Lani
01-21-2011, 11:33 AM
herceptin+vinorelbine to herceptin+taxane WITH A LOT LESS RISK OF COMPLICATIONS such as neutropenia, neuropathy, fatigue,infections, edema etc
Be forewarned: it has statistics, but better ones, and getting better all the time with new targeted agents
© 2010 by American Society of Clinical Oncology
Chemotherapy Agents in Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: Time to Step Out of the Limelight
Nancy U. Lin and Eric P. Winer
+ Author Affiliations
Dana-Farber Cancer Institute, Boston, MA
Human epidermal growth factor receptor 2 (HER2) is amplified and/or overexpressed in approximately 15% to 20% of invasive breast carcinomas.1,2 Synergistic activity against HER2-overexpressing breast cancer cell lines has been observed with trastuzumab plus vinorelbine and trastuzumab plus docetaxel; additive activity was seen with trastuzumab plus paclitaxel.3 These and other preclinical studies prompted intense evaluation of trastuzumab with a variety of cytotoxic agents within clinical trials.
On the basis of its efficacy in phase II and/or phase III trials, the 2010 National Comprehensive Cancer Network Clinical Practice Guidelines list paclitaxel (with or without carboplatin), docetaxel, vinorelbine, and capecitabine as preferred first-line agents for use in combination with trastuzumab in patients with HER2-positive, metastatic breast cancer. Notably, of these regimens, only the combination of trastuzumab and paclitaxel has gained US Food and Drug Administration approval on the basis of a progression-free and overall survival (OS) advantage in the initial pivotal trial.4 A survival advantage was also noted in a randomized phase II trial comparing trastuzumab/docetaxel to docetaxel alone, supporting approval of this regimen by the European Medicines Agency.5 Although reasonably well-tolerated, docetaxel and paclitaxel are associated with alopecia, peripheral neuropathy, hypersensitivity reactions, and requirements for corticosteroid premedication. Fatigue, hematological toxicity, and febrile neutropenia can be seen with either taxane, though more frequently with docetaxel. For these reasons, many oncologists choose to partner trastuzumab with vinorelbine, or, less frequently, capecitabine, in the first-line setting. However, until now, no adequately powered, randomized trial has directly compared the approved taxane-based regimens to nontaxane regimens in this setting.
In this issue of Journal of Clinical Oncology, Andersson et al6 present results of the Herceptin Plus Navelbine or Taxotere (HERNATA) study—a randomized, phase III trial that enrolled patients with HER2-positive, metastatic breast cancer who had not received prior chemotherapy or HER2-targeted therapy for the treatment of advanced disease. The primary study end point was time to progression (TTP). A total of 284 patients were randomly assigned to docetaxel 100 mg/m2 once every three weeks or to vinorelbine (30 mg/m2 or 35 mg/m2, according to institutional predefined preference) on days 1 and 8 of a 21-day cycle. Trastuzumab was administered to all patients on a standard once every 3 weeks schedule. Notably, all but four patients were taxane naive at study entry. The study was designed to have 90% power to reject the null hypothesis of similar TTP, assuming inferiority of vinorelbine with a hazard ratio (HR) of 1.77. As reported by Andersson et al, no differences were observed in TTP (median, 12.4 months for docetaxel, 15.3 months for vinorelbine; HR, 0.94; 95% CI, 0.71 to 1.25; P = .67), objective response rate (59.3% in both arms), or OS (median, 35.7 v 38.8 months; HR, 1.01; 95% CI, 0.71 to 1.42; P = .98). Time to treatment failure—defined as time from date of random assignment to the date of last study chemotherapy (ie, date of last vinorelbine or docetaxel, allowing for continuation of trastuzumab)—was significantly shorter in the docetaxel group (median, 5.6 v 7.7 months; HR, 0.50; 95% CI, 0.38 to 0.64; P = .0001). The rate of grade 3 or 4 toxicity associated with docetaxel was significantly higher across a variety of domains, including hematologic toxicity, febrile neutropenia, infections, edema, nail changes, and sensory neuropathy. As a result, there were more frequent dose reductions of docetaxel in comparison with vinorelbine. Furthermore, the rate of treatment discontinuation resulting from toxicity was approximately three-fold higher with docetaxel (20.1% v 6.5%; P < .001).
What are the clinical and research implications of the HERNATA findings? Although the study was not powered to demonstrate equivalence, from a clinical perspective, given the more favorable toxicity profile and the failure to conclude that docetaxel is superior to vinorelbine, we believe this study firmly establishes the role of trastuzumab plus vinorelbine as an acceptable, and even preferred, option for the first-line treatment of patients with HER2-positive metastatic breast cancer. Moreover, assuming HRs of 0.80 and 1.25 as cut points between clinically equivalent and clinically different, Bayesian analysis conditioned on results of the HERNATA trial indicate that the probability that trastuzumab plus vinorelbine is actually inferior to trastuzumab plus docetaxel is only 3%, whereas the probability that they are equivalent is 80% (D.A. Berry, personal communication, September 2010). Placed in the context of existing data, the results are consistent with an evolving view that, in the presence of HER2-directed therapy, the choice of chemotherapy partner is a secondary consideration. The HERNATA results are consistent with those of the Trastuzumab Plus Vinorelbine or Taxane (TRAVIOTA) study, which terminated early as a result of poor accrual; TRAVIOTA also failed to show a statistically significant difference in objective response rate (taxane 40% v vinorelbine 51%; P = .37) or TTP (median, 6.0 v 8.5 months; P = .09) between arms.7 Including those treated on the HERNATA and TRAVIOTA trials, more than 400 women have received trastuzumab plus vinorelbine as part of at least seven prospective phase II or III trials conducted in the first-line setting, all of which have confirmed the clinical activity of this regimen.7–12
From a research perspective, several issues should be emphasized. First, it is unlikely that there will ever be another randomized trial comparing regimens of trastuzumab plus taxane versus trastuzumab plus vinorelbine, and we would argue that it would be a poor use of patient and financial resources. Although trastuzumab plus chemotherapy combinations have improved the lives of patients with HER2-positive metastatic breast cancer, almost all patients eventually succumb to progressive disease, with a median OS of 2 to 4 years (E. Olson, personal communication, September 2010).4,5,13–15 Given the increasing number of novel therapies for HER2-positive disease (ie, TDM1, pertuzumab, neratinib, BIBW 2992, PI3 kinase inhibitors, Akt inhibitors, HSP90 inhibitors, among others), it is time to prioritize the development of new molecularly targeted approaches over the optimization of existing cytotoxic agents. In our view, little will be gained by playing musical chairs with chemotherapeutic agents. For that matter, it remains unlikely that chemotherapy intensification using more than one cytotoxic agent substantially improves patient outcomes.16,17 In light of these data, we believe that the most judicious approach to dealing with limited patient resources is to prioritize the development of novel targeted agents, ultimately with the goal of matching specific tumor characteristics to the appropriate treatment.
Second, the HERNATA results argue strongly for the allowance of trastuzumab plus vinorelbine as a comparator arm in US Food and Drug Administration registration trials. In some cases, the ability to use vinorelbine, or perhaps other non–taxane-based chemotherapies, will accelerate drug development given that some new agents may have overlapping toxicities with the taxanes. As a greater proportion of women are treated with taxane plus trastuzumab regimens in the adjuvant setting, a trastuzumab plus taxane control arm in the metastatic setting also becomes both less attractive and less reflective of clinical practice.
Despite more than a decade of experience with trastuzumab, we know remarkably little about the factors that drive de novo and, especially, acquired resistance to trastuzumab in human tumors, although this situation is rapidly changing. On study of primary tumor specimens, several promising leads have been identified, such as alterations in the PI3 kinase pathway, expression of p95, HER2/HER3 heterodimers, basal-like expression patterns, and overexpression of insulin-like growth factor 1 receptor, among others.18–22 These and other variables will be assessed in the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALLTO) and neoALLTO trials, as well as in neoadjuvant trials being led by Cancer and Leukemia Group B and the National Surgical Adjuvant Breast and Bowel Project. In the metastatic setting, the next generation of clinical trials should incorporate these markers into correlative analyses and, in some cases, select patients after an interrogation of their tumors for resistance mechanisms. For example, a planned randomized phase II trial will evaluate the use of lapatinib-based versus trastuzumab-based chemotherapy in patients with p95-positive tumors. Several ongoing and planned trials will evaluate PI3 kinase inhibitors in patients with activating mutations in PIK3CA and/or phosphatase and tensin homolog loss. Importantly, many of these trials include biopsies of metastatic lesions. In the metastatic setting, it is still unclear why and how resistance develops to virtually all treatments over time. Although both genetic and epigenetic causes of resistance have been invoked, it is not understood whether resistance arises due to alterations in individual tumor cells or, alternatively, clonal selection induced by treatment. Conversely, in a subset of patients, resistance does not seem to arise as readily. For example, in the HERNATA trial, approximately 10% of patients were alive and free of progression at 3 years without any need for a change in regimen. Who are these patients, and what characteristics predict for the tail of the curve? Many or all of these patients may not need one of the newer targeted agents if they can do well with the present standard of care.
In summary, the HERNATA trial strongly supports trastuzumab plus vinorelbine as an active and well-tolerated option for patients with HER2-positive metastatic breast cancer. In the context of other trials evaluating trastuzumab plus chemotherapy combinations, the study is consistent with the concept of trastuzumab as a great equalizer, rendering the specific choice of chemotherapy secondary. In the presence of HER2-directed therapy, we have likely reached a point of diminishing returns for optimization of chemotherapy partner(s). We believe it is time for chemotherapy to take a supporting role and for individualized and targeted approaches to claim the limelight. In addition, although at the moment this is primarily true of HER2-positive breast cancer, it is conceivable that the same lesson may be repeated in the future with other targeted agents (eg, poly [ADP-ribose] polymerase inhibitors, apoptosis enhancers) whose primary mode of action may be to potentiate the effects of chemotherapy. As we look ahead to the future, let us not allow debates about the “best” chemotherapy partner get in the way of developing truly promising leads.
Next Section
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Nancy U. Lin, Genentech, GlaxoSmithKline, Boehringer Ingelheim, Infinity Pharmaceuticals; Eric P. Winer, Genentech Expert Testimony: None Other Remuneration: None
Previous Section
Next Section
AUTHOR CONTRIBUTIONS
Manuscript writing: Nancy U. Lin, Eric P. Winer
Final approval of manuscript: Nancy U. Lin, Eric P. Winer
Previous Section
Next Section
Acknowledgment
We thank Donald A. Berry for statistical consultation and input in the writing of this editorial.
Be forewarned: it has statistics, but better ones, and getting better all the time with new targeted agents
© 2010 by American Society of Clinical Oncology
Chemotherapy Agents in Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: Time to Step Out of the Limelight
Nancy U. Lin and Eric P. Winer
+ Author Affiliations
Dana-Farber Cancer Institute, Boston, MA
Human epidermal growth factor receptor 2 (HER2) is amplified and/or overexpressed in approximately 15% to 20% of invasive breast carcinomas.1,2 Synergistic activity against HER2-overexpressing breast cancer cell lines has been observed with trastuzumab plus vinorelbine and trastuzumab plus docetaxel; additive activity was seen with trastuzumab plus paclitaxel.3 These and other preclinical studies prompted intense evaluation of trastuzumab with a variety of cytotoxic agents within clinical trials.
On the basis of its efficacy in phase II and/or phase III trials, the 2010 National Comprehensive Cancer Network Clinical Practice Guidelines list paclitaxel (with or without carboplatin), docetaxel, vinorelbine, and capecitabine as preferred first-line agents for use in combination with trastuzumab in patients with HER2-positive, metastatic breast cancer. Notably, of these regimens, only the combination of trastuzumab and paclitaxel has gained US Food and Drug Administration approval on the basis of a progression-free and overall survival (OS) advantage in the initial pivotal trial.4 A survival advantage was also noted in a randomized phase II trial comparing trastuzumab/docetaxel to docetaxel alone, supporting approval of this regimen by the European Medicines Agency.5 Although reasonably well-tolerated, docetaxel and paclitaxel are associated with alopecia, peripheral neuropathy, hypersensitivity reactions, and requirements for corticosteroid premedication. Fatigue, hematological toxicity, and febrile neutropenia can be seen with either taxane, though more frequently with docetaxel. For these reasons, many oncologists choose to partner trastuzumab with vinorelbine, or, less frequently, capecitabine, in the first-line setting. However, until now, no adequately powered, randomized trial has directly compared the approved taxane-based regimens to nontaxane regimens in this setting.
In this issue of Journal of Clinical Oncology, Andersson et al6 present results of the Herceptin Plus Navelbine or Taxotere (HERNATA) study—a randomized, phase III trial that enrolled patients with HER2-positive, metastatic breast cancer who had not received prior chemotherapy or HER2-targeted therapy for the treatment of advanced disease. The primary study end point was time to progression (TTP). A total of 284 patients were randomly assigned to docetaxel 100 mg/m2 once every three weeks or to vinorelbine (30 mg/m2 or 35 mg/m2, according to institutional predefined preference) on days 1 and 8 of a 21-day cycle. Trastuzumab was administered to all patients on a standard once every 3 weeks schedule. Notably, all but four patients were taxane naive at study entry. The study was designed to have 90% power to reject the null hypothesis of similar TTP, assuming inferiority of vinorelbine with a hazard ratio (HR) of 1.77. As reported by Andersson et al, no differences were observed in TTP (median, 12.4 months for docetaxel, 15.3 months for vinorelbine; HR, 0.94; 95% CI, 0.71 to 1.25; P = .67), objective response rate (59.3% in both arms), or OS (median, 35.7 v 38.8 months; HR, 1.01; 95% CI, 0.71 to 1.42; P = .98). Time to treatment failure—defined as time from date of random assignment to the date of last study chemotherapy (ie, date of last vinorelbine or docetaxel, allowing for continuation of trastuzumab)—was significantly shorter in the docetaxel group (median, 5.6 v 7.7 months; HR, 0.50; 95% CI, 0.38 to 0.64; P = .0001). The rate of grade 3 or 4 toxicity associated with docetaxel was significantly higher across a variety of domains, including hematologic toxicity, febrile neutropenia, infections, edema, nail changes, and sensory neuropathy. As a result, there were more frequent dose reductions of docetaxel in comparison with vinorelbine. Furthermore, the rate of treatment discontinuation resulting from toxicity was approximately three-fold higher with docetaxel (20.1% v 6.5%; P < .001).
What are the clinical and research implications of the HERNATA findings? Although the study was not powered to demonstrate equivalence, from a clinical perspective, given the more favorable toxicity profile and the failure to conclude that docetaxel is superior to vinorelbine, we believe this study firmly establishes the role of trastuzumab plus vinorelbine as an acceptable, and even preferred, option for the first-line treatment of patients with HER2-positive metastatic breast cancer. Moreover, assuming HRs of 0.80 and 1.25 as cut points between clinically equivalent and clinically different, Bayesian analysis conditioned on results of the HERNATA trial indicate that the probability that trastuzumab plus vinorelbine is actually inferior to trastuzumab plus docetaxel is only 3%, whereas the probability that they are equivalent is 80% (D.A. Berry, personal communication, September 2010). Placed in the context of existing data, the results are consistent with an evolving view that, in the presence of HER2-directed therapy, the choice of chemotherapy partner is a secondary consideration. The HERNATA results are consistent with those of the Trastuzumab Plus Vinorelbine or Taxane (TRAVIOTA) study, which terminated early as a result of poor accrual; TRAVIOTA also failed to show a statistically significant difference in objective response rate (taxane 40% v vinorelbine 51%; P = .37) or TTP (median, 6.0 v 8.5 months; P = .09) between arms.7 Including those treated on the HERNATA and TRAVIOTA trials, more than 400 women have received trastuzumab plus vinorelbine as part of at least seven prospective phase II or III trials conducted in the first-line setting, all of which have confirmed the clinical activity of this regimen.7–12
From a research perspective, several issues should be emphasized. First, it is unlikely that there will ever be another randomized trial comparing regimens of trastuzumab plus taxane versus trastuzumab plus vinorelbine, and we would argue that it would be a poor use of patient and financial resources. Although trastuzumab plus chemotherapy combinations have improved the lives of patients with HER2-positive metastatic breast cancer, almost all patients eventually succumb to progressive disease, with a median OS of 2 to 4 years (E. Olson, personal communication, September 2010).4,5,13–15 Given the increasing number of novel therapies for HER2-positive disease (ie, TDM1, pertuzumab, neratinib, BIBW 2992, PI3 kinase inhibitors, Akt inhibitors, HSP90 inhibitors, among others), it is time to prioritize the development of new molecularly targeted approaches over the optimization of existing cytotoxic agents. In our view, little will be gained by playing musical chairs with chemotherapeutic agents. For that matter, it remains unlikely that chemotherapy intensification using more than one cytotoxic agent substantially improves patient outcomes.16,17 In light of these data, we believe that the most judicious approach to dealing with limited patient resources is to prioritize the development of novel targeted agents, ultimately with the goal of matching specific tumor characteristics to the appropriate treatment.
Second, the HERNATA results argue strongly for the allowance of trastuzumab plus vinorelbine as a comparator arm in US Food and Drug Administration registration trials. In some cases, the ability to use vinorelbine, or perhaps other non–taxane-based chemotherapies, will accelerate drug development given that some new agents may have overlapping toxicities with the taxanes. As a greater proportion of women are treated with taxane plus trastuzumab regimens in the adjuvant setting, a trastuzumab plus taxane control arm in the metastatic setting also becomes both less attractive and less reflective of clinical practice.
Despite more than a decade of experience with trastuzumab, we know remarkably little about the factors that drive de novo and, especially, acquired resistance to trastuzumab in human tumors, although this situation is rapidly changing. On study of primary tumor specimens, several promising leads have been identified, such as alterations in the PI3 kinase pathway, expression of p95, HER2/HER3 heterodimers, basal-like expression patterns, and overexpression of insulin-like growth factor 1 receptor, among others.18–22 These and other variables will be assessed in the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALLTO) and neoALLTO trials, as well as in neoadjuvant trials being led by Cancer and Leukemia Group B and the National Surgical Adjuvant Breast and Bowel Project. In the metastatic setting, the next generation of clinical trials should incorporate these markers into correlative analyses and, in some cases, select patients after an interrogation of their tumors for resistance mechanisms. For example, a planned randomized phase II trial will evaluate the use of lapatinib-based versus trastuzumab-based chemotherapy in patients with p95-positive tumors. Several ongoing and planned trials will evaluate PI3 kinase inhibitors in patients with activating mutations in PIK3CA and/or phosphatase and tensin homolog loss. Importantly, many of these trials include biopsies of metastatic lesions. In the metastatic setting, it is still unclear why and how resistance develops to virtually all treatments over time. Although both genetic and epigenetic causes of resistance have been invoked, it is not understood whether resistance arises due to alterations in individual tumor cells or, alternatively, clonal selection induced by treatment. Conversely, in a subset of patients, resistance does not seem to arise as readily. For example, in the HERNATA trial, approximately 10% of patients were alive and free of progression at 3 years without any need for a change in regimen. Who are these patients, and what characteristics predict for the tail of the curve? Many or all of these patients may not need one of the newer targeted agents if they can do well with the present standard of care.
In summary, the HERNATA trial strongly supports trastuzumab plus vinorelbine as an active and well-tolerated option for patients with HER2-positive metastatic breast cancer. In the context of other trials evaluating trastuzumab plus chemotherapy combinations, the study is consistent with the concept of trastuzumab as a great equalizer, rendering the specific choice of chemotherapy secondary. In the presence of HER2-directed therapy, we have likely reached a point of diminishing returns for optimization of chemotherapy partner(s). We believe it is time for chemotherapy to take a supporting role and for individualized and targeted approaches to claim the limelight. In addition, although at the moment this is primarily true of HER2-positive breast cancer, it is conceivable that the same lesson may be repeated in the future with other targeted agents (eg, poly [ADP-ribose] polymerase inhibitors, apoptosis enhancers) whose primary mode of action may be to potentiate the effects of chemotherapy. As we look ahead to the future, let us not allow debates about the “best” chemotherapy partner get in the way of developing truly promising leads.
Next Section
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Nancy U. Lin, Genentech, GlaxoSmithKline, Boehringer Ingelheim, Infinity Pharmaceuticals; Eric P. Winer, Genentech Expert Testimony: None Other Remuneration: None
Previous Section
Next Section
AUTHOR CONTRIBUTIONS
Manuscript writing: Nancy U. Lin, Eric P. Winer
Final approval of manuscript: Nancy U. Lin, Eric P. Winer
Previous Section
Next Section
Acknowledgment
We thank Donald A. Berry for statistical consultation and input in the writing of this editorial.