Dinesh Doval

Efficacy and Safety of Lapatinib As First-Line Therapy for ErbB2-Amplified Locally Advanced or Metastatic Breast Cancer

PURPOSE This study (EGF20009) assessed the efficacy and tolerability of two lapatinib administration schedules as first-line monotherapy in women with ErbB2-amplified locally advanced or metastatic breast cancer. PATIENTS AND METHODS Patients with ErbB2-amplified, locally advanced or metastatic breast cancer previously untreated in the metastatic setting were randomly assigned to one of two lapatinib dose cohorts and received either 1,500 mg once daily or 500 mg twice daily. Clinical response was assessed at weeks 8 and 12 and every 12 weeks thereafter. RESULTS A total of 138 patients were treated with lapatinib for a median of 17.6 weeks. The overall response rate (complete response [CR] plus partial response [PR]) was 24% in the intent-to-treat population, and 31% of patients derived clinical benefit (CR, PR, or stable disease for >or= 24 weeks). The median time to response was 7.9 weeks, and the progression-free survival rates at 4 and 6 months were 63% and 43%, respectively. The most common lapatinib-related adverse events (AEs) were diarrhea, rash, pruritus, and nausea, and these events were primarily grade 1 or 2. There were no significant differences in clinical activity or the AE profile between the dosing schedules. CONCLUSION Lapatinib demonstrated clinical activity and was well tolerated as first-line therapy in ErbB2-amplified locally advanced or metastatic breast cancer. This study supports further evaluation of lapatinib in first-line and early-stage ErbB2-overexpressing breast cancer.

Antitumor Activity and Safety of Tivozanib (AV-951) in a Phase II Randomized Discontinuation Trial in Patients With Renal Cell Carcinoma

PURPOSE The antitumor activity and safety of tivozanib, which is a potent and selective vascular endothelial growth factor receptor-1, -2, and -3 inhibitor, was assessed in patients with advanced/metastatic renal cell carcinoma (RCC). PATIENTS AND METHODS In this phase II, randomized discontinuation trial, 272 patients received open-label tivozanib 1.5 mg/d (one cycle equaled three treatment weeks followed by a 1-week break) orally for 16 weeks. Thereafter, 78 patients who demonstrated ≥ 25% tumor shrinkage continued to take tivozanib, and 118 patients with less than 25% tumor change were randomly assigned to receive tivozanib or a placebo in a double-blind manner; patients with ≥ 25% tumor growth were discontinued. Primary end points included safety, the objective response rate (ORR) at 16 weeks, and the percentage of randomly assigned patients who remained progression free after 12 weeks of double-blind treatment; secondary end points included progression-free survival (PFS). RESULTS Of 272 patients enrolled onto the study, 83% of patients had clear-cell histology, 73% of patients had undergone nephrectomy, and 54% of patients were treatment naive. The ORR after 16 weeks of tivozanib treatment was 18% (95% CI, 14% to 23%). Of the 118 randomized patients, significantly more patients who were randomly assigned to receive double-blind tivozanib remained progression free after 12 weeks versus patients who received the placebo (49% v 21%; P = .001). Throughout the study, the ORR was 24% (95% CI, 19% to 30%), and the median PFS was 11.7 months (95% CI, 8.3 to 14.3 months) in the overall study population. The most common grade 3 and 4 treatment-related adverse event was hypertension (12%). CONCLUSION Tivozanib was active and well tolerated in patients with advanced RCC. These data support additional development of tivozanib in advanced RCC.

A Randomized, Double-Blind, Placebo-Controlled, Phase II Study of Oral Talactoferrin in Combination with Carboplatin and Paclitaxel in Previously Untreated Locally Advanced or Metastatic Non-small Cell Lung Cancer

Introduction: The aim of the study is to investigate the activity and safety of oral talactoferrin (TLF) plus carboplatin and paclitaxel (C/P) in patients with previously untreated stage IIIB/IV non-small cell lung cancer. Methods: Patients (n = 110) were randomly assigned to receive C/P plus either TLF (C/P/T) or placebo (C/P/P). The primary objective of this exploratory study was assessment of confirmed response rate (RR) in the prospectively defined evaluable population with a one-tailed p = 0.05. Secondary objectives included assessment of progression-free survival (PFS), duration of response, overall survival (OS), and safety. Results: The trial met the primary end point of improvement in confirmed RR in the prospectively defined evaluable population. Compared with the C/P/P group, RR increased in the C/P/T group by 18% (29–47%; p = 0.05) and 15% (27–42%; p = 0.08) in the evaluable and intent-to-treat populations, respectively. Compared with the C/P/P group, the C/P/T group had a longer median PFS (4.2 versus 7.0 months), OS (8.5 versus 10.4 months), and duration of response (5.5 versus 7.6 months), although the differences were not statistically significant. Adverse events (AEs) were consistent with C/P therapy. There were fewer total AEs (472 versus 569; two-tailed p = 0.003) and grade 3/4 AEs (78 versus 105; p = 0.05) in the C/P/T group compared with the C/P/P group. Conclusion: TLF, in combination with C/P, demonstrated an apparent improvement in RR, PFS, and OS in patients with previously untreated stage IIIB/IV non-small cell lung cancer and appears to enhance activity without significant additional toxicity. These results need to be confirmed in a phase III trial.

Clinical Experience with Gefitinib in Indian Patients

Introduction: Treatment options are limited in patients with advanced or refractory non-small cell lung cancer and lead to suboptimal outcome and/or benefit. The epidermal growth factor tyrosine kinase inhibitor gefitinib (IRESSA) has been approved in many countries. Increased responsiveness to gefitinib has been demonstrated in particular subsets of patients, for example never smokers and patients of Asian origin. However, to date, little is known of its use specifically in patients from India. Methods: Retrospective ad hoc analysis of clinical data from experience with gefitinib in patients with advanced NSCLC from India enrolled in the IRESSA Survival Evaluation in Lung (ISEL) study (n = 77) or included in the gefitinib expanded-access program in India (n = 133). Results: Among Indian patients enrolled in the ISEL study, median survival was 6.4 months with gefitinib and 5.1 month with placebo. The objective response rate in Indian patients was 14% with gefitinib versus 0% with placebo. In ISEL, tolerability data from Indian patients were consistent with the overall study population. In the Indian gefitinib expanded-access program, median survival was 6 months and gefitinib was well tolerated. Conclusions: Gefitinib seems well tolerated in Indian patients with advanced NSCLC, with some clinical benefit observed.

Efficacy of erlotinib as first-line maintenance therapy in patients with locally advanced or metastatic nonsmall cell lung cancer who have not experienced disease progression or unacceptable toxicity during chemotherapy.

Background: First-line maintenance with erlotinib in nonsmall cell lung cancer (NSCLC) patients without progression after four cycles of chemotherapy was well tolerated and significantly prolonged progression-free survival (PFS) compared with placebo. Aim and Design: This open-label, single arm, Phase IV, interventional study was designed to evaluate erlotinib as first-line maintenance after chemotherapy in Indian NSCLC patients. Primary efficacy objective was to evaluate PFS rate (PFSR) at week 52 and secondary objectives were determination of PFS, overall survival (OS), overall response rate (ORR), disease control rate, and safety. Subjects and Methods: Patients were treated with erlotinib until disease progression/death/unacceptable toxicity or end of study. Patients with disease progression underwent scheduled clinical assessments every 12 weeks thereafter. Kaplan–Meier estimates were used to evaluate PFSR, PFS, and OS. The ORR was summarized using number and percentage along with two-sided 95% Clopper–Pearson confidence interval. The incidence of adverse events (AEs) and serious AEs (SAEs) was tabulated according to severity, outcome, and relationship to erlotinib. Results: Of the 51 enrolled patients, 47 patients completed the study (2: Continuing treatment, 41: Disease progression, and 4: Death) and four patients discontinued treatment (3: Lost to follow-up; 1: Withdrew consent). PFSR was 22.5% at 12 months, median PFS 99 days (14.14 weeks), and median OS was 671 days (22 months). The probability of OS was 74.5% at 14 months. The ORR was 25.5%, and disease control rate was 55.3%. AEs were reported in 62.7% and SAE in 7.8% of patients. Common AEs were diarrhea and rash. Conclusions: Erlotinib was well tolerated by Indian patients in first-line maintenance setting and resulted in median PFS of 14 weeks and median OS of 22 months better than previously reported and with no new safety concerns in this population.

Treatment conundrums in osteosarcoma of the breast: Two clinical cases from a tertiary care cancer center in India

Extraosseous sarcoma of the breast occurs infrequently and is a harbinger of poor prognosis. The histogenesis of this tumor is ambiguous, and it can arise both in de novo and metastatic settings. Morphologically, it is indistinguishable from its skeletal counterpart, and clinically, it presents similarly to any other subtype of breast cancer. Tumor recurrence with a propensity for hematogenous rather than lymphatic spread plagues this malicious disease. The treatment guidelines are mainly derived from the those of other extraskeletal sarcomas as the literature is limited in this context. We hereby present 2 clinical cases with similar clinical profiles and different treatment outcomes. The intent of this case report is to contribute to the limited database available for the management of this rare disease.

Practical consensus recommendations on management of HR + ve early breast cancer with specific reference to genomic profiling

Breast cancer is a heterogeneous disease and patients are managed clinically based on ER, PR, HER2 expression, and key risk factors. The use of gene expression assays for early stage disease is already common practice. These tests have found a place in risk stratifying the heterogeneous group of stage I–II breast cancers for recurrence, for predicting chemotherapy response, and for predicting breast cancer-related mortality. Most guidelines for hormone receptor (HR)–positive early breast cancer recommend addition of adjuvant chemotherapy for most women, leading to overtreatment, which causes considerable morbidity and cost. Expert oncologist discussed about strategies of gene expression assays and aid in chemotherapy recommendations for treatment of HR + ve EBC and the expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at this practical consensus recommendations for the benefit of community oncologists.

[Experts' Opinion] Novel formulations of docetaxel, paclitaxel and doxorubicin in the management of metastatic breast cancer

The management of breast cancer with advanced disease or metastasis is a common problem in India and other countries. A panel of 13 oncology experts deliberated on the sidelines of the 35th Indian Cooperative Oncology Network Conference held in Mumbai to formulate an expert opinion recommendation on the novel drug delivery system (NDDS) formulations in the treatment of metastatic breast cancer (MBC). The survey comprised of 39 questions related to limitations of conventional formulations and therapeutic positioning of NDDS formulations of docetaxel, paclitaxel and doxorubicin in the management of MBC. The experts used data from published literature and their practical experience to provide expert opinion and recommendations for use by the community oncologists. The experts opined that the newer NDDS formulations should provide a significant efficacy advantage in terms of overall survival and progression-free survival, or demonstrate better tolerability when compared with conventional formulations. The newer NDDS formulations of taxanes should be considered in special circumstances such as diabetes, in patients who have had hypersensitivity reactions and in cases where steroids need to be avoided. The novel formulations of doxorubicin should be used in the elderly and in patients with borderline cardiac function.

Breast cancer recurrence presenting as solitary intraparotid nodal metastasis detected by 18F-Fluorodeoxyglucose positron emission tomography: a very unusual occurrence

Primary malignancies of the salivary gland itself are uncommon, while secondary metastatic deposits are further very rare with description of only few case reports in the literature. The most common site of metastatic deposit to parotid gland is from squamous cell malignancies of head and neck, while secondary deposits from primary in infraclavicular location are very rarely described. We herein describe the case of an elderly lady who while on adjuvant endocrine therapy developed metastatic disease with right intraparotid node as the sole site of metastasis detected on FDG PET scan. This type of presentation of recurrence is very uncommon, especially in hormonal receptor-positive cases, with <30 cases described in the literature to the best of our knowledge. This patient underwent metastasectomy followed by palliative the second-line hormonal therapy and achieved long-term survival more than usually seen with other metastatic breast cancers highlighting the importance of metastasectomy in metastatic breast cancer patients on hormonal therapy who develop metachronous oligometastatic disease.

Development of a Novel Proteomic Risk-Classifier for Prognostication of Patients With Early-Stage Hormone Receptor–Positive Breast Cancer

Use of proteomic strategies to identify a risk classifier that estimates probability of distant recurrence in early-stage hormone receptor (HR)-positive breast cancer is relevant to physiological cellular function and therefore to intrinsic tumor biology. We used a 298-sample retrospective training set to develop an immunohistochemistry-based novel risk classifier called CanAssist-Breast (CAB) which combines 5 prognostically relevant biomarkers and 3 clinico-pathological parameters to arrive at probability of distant recurrence within 5 years from diagnosis. Five selected biomarkers, namely, CD44, ABCC4, ABCC11, N-cadherin, and pan-cadherin, were chosen based on their role in tumor metastasis. The chosen biomarkers represent the hallmarks of cancer and are distinct from other proliferation and gene expression–based prognostic signatures. The 3 clinico-pathological parameters integrated into the machine learning–based CAB algorithm are tumor size, tumor grade, and node status. These features are used to calculate a “CAB risk score” that classifies patients into low- or high-risk groups and predicts probability of distant recurrence in 5 years. Independent clinical validation of CAB in a retrospective study comprising 196 patients indicated that distant metastasis-free survival (DMFS) was significantly different in the 2 risk groups. The difference in DMFS between the low- and high-risk categories was 19% in the validation cohort (P = .0002). In multivariate analysis, CAB risk score was the most significant independent predictor of distant recurrence with a hazard ratio of 4.3 (P = .0003). CanAssist-Breast is a precise and unique machine learning–based proteomic risk-classifier that can assist in risk stratification of patients with early-stage HR+ breast cancer.