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Journal of Clinical Oncology

Journal of Clinical Oncology RSS feed - Early Release
Journal of Clinical Oncology






Purpose

Metastatic cervical cancer is a prototypical chemotherapy-refractory epithelial malignancy for which better treatments are needed. Adoptive T-cell therapy (ACT) is emerging as a promising cancer treatment, but its study in epithelial malignancies has been limited. This study was conducted to determine if ACT could mediate regression of metastatic cervical cancer.

Patients and Methods

Patients enrolled onto this protocol were diagnosed with metastatic cervical cancer and had previously received platinum-based chemotherapy or chemoradiotherapy. Patients were treated with a single infusion of tumor-infiltrating T cells selected when possible for human papillomavirus (HPV) E6 and E7 reactivity (HPV-TILs). Cell infusion was preceded by lymphocyte-depleting chemotherapy and was followed by administration of aldesleukin.

Results

Three of nine patients experienced objective tumor responses (two complete responses and one partial response). The two complete responses were ongoing 22 and 15 months after treatment, respectively. One partial response was 3 months in duration. The HPV reactivity of T cells in the infusion product (as measured by interferon gamma production, enzyme-linked immunospot, and CD137 upregulation assays) correlated positively with clinical response (P = .0238 for all three assays). In addition, the frequency of HPV-reactive T cells in peripheral blood 1 month after treatment was positively associated with clinical response (P = .0238).

Conclusion

Durable, complete regression of metastatic cervical cancer can occur after a single infusion of HPV-TILs. Exploratory studies suggest a correlation between HPV reactivity of the infusion product and clinical response. Continued investigation of this therapy is warranted.


Purpose

Surveillance imaging of asymptomatic patients with diffuse large B-cell lymphoma (DLBCL) in first remission remains controversial. A decision-analytic Markov model was developed to evaluate the cost-effectiveness of follow-up strategies following first-line immunochemotherapy.

Patients and Methods

Three strategies were compared in 55-year-old patient cohorts: routine clinical follow-up without serial imaging, routine follow-up with biannual computed tomography (CT) scans for 2 years, or routine follow-up with biannual [18F]-fluorodeoxyglucose positron emission tomography–computed tomography (PET/CT) for 2 years. The baseline model favored imaging-based strategies by associating asymptomatic imaging-detected relapses with improved clinical outcomes. Lifetime costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated for each surveillance strategy.

Results

Surveillance strategies utilizing 2 years of routine CT or PET/CT scans were associated with minimal survival benefit when compared with clinical follow-up without routine imaging (life-years gained: CT, 0.03 years; PET/CT, 0.04 years). The benefit of imaging-based follow-up remained small after quality-of-life adjustments (CT, 0.020 QALYs; PET/CT, 0.025 QALYs). Costs associated with imaging-based surveillance strategies are considerable; ICERs for imaging strategies compared with clinical follow-up were $164,960/QALY (95% CI, $116,510 to $766,930/QALY) and $168,750/QALY (95% CI, $117,440 to 853,550/QALY) for CT and PET/CT, respectively. Model conclusions were robust and remained stable on one-way and probabilistic sensitivity analyses.

Conclusion

Our cost-effectiveness analysis suggests surveillance imaging of asymptomatic DLBCL patients in remission offers little clinical benefit at substantial economic costs.


Purpose

Blockade of the programmed death-1 inhibitory cell-surface molecule on immune cells using the fully human immunoglobulin G4 antibody nivolumab mediates tumor regression in a portion of patients with advanced treatment-refractory solid tumors. We report clinical activity, survival, and long-term safety in patients with advanced renal cell carcinoma (RCC) treated with nivolumab in a phase I study with expansion cohorts.

Patients and Methods

A total of 34 patients with previously treated advanced RCC, enrolled between 2008 and 2012, received intravenous nivolumab (1 or 10 mg/kg) in an outpatient setting once every two weeks for up to 96 weeks and were observed for survival and duration of response after treatment discontinuation.

Results

Ten patients (29%) achieved objective responses (according to RECIST [version 1.0]), with median response duration of 12.9 months; nine additional patients (27%) demonstrated stable disease lasting > 24 weeks. Three of five patients who stopped treatment while in response continued to respond for ≥ 45 weeks. Median overall survival in all patients (71% with two to five prior systemic therapies) was 22.4 months; 1-, 2-, and 3-year survival rates were 71%, 48%, and 44%, respectively. Grade 3 to 4 treatment-related adverse events occurred in 18% of patients; all were reversible.

Conclusion

Patients with advanced treatment-refractory RCC treated with nivolumab demonstrated durable responses that in some responders persisted after drug discontinuation. Overall survival is encouraging, and toxicities were generally manageable. Ongoing randomized clinical trials will further assess the impact of nivolumab on overall survival in patients with advanced RCC.


Purpose

Recent literature reports a potential association between high vitamin D and improved lymphoma prognosis. We evaluated the impact of pretreatment vitamin D on follicular lymphoma (FL) outcome.

Patients and Methods

SWOG participants were previously untreated patients with FL enrolled onto SWOG clinical trials (S9800, S9911, or S0016) involving CHOP chemotherapy plus an anti-CD20 antibody (rituximab or iodine-131 tositumomab) between 1998 and 2008. Participants included in our second independent cohort were also previously untreated patients with FL enrolled onto the Lymphoma Study Association (LYSA) PRIMA trial of rituximab plus chemotherapy (randomly assigned to rituximab maintenance v observation) between 2004 and 2007. Using the gold-standard liquid chromatography–tandem mass spectrometry method, 25-hydroxyvitamin D was measured in stored baseline serum samples. The primary end point was progression-free survival (PFS).

Results

After a median follow-up of 5.4 years, the adjusted PFS and overall survival hazard ratios for the SWOG cohort were 1.97 (95% CI, 1.10 to 3.53) and 4.16 (95% CI, 1.66 to 10.44), respectively, for those who were vitamin D deficient (< 20 ng/mL; 15% of cohort). After a median follow-up of 6.6 years, the adjusted PFS and overall survival hazard ratios for the LYSA cohort were 1.50 (95% CI, 0.93 to 2.42) and 1.92 (95% CI, 0.72 to 5.13), respectively, for those who were vitamin D deficient (< 10 ng/mL; 25% of cohort).

Conclusion

Although statistical significance was not reached in the LYSA cohort, the consistent estimates of association between low vitamin D levels and FL outcomes in two independent cohorts suggests that serum vitamin D might be the first potentially modifiable factor to be associated with FL survival. Further investigation is needed to determine the effects of vitamin D supplementation in this clinical setting.













Purpose

Randomized controlled trials have supported integrated oncology and palliative care (PC); however, optimal timing has not been evaluated. We investigated the effect of early versus delayed PC on quality of life (QOL), symptom impact, mood, 1-year survival, and resource use.

Patients and Methods

Between October 2010 and March 2013, 207 patients with advanced cancer at a National Cancer Institute cancer center, a Veterans Affairs Medical Center, and community outreach clinics were randomly assigned to receive an in-person PC consultation, structured PC telehealth nurse coaching sessions (once per week for six sessions), and monthly follow-up either early after enrollment or 3 months later. Outcomes were QOL, symptom impact, mood, 1-year survival, and resource use (hospital/intensive care unit days, emergency room visits, chemotherapy in last 14 days, and death location).

Results

Overall patient-reported outcomes were not statistically significant after enrollment (QOL, P = .34; symptom impact, P = .09; mood, P = .33) or before death (QOL, P = .73; symptom impact, P = .30; mood, P = .82). Kaplan-Meier 1-year survival rates were 63% in the early group and 48% in the delayed group (difference, 15%; P = .038). Relative rates of early to delayed decedents' resource use were similar for hospital days (0.73; 95% CI, 0.41 to 1.27; P = .26), intensive care unit days (0.68; 95% CI, 0.23 to 2.02; P = .49), emergency room visits (0.73; 95% CI, 0.45 to 1.19; P = .21), chemotherapy in last 14 days (1.57; 95% CI, 0.37 to 6.7; P = .27), and home death (27 [54%] v 28 [47%]; P = .60).

Conclusion

Early-entry participants' patient-reported outcomes and resource use were not statistically different; however, their survival 1-year after enrollment was improved compared with those who began 3 months later. Understanding the complex mechanisms whereby PC may improve survival remains an important research priority.


Purpose

The use of multiple and/or inappropriate medications in seniors is a significant public health problem, and cancer treatment escalates its prevalence and complexity. Existing studies are limited by patient self-report and medical record extraction compared with a pharmacist-led comprehensive medication assessment.

Patients and Methods

We retrospectively examined medication use in ambulatory senior adults with cancer to determine the prevalence of polypharmacy (PP) and potentially inappropriate medication (PIM) use and associated factors. PP was defined as concurrent use of five or more and less than 10 medications, and excessive polypharmacy (EPP) was defined as 10 or more medications. PIMs were categorized by 2012 Beers Criteria, Screening Tool of Older Person's Prescriptions (STOPP), and the Healthcare Effectiveness Data and Information Set (HEDIS).

Results

A total of 248 patients received a geriatric oncology assessment between January 2011 and June 2013 (mean age was 79.9 years, 64% were women, 74% were white, and 87% had solid tumors). Only 234 patients (evaluated by pharmacists) were included in the final analysis. Mean number of medications used was 9.23. The prevalence of PP, EPP, and PIM use was 41% (n = 96), 43% (n = 101), and 51% (n = 119), respectively. 2012 Beers, STOPP, and HEDIS criteria classified 173 occurrences of PIMs, which were present in 40%, 38%, and 21% of patients, respectively. Associations with PIM use were PP (P < .001) and increased comorbidities (P = .005).

Conclusion

A pharmacist-led comprehensive medication assessment demonstrated a high prevalence of PP, EPP, and PIM use. Medication assessments that integrate both 2012 Beers and STOPP criteria and consider cancer diagnosis, prognosis, and cancer-related therapy are needed to optimize medication use in this population.



Purpose

To determine the effect of early versus delayed initiation of a palliative care intervention for family caregivers (CGs) of patients with advanced cancer.

Patients and Methods

Between October 2010 and March 2013, CGs of patients with advanced cancer were randomly assigned to receive three structured weekly telephone coaching sessions, monthly follow-up, and a bereavement call either early after enrollment or 3 months later. CGs of patients with advanced cancer were recruited from a National Cancer Institute cancer center, a Veterans Administration Medical Center, and two community outreach clinics. Outcomes were quality of life (QOL), depression, and burden (objective, stress, and demand).

Results

A total of 122 CGs (early, n = 61; delayed, n = 61) of 207 patients participated; average age was 60 years, and most were female (78.7%) and white (92.6%). Between-group differences in depression scores from enrollment to 3 months (before delayed group started intervention) favored the early group (mean difference, –3.4; SE, 1.5; d = –.32; P = .02). There were no differences in QOL (mean difference, –2; SE, 2.3; d = –.13; P = .39) or burden (objective: mean difference, 0.3; SE, .7; d = .09; P = .64; stress: mean difference, –.5; SE, .5; d = –.2; P = .29; demand: mean difference, 0; SE, .7; d = –.01; P = .97). In decedents' CGs, a terminal decline analysis indicated between-group differences favoring the early group for depression (mean difference, –3.8; SE, 1.5; d = –.39; P = .02) and stress burden (mean difference, –1.1; SE, .4; d = –.44; P = .01) but not for QOL (mean difference, –4.9; SE, 2.6; d = –.3; P = .07), objective burden (mean difference, –.6; SE, .6; d = –.18; P = .27), or demand burden (mean difference, –.7; SE, .6; d = –.23; P = .22).

Conclusion

Early-group CGs had lower depression scores at 3 months and lower depression and stress burden in the terminal decline analysis. Palliative care for CGs should be initiated as early as possible to maximize benefits.


Purpose

The outcome for patients with metastatic or recurrent sarcoma remains poor. Adoptive therapy with tumor-directed T cells is an attractive therapeutic option but has never been evaluated in sarcoma.

Patients and Methods

We conducted a phase I/II clinical study in which patients with recurrent/refractory human epidermal growth factor receptor 2 (HER2) –positive sarcoma received escalating doses (1 x 104/m2 to 1 x 108/m2) of T cells expressing an HER2-specific chimeric antigen receptor with a CD28. signaling domain (HER2-CAR T cells).

Results

We enrolled 19 patients with HER2-positive tumors (16 osteosarcomas, one Ewing sarcoma, one primitive neuroectodermal tumor, and one desmoplastic small round cell tumor). HER2-CAR T-cell infusions were well tolerated with no dose-limiting toxicity. At dose level 3 (1 x 105/m2) and above, we detected HER2-CAR T cells 3 hours after infusion by quantitative polymerase chain reaction in 14 of 16 patients. HER2-CAR T cells persisted for at least 6 weeks in seven of the nine evaluable patients who received greater than 1 x 106/m2 HER2-CAR T cells (P = .005). HER2-CAR T cells were detected at tumor sites of two of two patients examined. Of 17 evaluable patients, four had stable disease for 12 weeks to 14 months. Three of these patients had their tumor removed, with one showing ≥ 90% necrosis. The median overall survival of all 19 infused patients was 10.3 months (range, 5.1 to 29.1 months).

Conclusion

This first evaluation of the safety and efficacy of HER2-CAR T cells in patients with cancer shows the cells can persist for 6 weeks without evident toxicities, setting the stage for studies that combine HER2-CAR T cells with other immunomodulatory approaches to enhance their expansion and persistence.


Purpose

Current diagnostic tests for diffuse large B-cell lymphoma use the updated WHO criteria based on biologic, morphologic, and clinical heterogeneity. We propose a refined classification system based on subset-specific B-cell–associated gene signatures (BAGS) in the normal B-cell hierarchy, hypothesizing that it can provide new biologic insight and diagnostic and prognostic value.

Patients and Methods

We combined fluorescence-activated cell sorting, gene expression profiling, and statistical modeling to generate BAGS for naive, centrocyte, centroblast, memory, and plasmablast B cells from normal human tonsils. The impact of BAGS-assigned subtyping was analyzed using five clinical cohorts (treated with cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP], n = 270; treated with rituximab plus CHOP [R-CHOP], n = 869) gathered across geographic regions, time eras, and sampling methods. The analysis estimated subtype frequencies and drug-specific resistance and included a prognostic meta-analysis of patients treated with first-line R-CHOP therapy.

Results

Similar BAGS subtype frequencies were assigned across 1,139 samples from five different cohorts. Among R-CHOP–treated patients, BAGS assignment was significantly associated with overall survival and progression-free survival within the germinal center B-cell–like subclass; the centrocyte subtype had a superior prognosis compared with the centroblast subtype. In agreement with the observed therapeutic outcome, centrocyte subtypes were estimated as being less resistant than the centroblast subtype to doxorubicin and vincristine. The centroblast subtype had a complex genotype, whereas the centrocyte subtype had high TP53 mutation and insertion/deletion frequencies and expressed LMO2, CD58, and stromal-1–signature and major histocompatibility complex class II–signature genes, which are known to have a positive impact on prognosis.

Conclusion

Further development of a diagnostic platform using BAGS-assigned subtypes may allow pathogenetic studies to improve disease management.


Purpose

To determine long-term survival and associated prognostic factors after intraperitoneal (IP) chemotherapy in patients with advanced ovarian cancer.

Patients and Methods

Data from Gynecologic Oncology Group protocols 114 and 172 were retrospectively analyzed. Cox proportional hazards regression models were used for statistical analyses.

Results

In 876 patients, median follow-up was 10.7 years. Median survival with IP therapy was 61.8 months (95% CI, 55.5 to 69.5), compared with 51.4 months (95% CI, 46.0 to 58.2) for intravenous therapy. IP therapy was associated with a 23% decreased risk of death (adjusted hazard ratio [AHR], 0.77; 95% CI, 0.65 to 0.90; P = .002). IP therapy improved survival of those with gross residual (≤ 1 cm) disease (AHR, 0.75; 95% CI, 0.62 to 0.92; P = .006). Risk of death decreased by 12% for each cycle of IP chemotherapy completed (AHR, 0.88; 95% CI, 0.83 to 0.94; P < .001). Factors associated with poorer survival included: clear/mucinous versus serous histology (AHR, 2.79; 95% CI, 1.83 to 4.24; P < .001), gross residual versus no visible disease (AHR, 1.89; 95% CI, 1.48 to 2.43; P < .001), and fewer versus more cycles of IP chemotherapy (AHR, 0.88; 95% CI, 0.83 to 0.94; P < .001). Younger patients were more likely to complete the IP regimen, with a 5% decrease in probability of completion with each year of age (odds ratio, 0.95; 95% CI, 0.93 to 0.96; P < .001).

Conclusion

The advantage of IP over intravenous chemotherapy extends beyond 10 years. IP therapy enhanced survival of those with gross residual disease. Survival improved with increasing number of IP cycles.


Purpose

Trials in castration-resistant prostate cancer (CRPC) need new clinical end points that are valid surrogates for survival. We evaluated circulating tumor cell (CTC) enumeration as a surrogate outcome measure.

Patients and Methods

Examining CTCs alone and in combination with other biomarkers as a surrogate for overall survival was a secondary objective of COU-AA-301, a multinational, randomized, double-blind phase III trial of abiraterone acetate plus prednisone versus prednisone alone in patients with metastatic CRPC previously treated with docetaxel. The biomarkers were measured at baseline and 4, 8, and 12 weeks, with 12 weeks being the primary measure of interest. The Prentice criteria were applied to test candidate biomarkers as surrogates for overall survival at the individual-patient level.

Results

A biomarker panel using CTC count and lactate dehydrogenase (LDH) level was shown to satisfy the four Prentice criteria for individual-level surrogacy. Twelve-week surrogate biomarker data were available for 711 patients. The abiraterone acetate plus prednisone and prednisone-alone groups demonstrated a significant survival difference (P = .034); surrogate distribution at 12 weeks differed by treatment (P < .001); the discriminatory power of the surrogate to predict mortality was high (weighted c-index, 0.81); and adding the surrogate to the model eliminated the treatment effect on survival. Overall, 2-year survival of patients with CTCs < 5 (low risk) versus patients with CTCs ≥ 5 cells/7.5 mL of blood and LDH > 250 U/L (high risk) at 12 weeks was 46% and 2%, respectively.

Conclusion

A biomarker panel containing CTC number and LDH level was shown to be a surrogate for survival at the individual-patient level in this trial of abiraterone acetate plus prednisone versus prednisone alone for patients with metastatic CRPC. Additional trials are ongoing to validate the findings.







Purpose

To investigate the association between blood levels of C-reactive protein (CRP) in patients with melanoma and overall survival (OS), melanoma-specific survival (MSS), and disease-free survival.

Patients and Methods

Two independent sets of plasma samples from a total of 1,144 patients with melanoma (587 initial and 557 confirmatory) were available for CRP determination. Kaplan-Meier method and Cox regression were used to evaluate the relationship between CRP and clinical outcome. Among 115 patients who underwent sequential blood draws, we evaluated the relationship between change in disease status and change in CRP using nonparametric tests.

Results

Elevated CRP level was associated with poorer OS and MSS in the initial, confirmatory, and combined data sets (combined data set: OS hazard ratio, 1.44 per unit increase of logarithmic CRP; 95% CI, 1.30 to 1.59; P < .001; MSS hazard ratio, 1.51 per unit increase of logarithmic CRP; 95% CI, 1.36 to 1.68; P < .001). These findings persisted after multivariable adjustment. As compared with CRP < 10 mg/L, CRP ≥ 10 mg/L conferred poorer OS in patients with any-stage, stage I/II, or stage III/IV disease and poorer disease-free survival in those with stage I/II disease. In patients who underwent sequential evaluation of CRP, an association was identified between an increase in CRP and melanoma disease progression.

Conclusion

CRP is an independent prognostic marker in patients with melanoma. CRP measurement should be considered for incorporation into prospective studies of outcome in patients with melanoma and clinical trials of systemic therapies for those with melanoma.


Poly (ADP-ribose) polymerase (PARP) inhibitors have shown promising activity in epithelial ovarian cancers, especially relapsed platinum-sensitive high-grade serous disease. Consistent with preclinical studies, ovarian cancers and a number of other solid tumor types occurring in patients with deleterious germline mutations in BRCA1 or BRCA2 seem to be particularly sensitive. However, it is also becoming clear that germline BRCA1/2 mutations are neither necessary nor sufficient for patients to derive benefit from PARP inhibitors. We provide an update on PARP inhibitor clinical development, describe recent advances in our understanding of PARP inhibitor mechanism of action, and discuss current issues in the development of these agents.


More than 50 monoclonal antibodies (mAbs), including several antibody–drug conjugates, are in advanced clinical development, forming an important part of the many molecularly targeted anticancer therapeutics currently in development. Drug development is a relatively slow and expensive process, limiting the number of drugs that can be brought into late-stage trials. Development decisions could benefit from quantitative biomarkers, enabling visualization of the tissue distribution of (potentially modified) therapeutic mAbs to confirm effective whole-body target expression, engagement, and modulation and to evaluate heterogeneity across lesions and patients. Such biomarkers may be realized with positron emission tomography imaging of radioactively labeled antibodies, a process called immunoPET. This approach could potentially increase the power and value of early trials by improving patient selection, optimizing dose and schedule, and rationalizing observed drug responses. In this review, we summarize the available literature and the status of clinical trials regarding the potential of immunoPET during early anticancer drug development.


Purpose

The number of long-term survivors after hematopoietic stem-cell transplantation (HSCT) for malignant and nonmalignant disorders is increasing, and late effects are gaining importance. Osteoporosis and fractures can worsen the quality of life of HSCT survivors, but the burden of the disease is unknown.

Patients and Methods

We conducted a retrospective study of patients older than age 18 years who underwent an HSCT at The University of Texas MD Anderson Cancer Center from January 1, 1997, to December 31, 2011, and were observed until December 31, 2013, to ascertain occurrence of fractures. Cumulative incidence rates of fractures were calculated with death as a competing risk. Age- and sex-specific incidence rates per person-year of fracture were compared with those of the US general population by using estimated rates from the 1994 National Health Interview Survey and the 2004 National Hospital Discharge Survey.

Results

A total of 7,620 patients underwent an HSCT from 1997 to 2011 at the MD Anderson Cancer Center of whom 602 (8%) developed a fracture. Age, underlying disease, and HSCT type were significantly associated with fracture. Age- and sex-specific fracture incidence rates after HSCT were significantly greater than those of the US general population in almost all subgroups. The striking difference was an approximately eight times greater risk in females and approximately seven to nine times greater risk in males age 45 to 64 years old when compared with the National Health Interview Survey and National Hospital Discharge Survey fracture rates.

Conclusion

The incidence of fractures is compellingly higher after HSCT.


Purpose

Bortezomib has become a cornerstone in the treatment of AL amyloidosis. In this study, we addressed the prognostic impact of cytogenetic aberrations for bortezomib-treated patients.

Patients and Methods

We analyzed a consecutive series of 101 patients with AL amyloidosis treated with bortezomib-dexamethasone as first-line treatment by interphase fluorescence in situ hybridization (iFISH). Patients were ineligible for high-dose chemotherapy, which would put them at risk for cardiac or renal failure, and thus represented a poor-risk group.

Results

Presence of t(11;14), versus its absence, was associated with inferior hematologic event-free survival (median, 3.4 v 8.8 months, respectively; P = .002), overall survival (median, 8.7 v 40.7 months, respectively; P = .05), and remission rate (≥ very good partial remission; 23% v 47%, respectively; P = .02). In multivariable Cox regression models incorporating established hematologic and clinical risk factors, t(11;14) was an independent adverse prognostic marker for hematologic event-free survival (hazard ratio, 2.94; 95% CI, 1.37 to 6.25; P = .006) and overall survival (hazard ratio, 3.13; 95% CI, 1.16 to 8.33; P = .03), but not for remission (≥ very good partial remission). Markedly, the multiple myeloma high-risk iFISH aberrations t(4;14), t(14;16), del(17p), and gain of 1q21 conferred no adverse prognosis in this bortezomib-dexamethasone–treated group. After backward variable selection, the final multivariable model was validated in a consecutive series of 32 patients treated with bortezomib, dexamethasone, and cyclophosphamide.

Conclusion

iFISH results are important independent prognostic factors in AL amyloidosis. In contrast to our recently published results with melphalan and dexamethasone standard therapy, bortezomib is less beneficial to patients harboring t(11;14), whereas it effectively alleviates the poor prognosis inherent to high-risk aberrations. Given the discrepant response to different treatment modalities, iFISH may help to guide therapeutic choices in these poor-risk patients requiring rapid hematologic response.


Purpose

The efficacy of lapatinib versus trastuzumab combined with taxanes in the first-line setting of human epidermal growth factor receptor 2 (HER2) –positive metastatic breast cancer (BC) is unknown.

Patients and Methods

The MA.31 trial compared a combination of first-line anti-HER2 therapy (lapatinib or trastuzumab) and taxane therapy for 24 weeks, followed by the same anti-HER2 monotherapy until progression. Stratification was by prior (neo)adjuvant anti-HER2 therapy, prior (neo)adjuvant taxane, planned taxane, and liver metastases. The primary end point was intention-to-treat (ITT) progression-free survival (PFS), defined as time from random assignment to progression by RECIST (version 1.0) criteria, or death for patients with locally assessed HER2-positive tumors. The primary test statistic was a stratified log-rank test for noninferiority. PFS was also assessed for patients with centrally confirmed HER2-positive tumors.

Results

From July 17, 2008, to December 1, 2011, 652 patients were accrued from 21 countries, resulting in 537 patients with centrally confirmed HER2-positive tumors. Median follow-up was 21.5 months. Median ITT PFS was 9.0 months with lapatinib and 11.3 months with trastuzumab. By ITT analysis, PFS was inferior for lapatinib compared with trastuzumab, with a stratified hazard ratio (HR) of 1.37 (95% CI, 1.13 to 1.65; P = .001). In patients with centrally confirmed HER2-positive tumors, median PFS was 9.1 months with lapatinib and 13.6 months with trastuzumab (HR, 1.48; 95% CI, 1.20 to 1.83; P < .001). More grade 3 or 4 diarrhea and rash were observed with lapatinib (P < .001). PFS results were supported by the secondary end point of overall survival, with an ITT HR of 1.28 (95% CI, 0.95 to 1.72; P = .11); in patients with centrally confirmed HER2-positive tumors, the HR was 1.47 (95% CI, 1.03 to 2.09; P = .03).

Conclusion

As first-line therapy for HER2-positive metastatic BC, lapatinib combined with taxane was associated with shorter PFS and more toxicity compared with trastuzumab combined with taxane.