Introduction 50–70% of epithelial ovarian cancers overexpress epidermal growth factor receptor, and its expression has been correlated with poor prognosis. We conducted a phase Ib/II trial to examine the efficacy, safety, and toxicity of gefitinib, a tyrosine kinase inhibitor, combined with topotecan in women with recurrent ovarian cancer with epidermal growth factor receptor positivity.
Methods Patients with measurable recurrent or persistent cancer after treatment with a platinum containing regimen with positive epidermal growth factor receptor expression, as determined by immunohistochemistry, were eligible for the study. Initial treatment was 250 mg/day gefitinib (oral) and 2.0 mg/m2 topotecan (intravenous) on days 1, 8, and 15, on a 28 day cycle. Dose escalations were planned for topotecan (dose levels 1–3: 2, 3, and 4 mg/m2) until the maximum tolerated dose was reached.
Results 19 patients received a total of 61 cycles. Median age was 59.8 years (range 42–76 years). Histologic types in treated patients included 74% serous (n=14), 11% mixed (n=2), 11% transitional (n=2), and 5% clear cell (n=1). For phase Ib, three patients were treated at dose level 1, three at dose level 2, and three at dose level 3 for topotecan. The maximum tolerated dose was 4.0 mg/m2 (days 1, 8, and 15) for topotecan and 250 mg (daily) for gefitinib. Therefore, dose level 3 was used for phase II. Among the 19 patients, 63.2% (n=12) had progressive disease, 15.8% (n=3) had stable disease, 10.5% (n=2) had a partial response, and 10.5% (n=2) were not evaluable. The most serious adverse events of any grade attributed to the therapy were anemia (89.4%), neutropenia (68.4%), abdominal pain (84%), constipation (78.9%), and diarrhea (78.9%).
Conclusion Although the drug combination was relatively well tolerated, this prospective phase Ib/II clinical trial did not show sufficient clinical activity of topotecan combined with gefitinib in patients with epidermal growth factor receptor positive recurrent ovarian, fallopian tube, or peritoneal cancers.
- ovarian neoplasms
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This is the first study investigating the combination of topotecan with gefitinib in platinum resistant ovarian cancer
The combination demonstrated objective responses of 10.5%
The most significant drug related severe adverse events were anemia, neutropenia, and fatigue
The American Cancer Society has estimated that about 21 750 women will be diagnosed with ovarian cancer and about 13 940 women will die from ovarian cancer in the United States in 2020.1 A major unmet need that clinicians face is how to optimally treat recurrent disease. Currently, information on prior response to platinum based therapy is the major criterion used as predictive of reinduction treatment with platinum agents.2 In a retrospective analysis of carboplatin and paclitaxel as initial secondline therapy for platinum sensitive recurrent cancer with a follow-up of 27 months, Dizon et al reported 3-year survival rate according to initial treatment free interval as follows: 6–11 months, 49%; 12–24 months, 63%; >24 months, 84%.3 However, patients with platinum resistant recurrent cancer were shown to have an overall response rate of only about 10% after re-treatment with single-agent chemotherapy.4–6
One such agent used for the treatment of platinum resistant disease is topotecan, a water soluble, semi-synthetic analog of camptothecin that exerts its antitumor activity through its inhibition of topoisomerase I. Agents that target topoisomerase I stabilize a covalent DNA topoisomerase complex, which leads to DNA cleavage. Topoisomerase is an important player in DNA transcription and replication.7 Topotecan received approval from the Food and Drug Administration (FDA) in 1996 for the treatment of relapsed ovarian and small cell lung carcinomas and stage IVB recurrent cervical cancer.
Fifty to seventy per cent of epithelial ovarian tumors have been shown to overexpress epidermal growth factor receptor, which correlated with poor prognosis in many cases.8 Epidermal growth factor receptor is a highly expressed protein in many types of cancer. Epidermal growth factor receptor inhibition rapidly shifted the treatment paradigm from traditional chemotherapy to targeted therapy and is now considered the standard of care in metastatic colorectal and non-small cell lung cancer.9
Preclinical evidence exists to support the combination of an epidermal growth factor receptor–tyrosine kinase inhibitor with topotecan. Erlichman et al reported synergistic activity of SN38 (topotecan) with CI1003, a tyrosine kinase inhibitor, in glioblastoma and colon cancer cell lines. The findings of that study showed that the tyrosine kinase inhibitor increased the intracellular levels of topotecan by decreasing efflux of the drug from the cell.10 Furthermore, two positive clinical trials performed in patients with lung or colorectal cancer showed that the addition of gefitinib to chemotherapy enhanced the effects of a variety of chemotherapeutic agents, including platinum compounds and topoisomerase I and II inhibitors.11 12
Taken together, this information supports the evaluation of the combination of topotecan and an epidermal growth factor receptor antagonist in patients with recurrent ovarian cancer. We report, to the best of our knowledge, the first comprehensive phase Ib/II trial of topoisomerase I inhibition in combination with epidermal growth factor receptor–tyrosine kinase inhibitor for the treatment of recurrent platinum resistant ovarian, peritoneal, or fallopian tube cancers that are epidermal growth factor receptor positive.
We conducted a single center, prospective, open label, dose escalation phase Ib/II study at the University of Texas MD Anderson Cancer Center. The study was registered on the clinical trial website of the National Cancer Institute (clinicaltrials.gov NCT00317772) and approved by the the University of Texas MD Anderson Cancer Center institutional review board. Written informed consent was obtained from all participants. In accordance with the journal’s guidelines, we will provide our data for the reproducibility of this study in other centers if requested.
Study Design and Participants
Eligible patients had platinum resistant, histologically confirmed epithelial ovarian, fallopian tube, or peritoneal cancer. Resistance was defined as progression of disease during platinum chemotherapy or progression of disease within 6 months of completing platinum chemotherapy, or as failure of the treatment to achieve a complete response, with persistent macroscopic disease after an adequate trial of primary therapy. Inclusion criteria were epidermal growth factor receptor positive expression, as determined by immunohistochemistry (ie, 1+ or greater); measurable disease, defined as at least one lesion ≥20 mm that could be accurately measured in at least one dimension; and Zubrod performance status ≤2. Patients may have had an unlimited number of prior chemotherapy regimens.
Additionally, patients with known hypersensitivity to platinum compounds, whose desensitization regimen failed, or who, in the opinion of the investigator, were not good candidates for desensitization were included. Pretreatment hematologic, renal, and hepatic function tests were required to be grade 0 or 1 according to Common Terminology Criteria for Adverse Events (version 3.0).
Exclusion criteria were: borderline or low malignant potential tumors, prior treatment with topoisomerase I inhibitor(s) and/or prior anti-epidermal growth factor receptor therapy, concurrent uncontrolled medical or psychiatric disorders, severe cardiovascular disease, active infection, or known hypersensitivity to topotecan or gefitinib.
Treatment Plan, Response Evaluation/Endpoints, and Assessments
The first objective of the study was to evaluate the safety of any dose level of topotecan administered on a weekly schedule in combination with standard dose gefitinib, administered orally daily in recurrent ovarian cancer patients. The second objective was to determine the response rate and response duration in the treated patient population.
The phase Ib portion of the trial used the standard dose of gefitinib (250 mg by mouth daily) with a dose escalation/expansion of topotecan from 2 mg/m2 to 4 mg/m2, administered intravenously on days 1, 8, and 15 of a 28 day cycle. A conventional 3+3 algorithm was followed. Three patients were treated at a given dose level, and if there were no dose limiting toxicities, we then proceeded to the next dose level. If there was one dose limiting toxicity, an additional three patients were enrolled at that dose level. Analysis of the phase I data was conducted and the results were submitted to the institutional review board prior to proceeding to the phase II portion of the study.
The phase II portion of the trial included 10 patients treated at the maximum tolerated dose in the phase Ib portion. Records of study medication used, doses administered, and intervals between visits were kept during the study. Response Evaluation Criteria in Solid Tumors (RECIST 1.0) was used to assess the overall response rate. Weekly laboratory studies, or as frequently as needed, were used to define drug toxicity. Prior to each course, assessments of laboratory studies, interim history, performance status (determined along with a physical examination), and clinically measurable disease were obtained. A schematic representation of the study design is shown in the flowchart in Online supplemental Figure 1.
Toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (V.3.0). General guidelines for dose modifications in the event of hematologic and non-hematologic adverse effects are available in the protocol. For grade 4 hematologic and grade 3 treatment related non-hematologic adverse effects (except fatigue), the weekly infusion dose of topotecan was reduced by one dose level. For patients experiencing neutropenic complications (eg, febrile neutropenia, documented active infection during neutropenia), the dose was decreased by two levels. Patients who did not tolerate the 2.0 mg/m2 dose level were removed from the study.
The phase I portion of the trial used a conventional 3+3 algorithm of dose limiting toxicity and maximum tolerated dose, with a maximum potential number of patients of 18. The sample size for the phase II portion was established between a minimum of 10 patients and maximum of 40 patients at an accrual rate of two patients per month. The target response rate was set at 20%, and clinical outcomes were evaluated within 8 weeks of treatment. The trial was to be stopped if there was less than a 10% chance that the response rate was 20%. All analyses were descriptive and are presented with means, medians, and 95% confidence intervals.
Baseline Demographic and Clinical Characteristics
Nineteen patients were enrolled over 24 months. Median age was 59.8 years (range 42–76). Histologic types treated were as follows: 14 patients had serous, 2 had mixed, 2 had transitional, and 1 had clear cell. Half of the patients enrolled in the study were heavily pretreated patients who had received three or more prior chemotherapy regimens. Study participants received a total of 61 cycles of therapy during the study. Baseline characteristics of the enrolled patients are listed in Table 1.
During the dose escalation portion of the study (phase Ib portion), three patients were treated at dose level 1, three at dose level 2, and three at dose level 3. The maximum tolerated dose was 4.0 mg/m2 topotecan (administered intravenously on days 1, 8, and 15 of a 28 day cycle) and 250 mg gefitinib (administered orally every day for 28 days), which was dose level 3.
The overall response rate in the 19 patients was 10.5% (95% confidence interval 2.1% to 34.3%). Two patients received only one cycle of treatment and therefore were not evaluable for response to therapy. The longest duration of partial response was 61 weeks, observed in a patient who had received 15 courses and presented an elevated creatinine level after 2 weeks of delay and was taken off the study. The duration of the partial response observed in a second patient was 9 weeks. This patient showed cardiac toxicity and therefore the treatment was discontinued. Three patients who demonstrated stable disease had a duration of response of 13, 12, and 10 weeks, respectively. The overall responses in the intention-to-treat population (n=19) are shown in Table 2 and Online supplemental Figure 2.
The combination of gefitinib and topotecan was generally well tolerated (Tables 3 and 4). The safety population of 19 patients included all patients who received at least one dose of the study drugs. The most common grade 3 adverse events included anemia (n=3), neutropenia (n=4), abdominal pain (n=3), and fatigue (n=3). The most serious adverse events of any grade attributed to the therapy were anemia (89.4%, grades 1–3), neutropenia (68.4%, grades 1–3), abdominal pain (84%, grades 1–3), constipation (78.9%, grades 1–3), diarrhea (78.9%, grades 1–2), nausea (57.8%, grades 1–3), acne (57.8%, grade 1), fatigue (78.9%, grades 1–3), mood alterations (84.2%, grades 1–3), and neuropathy (57.8%, grade 1). No grade 4 serious adverse events were registered.
Our current prospective phase Ib/II study investigated the evidence based synergistic activity of the topoisomerase I inhibitor topotecan with the epidermal growth factor receptor–tyrosine kinase inhibitor, gefitinib, applying the combination of drugs to patients with recurrent platinum resistant ovarian, fallopian tube, or peritoneal cancer. Our results demonstrated that topotecan, at a dose of 4 mg/m2, in combination with gefitinib, at a dose of 250 mg, was well tolerated in patients with platinum resistant epithelial ovarian cancer but had limited activity and did not meet our efficacy parameters for objective response (ie, at least 20% response rate). Moreover, the overall benefits were not better than those previously described with weekly administrations of topotecan alone.13
Most adverse events we observed were consistent with those known for these agents. The patients in our study population had platinum resistant pretreated disease, having received two (42%), three (37%), or four (16%) prior chemotherapy regimens. Patients received different prior therapies before enrollment in our study. For approximately half of the patients, the penultimate therapy before enrolling in the trial was a platinum based regimen (52%), and for the rest of the patients, the last therapy included pegylated liposomal doxorubicin (47%), gemcitabine (21%), and docetaxel (37%). The poor response in our trial could be attributed to the heavy pretreatment in our population.
Although our study required eligible patients to have epidermal growth factor receptor positive expression, as determined by immunohistochemistry (1+ or greater), owing to the lack of clinical response, a correlation analysis between receptor status and clinical benefit could not be performed. However, investigators from other clinical trials observed no apparent relationship between the efficacy of the tyrosine kinase inhibitor and the level of epidermal growth factor receptor in the tumor, as determined by immunohistochemistry.11 12 These findings may suggest that patient selection in our study based only on epidermal growth factor receptor overexpression may not be appropriate.
Implementation of next generation sequencing for oncologic patients led to the development of various molecular biomarkers, which optimized the use of epidermal growth factor receptor–tyrosine kinase inhibitor in clinical practice. Currently, epidermal growth factor receptor–tyrosine kinase inhibitor represents a gold standard therapy for metastatic non-small cell lung cancer harboring an epidermal growth factor receptor activating mutation and for metastatic colorectal cancer with wild-type Kirsten rat sarcoma viral oncogene homolog (KRAS).9 Although such mutations are rare in ovarian cancer (3–4%), they may predict a favorable response to epidermal growth factor receptor–tyrosine kinase inhibitor. In a phase II trial, gefitinib showed a limited response rate in patients with platinum resistant pretreated ovarian cancer; only 1 of the 27 patients had a response (overall response rate of 4%). However, a mutation in the catalytic region of epidermal growth factor receptor was present in the tumor of the patient who responded to the treatment, and therefore the observation of a clinical benefit of epidermal growth factor receptor–tyrosine kinase inhibitor therapy in ovarian cancer when a mutation was present was consistent with the data for non-small cell lung cancer.14 Due to limited options for molecular testing for epidermal growth factor receptor or KRAS at the time our trial was performed, tumor samples from patients enrolled in this trial were not tested for epidermal growth factor receptor or KRAS mutations.
The combination of topotecan with the oral competitive tyrosine kinase inhibitor lapatinib, which is selective for epidermal growth factor receptor and human epidermal growth factor receptor 2, has been investigated in other phase II trials. With a similar trial design as our study, the LapTop trial enrolled a similar patient population, those with platinum refractory or resistant epithelial ovarian cancer with tumors presenting epidermal growth factor receptor overexpression, as assessed by immunohistochemistry. The clinical benefit rate in that study was 20%, one patient demonstrating partial response and three with stable disease.15 In another phase II study, investigating the same drug combination but in a different patient population which included patients with both platinum sensitive and platinum resistant disease, the median progression free survival duration was 1.8 months, the median overall survival duration was 10.5 months, and only two of 25 patients were alive without progression at 6 months. There was no overall response rate, which might be due to low epidermal growth factor receptor and human epidermal growth factor receptor 2 expression.16 Both studies demonstrated that the strategy of combining topotecan with the more potent epidermal growth factor receptor–tyrosine kinase inhibitor lapatinib had no advantage in terms of disease control rate. None of the studies showed a correlation between clinical benefit and epidermal growth factor receptor or human epidermal growth factor receptor 2 status.
Despite the intense interest in evaluating the epidermal growth factor receptor pathway owing to its roles in proliferation, metastasis, and tumor cell survival, our study and several other trials showed disappointing results with epidermal growth factor receptor inhibition in patients with recurrent ovarian cancer. Therefore, there remains an unmet need to identify targeted therapies that may improve the outcomes of this group of patients. Nevertheless, the development of epidermal growth factor receptor–tyrosine kinase inhibitor has accelerated over the past decade, enhancing tumor selectivity while minimizing adverse effects.
Indeed, in 2015, the FDA approved gefitinib for the treatment of patients with metastatic non-small cell lung cancer whose tumors had an epidermal growth factor receptor exon 19 deletion or exon 21 L858R substitution mutations.17 Recently, treatment with third generation epidermal growth factor receptor–tyrosine kinase inhibitors, such as osimertinib, led to dramatic improvement in progression free survival and overall survival in patients with non-small cell lung cancer.18 This class of drugs may be considered for future trials in gynecologic cancer. Given the current availability of tumor sequencing in clinical practice, patient selection based on epidermal growth factor receptor mutation status would improve biomarker based enrollment in such trials.
The authors thank Scientific Publications, Research Medical Library at the University of Texas MD Anderson Cancer Center, for editing the manuscript, and Michael E Garcia, RN, BSN, for providing support with study documents.
Correction notice The following author names have been corrected to add their middle initial: Charles F Levenbeck, Brian M Slomovitz, David M Gershenson and Robert L Coleman.
Contributors Conception and design: all authors. Provision of study materials or patients: CFL, BMS, and JW. Collection and assembly of data: AC-R and RLC. Data analysis and interpretation: AC-R and RLC. Manuscript writing: AC-R. Final approval of the manuscript: all authors. The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors.
Competing interests BMS is consultant for Abbvie, AstraZeneca, Clovis, GOG Foundation, GSK, Merck, and Myriad. DCB receives research grants from the National Cancer Institute. DMG has equity interest in Biogen, Bristol Myers Squibb, Johnson & Johnson, Procter and Gamble; is a consultant for Genentech; received research grants from the National Cancer Institute and Novartis; received royalities from Elsevier and UpToDate; and is a board member of NCI Clinical Trials and Translational Research Advisory Committee. RLC has clinical research funding from Merck, AstraZeneca/Medimmune, Genentech/Roche, Novartis, Clovis Oncology, Abbvie, and Janssen Pharmaceuticals. RLC receives consulting fees from Genmab, Tesaro, Agenus, OncoMed, Novocure, Oncoquest, Merck, AstraZeneca/Medimmune, Genentech/Roche, Novartis, Clovis Oncology, Abbvie, Janssen Pharmaceuticals, Aravive, and OncoSec.
Patient consent for publication Not required.
Ethics approval The study was registered on the clinical trial website of the National Cancer Institute (clinicaltrials.gov NCT00317772) and approved by the the University of Texas MD Anderson Cancer Center institutional review board.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. In accordance with the journal’s guidelines, we will provide our data for the reproducibility of this study in other centers if such is requested.