analysis is limited by the relatively small number of studies included. Further research is needed to determine both whether: 1) TTD can serve as a pragmatic endpoint for analyses of RWE, and 2) is a more meaningful endpoint to patients. Citation Format: Gao JJ, Gong Y, Cheng J, Schroeder RJ, Amiri-Kordestani L, Khozin S, Kluetz P, Sridhara R, Pazdur R, Blumenthal G, Beaver JA, Prowell TM. Time to treatment discontinuation as a pragmatic endpoint: A U.S. Food and Drug Administration pooled analysis of CDK 4/6 inhibitors [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-14-02.

On March 29, 2018, the FDA granted accelerated approval for blinatumomab (Blincyto; Amgen, Inc.) for the treatment of adults and children with B-cell precursor acute lymphoblastic leukemia (BCP ALL) in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%. Blinatumomab is a CD3xCD19 bispecific antibody approved previously for the treatment of relapsed or refractory BCP ALL. The basis for this accelerated approval was a single-arm trial. For the 86 patients in first and second complete remission with MRD ≥ 0.1%, conversion to MRD < 0.01% was achieved after one cycle of blinatumomab by 85.2% [95% confidence interval (CI): 73.8%, 93.0%] and 72.0% (95% CI: 50.6%, 87.9%), respectively, and the estimated median hematologic relapse-free survivals (RFS) were 35.2 months (95% CI: 0.4–53.5) and 12.3 months (95% CI: 0.7–42.3), respectively. Hematologic RFS was considered substantial independent of whether patients underwent subsequent allogeneic stem cell transplantation. The safety profile for blinatumomab was established in prior studies, and no new safety signals were observed in the new population. Cytokine release syndrome and neurotoxicity remain significant risks. The FDA is requiring confirmation of clinical benefit in a randomized trial.

Background: Cyclin dependent kinase 4/6 inhibitors (CDKIs) are oral targeted agents approved for use in combination with endocrine therapy as 1st or 2nd line treatment of hormone-receptor positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. We previously reported the pooled analyses of progression-free survival (PFS) of patients in certain clinicopathological subgroups, all of whom received consistent benefit from the addition of a CDKI to hormonal therapy. Here, we report the pooled overall survival (OS) results in patients treated with a CDKI and fulvestrant. Methods: We pooled individual patient data (n=1948) from three phase III randomized breast cancer trials of CDKI in combination with fulvestrant submitted to the US Food and Drug Administration (FDA) in support of marketing applications. All analyzed patients received at least one dose of CDKI or placebo in combination with fulvestrant. The median OS was estimated using Kaplan-Meier (KM) methods, and hazard ratios (HR) with corresponding 95% confidence intervals (CIs) were estimated using Cox regression models. Patients were analyzed collectively, by number of prior lines of systemic endocrine therapy in any disease setting (1st-line or endocrine naive vs. 2nd -line and later), and in various clinicopathologic subgroups of interest. Findings: In all pooled patients (n=1948), the estimated OS HR was 0∙77 (95% CI 0∙68-0∙88), with a median follow-up of 43∙7 months (interquartile range, (IQR): 37∙8, 47∙7) and deaths in 48% of patients. The difference in estimated median OS was 7∙1 months, favoring CDKIs. In patients who were endocrine therapy naive and received CDKIs as 1st -line systemic endocrine therapy (2 trials, n=396), the estimated OS HR was 0∙74 (95% CI 0∙52-1∙07), with a median follow-up of 39∙4 months (IQR: 37∙0, 42∙2) and deaths in 31% of patients. The median OS difference could not be calculated, since median OS was not reached on CDKI arm. In patients who received CDKIs as 2nd-line or later systemic endocrine therapy (3 trials, n=1552), the estimated OS HR was 0∙77 (95% CI 0∙67-0∙89), with a median follow-up of 45∙1 months (IQR: 39∙2, 48∙5) and deaths in 52% of patients. The median OS difference was 7∙0 months, favoring CDKIs. Additional subgroup analyses of OS by progesterone receptor status, site of metastases, breast cancer histology, ECOG performance status, race, and de novo metastatic presentation all favored adding CDKI to fulvestrant. Patients with de novo metastatic disease (n=470, OS HR 0∙91 [95% CI 0∙68-1∙21]) and Asian patients (n=394, OS HR 0∙95 [95% CI 0∙81-1∙60]) appeared to benefit relatively less from the addition of CDKI to fulvestrant. Although the estimated OS HR appeared to favor fulvestrant alone in patients age < 40 [HR 1∙5 (95% CI 0∙75-3∙02)], this result must be interpreted with caution, given the small sample size (n=89) and correspondingly wide confidence interval. Evaluation of other age subgroups showed results in favor of the addition of CDKI to fulvestrant. All results presented are considered exploratory and hypothesis-generating. Interpretation: Addition of CDKIs to fulvestrant appears to confer a consistent overall survival benefit across all pooled patients and within most clinicopathological subgroups of interest. Funding: None. Declaration of Interest: All authors declare no competing interests. Ethical Approval: All patients in the included trials were required to provide informed written consent, and all trials had institutional review board or ethical approval.

This review provides a comprehensive assessment of recent literature reports describing atypical response patterns observed with immune checkpoint inhibitors (ICIs), modifications to response evaluation criteria for ICIs, and treatment beyond progression in clinical trials. Certain response patterns such as durable response, pseudoprogression, hyperprogression, and dissociated responses can be seen with ICI treatment. These patterns carry differing prognoses and are associated with varied factors. There are multiple modifications of standard Response Evaluation Criteria in Solid Tumors (RECIST) that have been proposed to better characterize immunotherapy response; however, standard RECIST1.1 remains most commonly used in clinical trials. Treatment beyond progression varies in frequency and benefit depending on assessment criteria and cancer type. Future research incorporating modified imaging criteria and biomarker assessments may serve to clarify who will benefit most from treatment beyond progression.

Tremendous progress has been made in treating patients with metastatic melanoma over the past decade. In that timeframe, the FDA has approved 12 novel treatments for patients with advanced unresectable melanoma, comprising both kinase-targeted therapies and immune checkpoint inhibitors (ICI), and five treatments for adjuvant (postoperative) use in patients with high-risk resectable stage III melanoma. It is not known whether outcomes can be further improved by administering kinase inhibitors or ICI in the neoadjuvant (presurgical) setting in patients with high-risk resectable melanomas. Noting research community interest in exploring the neoadjuvant approach for treating melanoma and recognizing that early harmonization of methodologies may expedite the development of therapeutics in this space, the FDA and Melanoma Research Alliance convened a public workshop on November 6, 2019, in National Harbor, Maryland, to discuss key issues. The workshop consisted of 23 faculty and included more than 250 live participants. Topics discussed included opportunities for advancing novel endpoints for regulatory purposes as well as translational research, clinical trial design considerations, and strategies for optimizing patient selection while mitigating risk.

On December 19, 2018, the U.S. Food and Drug Administration (FDA) granted approval to olaparib monotherapy for first-line maintenance treatment of BRCA-mutated (BRCAm) advanced ovarian cancer and, on May 8, 2020, expanded the indication of olaparib to include its use in combination with bevacizumab for first-line maintenance treatment of homologous recombination deficient (HRD)–positive advanced ovarian cancer. Both these approvals were based on randomized, double-blind, placebo-controlled trials. Approval for olaparib monotherapy was based on the SOLO-1 trial, comparing the efficacy of olaparib versus placebo in patients with BRCAm advanced ovarian, fallopian tube, or primary peritoneal cancer after surgical cytoreduction and first-line platinum-based chemotherapy. Two companion diagnostic (CDx) tests were approved with this indication: BRACAnalysis CDx, for germline BRCA1/2 alterations, and FoundationOne CDx, for BRCA1/2 alterations in tissue specimens. Approval for olaparib in combination with bevacizumab was based on the results of the PAOLA-1 trial that compared olaparib with bevacizumab versus placebo plus bevacizumab in patients with advanced high-grade epithelial ovarian cancer, fallopian tube, or primary peritoneal cancer after first-line platinum-based chemotherapy and bevacizumab. Myriad myChoice CDx was designated as a companion diagnostic device for use of olaparib plus bevacizumab combination for ovarian cancer associated with HRD-positive status. Both trials demonstrated clinically meaningful improvements in progression-free survival and favorable benefit-risk profiles for the indicated populations. This article summarizes the FDA thought process and data supporting the approval of olaparib as monotherapy and in combination with bevacizumab for maintenance therapy in this setting. Implications for Practice These approvals represent the first poly (ADP-ribose) polymerase inhibitor, alone or in combination with bevacizumab, approved in first-line maintenance treatment of women with advanced ovarian cancer after cytoreductive surgery and chemotherapy. In patients with BRCA-mutated tumors, olaparib monotherapy demonstrated a 70% reduction in the risk of disease progression or death compared with placebo, and olaparib in combination with bevacizumab demonstrated a 67% reduction in the risk of disease progression or death compared with bevacizumab alone in homologous recombination deficient–positive tumors. These approvals represent a major advance for the treatment of women with advanced ovarian cancer who are in complete or partial response after their initial platinum-based chemotherapy.