Assessment of tumor response as a surrogate endpoint of survival in recurrent/platinum-resistant ovarian carcinoma: A Gynecologic Oncology Group study

doi:10.1016/j.ygyno.2010.01.040

Gynecologic Oncology

Volume 117, Issue 2, May 2010, Pages 324-329

https://doi.org/10.1016/j.ygyno.2010.01.040 Get rights and content

Abstract

Purpose

We investigated whether tumor response rate (TRR), disease control rate (DCR), or progression-free survival (PFS) was a valid surrogate for overall survival (OS) in phase II trials of second-line therapies for patients with platinum-resistant ovarian carcinoma (PROC).

Methods

We retrospectively evaluated data from 11 second-line phase II trials conducted for PROC by the Gynecologic Oncology Group (GOG). TRR included complete response and partial response (CR/PR) and DCR was defined as either tumor response or stable disease (CR/PR + SD). Survival by tumor response was analyzed using a landmark approach. Correlations of OS with TRR, DCR, and PFS were estimated.

Results

Among 407 patients analyzed the TRR was 13.8% (56/407) and DCR was 38.8% (158/407). Median OS was 10.2 months while median PFS was only 2.4 months. Median OS among patients with a best response of CR/PR, SD, and progressive disease (PD) was 13.3, 12.1 and 5.7 months, respectively, showing no difference between CR/PR and SD. From a protocol level, DCR correlated better with OS (Pearson r = 0.748; Tau-b r = 0.514) compared to TRR (Pearson r = 0.564; Tau-b r = 0.404). PFS rate at 6 months (Pearson r = 0.661; Tau-b r = 0.514) also correlated strongly with OS.

Conclusions

This study demonstrates the limitations of the use of response rate alone in PROC. Clinical benefit, as defined by OS, appeared similar for patients with an objective response and those with SD. The DCR, by including tumor response and SD may have utility as a surrogate endpoint for survival in phase II therapeutic trials in PROC.

Introduction

Recurrent ovarian cancer patients are heterogeneous with respect to their potential for response to second-line therapy. Markman and Hoskins were the first to stratify these patients based on their treatment-free interval [1]. Patients were classified as having platinum-resistant ovarian cancer if there was progression on primary platinum-based therapy, less than a partial response to a platinum-based regimen, or recurrence within six months of completing a platinum-based regimen. Alternatively, patients were classified as having potentially platinum-sensitive ovarian cancer if they demonstrated at least a partial response to a platinum-based regimen and had a treatment-free interval of more than six months. The likelihood of response to re-treatment with platinum is directly related to the duration of the initial platinum-free interval, and some groups have used 12 months to define a more highly-responsive platinum-sensitive population. This stratification of patients has provided a useful framework for targeted development of clinical trials, and selection of treatment options for management of recurrent disease based on expectations of response to second-line therapy, as well as the duration of progression-free survival (PFS) and overall survival (OS).

The goals of chemotherapy in recurrent ovarian cancer include management of disease related symptoms, optimizing quality of life, prolonging symptom-free survival, and prolonging OS, all achieved with an acceptable level of treatment-related toxicity. When assessing the potential clinical benefit of a particular therapeutic intervention, numerous endpoints, including measurable disease response, PFS, OS, and more recently, quality of life, have been used. Most single-arm non-randomized phase II trials have evaluated the response rate of an experimental regimen with reference to historical thresholds to screen for evidence of clinical activity. Formal response criteria were established by the World Health Organization (WHO) (utilizing the sum of the products of the two largest diameters of the measurable lesions), but have more recently been replaced by Response Evaluation Criteria in Solid Tumors (RECIST-I and RECIST-II) (the sum of the largest diameter of the measurable lesions) [2].

Among clinical efficacy endpoints, OS has traditionally been considered the most definitive measure of clinical benefit and is the easiest to accurately determine, but requires long-term assessment. PFS is also a useful endpoint that avoids the confounding effect of subsequent interventions. However, the definition of progression can vary from serologic endpoints (i.e. doubling of serum tumor markers) to clinical (symptomatic) progression, or radiographic documentation of progression in tumor size and/or number. Furthermore, the frequency of disease assessments, particularly radiographic imaging, can bias results.

The platinum-resistant patient population has been characterized in numerous studies to have a low response rate to second-line cytotoxic chemotherapy with median OS of approximately 10 months. FDA approved agents in this setting have response rates of 10–15% but complete responses are seen in less than 1% of patients [3], [4]. In addition to those patients with objective evidence of tumor response, perhaps twice as many patients will have evidence of stable disease (SD) [5]. The benefit of SD as the best response to therapy in ovarian cancer is controversial, and can vary considerably in the context of small phase II studies. In some patients, this might predominantly reflect the natural history of the disease and not necessarily any clinical benefit associated with treatment. Conversely, others have stated “the attainment of stable disease with acceptable levels of toxicity is a valid clinical endpoint” [5]. Cesano et al. reported the survival for recurrent ovarian cancer patients treated in a randomized trial comparing topotecan to paclitaxel [6]. For either agent, the survival for patients who achieved a partial response (PR) was very similar to those achieving SD only as their best tumor response. More recently, Grundlund et al. reported 100 recurrent ovarian cancer patients treated with either topotecan or carboplatin and paclitaxel [7]. Patients with a complete response (CR), PR, or SD each survived significantly longer than patients with progressive disease (PD). Both studies support the potential clinical benefit of SD.

In this manuscript, we report an exploratory analysis of data from a series of consecutive Gynecologic Oncology Group (GOG) phase II trials in the setting of platinum-resistant ovarian cancer. We sought to compare surrogate measures of chemotherapy benefit including tumor response rate (TRR), disease control rate (DCR), PFS, and OS.

Section snippets

Methods

We retrospectively evaluated data from patients entered on a series of 11 consecutive second-line phase II studies conducted by the GOG in platinum-resistant ovarian cancer from 1994 to 2004 [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18]. In general, all patients had received only one prior chemotherapy regimen and had progressive measurable disease within six months of their last chemotherapy treatment. Patients who did not receive paclitaxel with their primary platinum-based

Results

Eleven phase II studies comprised of 407 patients were analyzed (Table 1). The median age was 58 years (range: 21–90 years) and 85% were Caucasian. Sixty-one percent had a performance status (PS) = 0 and 31% had a PS = 1. The majority of patients (71.5%) had serous cell type while clear cell and mucinous histology comprised 7.1% and 3.9%, respectively. Overall, 56 (13.8%) had a response (complete response: n = 17 and partial response: n = 39) and median duration from treatment to response was 2.15 months

Discussion

Phase II studies of chemotherapeutic agents have traditionally utilized response rates of measurable disease to determine efficacy. Direct tumor shrinkage is a clear cause and effect outcome that can be assessed early in the course of disease treatment. Additionally, shrinkage of tumors is more likely to benefit a patient who is symptomatic. Although the overall response rate (CR + PR) has been our traditional endpoint, it does not reflect the duration of response which is an additional important

Conflict of interest statement

Dr. Peter Rose has a relevant financial relationship with “Lilly Speaker's Bureau” for <$10,000.

Dr. Michael Bookman is a member of the Data Monitoring Committee (DMC) for a Genetech phase III trial evaluating bevacizumab in recurrent ovarian cancer (financially compensated). He also served on ad-hoc advisory boards for the pharmaceutical industry related to development of investigational drugs (financially compensated). Dr. Bookman reports that he has no commercial interests relevant to this

Acknowledgments

This study was supported by the National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA 27469) and the Gynecologic Oncology Group Statistical and Data Center (CA 37517). The following Gynecologic Oncology Group member institutions participated in this study: Roswell Park Cancer Institute, University of Alabama at Birmingham, Oregon Health Sciences University, Duke University Medical Center, Abington Memorial Hospital, University of Rochester Medical Center,

References (31)

B. Gronlund et al.
Is stabilization of disease a useful indicator for survival in second-line treatment of ovarian carcinoma pre-treated with paclitaxel–platinum?
Gynecol Oncol
(2004)
A. Manetta et al.
Evaluation of cisplatin and cyclosporin A in recurrent platinum-resistant ovarian cancer: a phase II study of the Gynecologic Oncology Group
Gynecol Oncol
(1998)
M. Markman et al.
Altretamine (hexamethylmelamine) in platinum-resistant and platinum-refractory ovarian cancer: a Gynecologic Oncology Group phase II trial
Gynecol Oncol
(1998)
M.A. Hoffman et al.
Phase II trial of CI-958 in recurrent platinum-refractory ovarian carcinoma: a Gynecologic Oncology Group study
Gynecol Oncol
(2000)
M. Markman et al.
Lack of Efficacy of 24-h infusional topotecan in platinum-refractory ovarian cancer: a Gynecologic Oncology Group trial
Gynecol Oncol
(1999)
D.S. Miller et al.
Phase II evaluation of 9-aminocamptothecin (9-AC, NSC #603071) in platinum-resistant ovarian and primary peritoneal carcinoma: a Gynecologic Oncology Group study
Gynecol Oncol
(2005)
P.G. Rose et al.
A phase II study of docetaxel in paclitaxel-resistant ovarian and peritoneal carcinoma: a Gynecologic Oncology Group study
Gynecol Oncol
(2003)
C.A. Brewer et al.
Cisplatin plus gemcitabine in platinum-refractory ovarian or primary peritoneal cancer: a phase II study of the Gynecologic Oncology Group
Gynecol Oncol
(2006)
M. Markman et al.
Phase II trial of weekly paclitaxel (80 mg/m²) in platinum and paclitaxel-resistant ovarian and primary peritoneal cancers: a Gynecologic Oncology Group study
Gynecol Oncol
(2006)
M. Prefontaine et al.
Reproducibility of tumor measurements in ovarian cancer: a study of interobserver variability
Gynecol Oncol
(1994)

A.N. Gordon et al.

Long-term survival advantage for women treated with pegylated liposomal doxorubicin compared with topotecan in a phase 3 randomized study of recurrent and refractory epithelial ovarian cancer

Gynecol Oncol

(2004)

H.M. Keys et al.

A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study

Gynecol Oncol

(2004)

T.I. Goonewardene et al.

Management of asymptomatic patients on follow-up for ovarian cancer with rising CA-125 concentrations

Lancet Oncol

(2007)

M. Markman et al.

Responses to salvage chemotherapy in ovarian cancer: a critical need for precise definitions of the treated population

J Clin Oncol

(1992)

P. Therasse et al.

New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada

J Natl Cancer Inst

(2000)

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Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial
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Citation Excerpt :
We did post-hoc analyses to describe clinically meaningful disease stabilisation in this late-line treatment population. The proportion of patients with clinical benefit has been positively associated with overall survival,24,25 particularly when patients remain progression free for 6 months or longer.26 Therefore, we assessed the proportion of patients achieving clinical benefit at 16 and 24 weeks, defined as the proportion of patients with a complete or partial response or patients with stable disease with a duration of at least 16 and 24 weeks.
Late-line treatment options for patients with ovarian cancer are few, with the proportion of patients achieving an overall response typically less than 10%, and median overall survival after third-line therapy of 5–9 months. In this study (QUADRA), we investigated the activity of niraparib monotherapy as the fourth or later line of therapy.
QUADRA was a multicentre, open-label, single-arm, phase 2 study that evaluated the safety and activity of niraparib in adult patients (≥18 years) with relapsed, high-grade serous (grade 2 or 3) epithelial ovarian, fallopian tube, or primary peritoneal cancer who had been treated with three or more previous chemotherapy regimens. The study was done in the USA and Canada, and 56 sites screened patients (50 sites treated at least one patient). Patients received oral niraparib 300 mg once daily continuously, beginning on day 1 and every cycle (28 days) thereafter until disease progression. The primary objective was the proportion of patients achieving an investigator-assessed confirmed overall response in patients with homologous recombination deficiency (HRD)-positive tumours (including patients with BRCA and without BRCA mutations) sensitive to their last platinum-based therapy who had received three or four previous anticancer therapy regimens (primary efficacy population). Efficacy analyses were additionally done in all dosed patients with measurable disease at baseline.
Between April 1, 2015 and Nov 1, 2017, we screened 729 patients for eligibility and enrolled 463 patients, who were initiated on niraparib therapy. At the time of database lock (April 11, 2018), enrolment had closed and the study was ongoing, with 21 patients still on treatment. Patients had received a median of four (IQR 3–5) previous lines of therapy, and the median follow-up for overall survival was 12·2 months (IQR 3·7–22·1). 151 (33%) of 463 patients were resistant and 161 (35%) of 463 patients were refractory to the last administered platinum therapy. 13 (28%) of 47 patients in the primary efficacy population achieved an overall response according to RECIST (95% CI 15·6–42·6; one-sided p=0·00053). The most common drug-related grade 3 or worse treatment-emergent adverse events were anaemia (113 [24%] of 463 patients) and thrombocytopenia (95 [21%] of 463 patients). The most common treatment-emergent serious adverse events were small intestinal obstruction (34 [7%] of 463 patients), thrombocytopenia (34 [7%] of 463 patients), and vomiting (27 [6%] of 463 patients). One death due to gastric haemorrhage was considered treatment related.
We observed clinically relevant activity of niraparib among women with heavily pretreated ovarian cancer, especially in patients with HRD-positive platinum-sensitive disease, which includes not only patients with a BRCA mutation but also a population with BRCA wild-type disease. We identified no new safety signals. Our data support expansion of the treatment indication for poly(ADP-ribose) polymerase inhibitors to include patients with HRD-positive ovarian cancer beyond those with BRCA mutations.
Tesaro.
Prexasertib, a cell cycle checkpoint kinase 1 and 2 inhibitor, in BRCA wild-type recurrent high-grade serous ovarian cancer: a first-in-class proof-of-concept phase 2 study
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High-grade serous ovarian carcinoma is characterised by TP53 mutations, DNA repair defects, and genomic instability. We hypothesised that prexasertib (LY2606368), a cell cycle checkpoint kinase 1 and 2 inhibitor, would be active in BRCA wild-type disease.
In an open-label, single-centre, two-stage, proof-of-concept phase 2 study, we enrolled women aged 18 years or older with measurable, recurrent high-grade serous or high-grade endometrioid ovarian carcinoma. All patients had a negative family history of hereditary breast and ovarian cancer or known BRCA wild-type status, measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status score 0–2, and adequate haematological, renal, hepatic, and bone-marrow function. Patients received intravenous prexasertib 105 mg/m² administered over 1 h every 14 days in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint of investigator-assessed tumour response, based on RECIST version 1.1, was assessed per protocol (assessable patients who had undergone CT imaging at baseline and attended at least one protocol-specified follow-up) and by intention to treat. The final analysis of this cohort of patients with BRCA wild-type high-grade serous ovarian carcinoma is reported here. This ongoing trial is registered with ClinicalTrials.gov, number NCT02203513, and continues to enrol patients for the BRCA-mutated ovarian cancer cohort.
Between Jan 20, 2015, and Nov 2, 2016, we enrolled 28 women with a median age of 64 years (IQR 58·0–69·5) who had previously received a median of 5·0 (IQR 2·5–5·0) systemic therapies. Most patients (22 [79%]) had platinum-resistant or platinum-refractory disease. All women received at least one dose of prexasertib, but four (14%) of 28 patients were not assessable for RECIST response. Eight (33%, 95% CI 16–55) of 24 patients assessable per protocol had partial responses. In the intention-to-treat population, eight (29%, 95% CI 13–49) of 28 had a partial responses. The most common (in >10% patients) grade 3 or 4 treatment-emergent adverse events were neutropenia in 26 (93%) of 28 patients, reduced white blood cell count in 23 (82%), thrombocytopenia in seven (25%), and anaemia in three (11%). Grade 4 neutropenia was reported in 22 (79%) patients after the first dose of prexasertib and was transient (median duration 6 days [IQR 4–8]) and recovered without growth-factor support in all cases. The treatment-related serious adverse event of grade 3 febrile neutropenia was reported in two (7%) patients. One patient died during the study due to tumour progression.
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To preserve randomization between studies, the study was used as a unit of analysis. Analysis was performed for two response outcomes (PSM as independent variables): (1) ORR (i.e., CR/PR) and (2) DCR (i.e., CR/PR/SD) [14,15]. The relationship of response with survival was evaluated using both PFS and OS as study endpoints (TCO as dependent variables) [16–18].
Evaluate literature to assess response rate as a surrogate endpoint of survival in ovarian cancer (OC).
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Between January 1, 2009, and December 31, 2014, the FDA approved marketing applications for 55 indications based on a surrogate, of which 25 were accelerated approvals and 30 were traditional approvals. We could not find any formal analyses of the strength of the surrogate-survival correlation in 14 out of 25 accelerated approvals (56%) and 11 out of 30 traditional approvals (37%). For accelerated approvals, just 4 approvals (16%) were made where a level 1 analysis (the most robust way to validate a surrogate) had been performed, with all 4 studies reporting low correlation (r≤0.7). For traditional approvals, a level 1 analysis had been performed for 15 approvals (50%): 8 (53%) reported low correlation (r≤0.7), 4 (27%) medium correlation (r>0.7 to r<0.85), and 3 (20%) high correlation (r≥0.85) with survival.
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Patients requiring more than 8 week dosing delays to meet these criteria were to be taken off study. Based on the gynecologic oncology group (GOG) outcomes in recent EOC studies for platinum-resistant recurrences, the null hypothesis set a PFS of 25% at 6 months without addition of bevacizumab [12]. The alternative hypothesis proposed a PFS rate of 50% at 6 months, in order to reject the null hypothesis.
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¹: Currently at Precision Therapeutics, Inc., Pittsburgh, PA, USA.

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