Lapatinib

Lapatinib plus Capecitabine for HER2-Positive Advanced Breast Cancer.

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Background

Lapatinib, a tyrosine kinase inhibitor of human epidermal growth factor receptor type 2 (HER2, also referred to as HER2/neu) and epidermal growth factor receptor (EGFR), is active in combination with capecitabine in women with HER2-positive metastatic breast cancer that has progressed after trastuzumab-based therapy. In this trial, we compared lapatinib plus capecitabine with capecitabine alone in such patients.

Methods

Women with HER2-positive, locally advanced or metastatic breast cancer that had progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab were randomly assigned to receive either combination therapy (lapatinib at a dose of 1250 mg per day continuously plus capecitabine at a dose of 2000 mg per square meter of body-surface area on days 1 through 14 of a 21-day cycle) or monotherapy (capecitabine alone at a dose of 2500 mg per square meter on days 1 through 14 of a 21-day cycle). The primary end point was time to progression, based on an evaluation by independent reviewers under blinded conditions.

Results

The interim analysis of time to progression met specified criteria for early reporting on the basis of superiority in the combination-therapy group. The hazard ratio for the independently assessed time to progression was 0.49 (95% confidence interval, 0.34 to 0.71; P<0.001), with 49 events in the combination-therapy group and 72 events in the monotherapy group. The median time to progression was 8.4 months in the combination-therapy group as compared with 4.4 months in the monotherapy group. This improvement was achieved without an increase in serious toxic effects or symptomatic cardiac events.

Conclusions

Lapatinib plus capecitabine is superior to capecitabine alone in women with HER2-positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab. (ClinicalTrials.gov number, NCT00078572.)

Metastatic breast cancer is the leading cause of death from cancer among women worldwide, accounting for more than 400,000 deaths per year.1 Women with breast cancer that overexpresses human epidermal growth factor receptor type 2 (HER2, also referred to as HER2/neu) are at greater risk for disease progression and death than women whose tumors do not overexpress HER2.2 Therapeutic strategies have been developed to block HER2 signaling pathways in order to improve the treatment of this cancer. Trastuzumab (Herceptin, Genentech), a recombinant, humanized, monoclonal antibody that binds to the extracellular domain of the HER2 protein, is a key component in the treatment of metastatic and early-stage HER2-positive breast cancer.3–7

Metastatic breast cancer eventually develops resistance to trastuzumab,8,9 and in some women, the cancer recurs after adjuvant therapy.6,7 For these reasons, there is a need for alternatives to block HER2 signaling. Lapatinib (Tykerb, GlaxoSmithKline) is an orally active small molecule that inhibits the tyrosine kinases of HER2 and epidermal growth factor receptor type 1 (EGFR). In preclinical studies, lapatinib was not cross-resistant with trastuzumab.10–12 The clinical activity of lapatinib in combination with capecitabine has been shown in women with HER2-positive breast cancer that progressed while they were receiving trastuzumab. The adverse-event profile of the combination therapy was similar to that of each drug individually, without relevant pharmacokinetic interactions at the recommended dose and schedule of the combination therapy (lapatinib at a dose of 1250 mg daily and capecitabine at a dose of 2000 mg per square meter of body-surface area daily on days 1 through 14 of a 21-day cycle).13

We conducted a phase 3, randomized, open-label study comparing lapatinib plus capecitabine with capecitabine alone in women with progressive, HER2-positive, locally advanced or metastatic breast cancer who had previously been treated with a minimum of an anthracycline, a taxane, and trastuzumab.

Methods

PATIENTS

Eligible patients had HER2-positive, locally advanced breast cancer (a T4 primary tumor and stage IIIB or IIIC disease) or metastatic breast cancer that had progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab. The HER2 status was considered positive if the local institution reported grade 3+ staining intensity (on a scale of 0 to 3) by means of immunohistochemical analysis or grade 2+ staining intensity by means of immunohistochemical analysis with gene amplification on fluorescence in situ hybridization. Previous therapies had to include, but were not limited to, at least four cycles of regimens that included an anthracycline and a taxane (two cycles if the disease progressed while the woman was receiving therapy) administered concurrently or separately as adjuvant therapy or for metastatic disease. Previous treatment with trastuzumab, alone or in combination with chemotherapy for locally advanced or metastatic disease, for at least 6 weeks was required. Women previously treated with capecitabine were ineligible; previous therapy with fluorouracil was permitted. Patients were required to have measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST), with the criteria modified to include lesions that were 15 to 19 mm in diameter as assessed by means of methods other than spiral computed tomography (CT)14; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; a left ventricular ejection fraction (LVEF) within the institution’s normal range; a life expectancy of at least 12 weeks; and adequate renal, hepatic, and hematologic function. Women with central nervous system (CNS) metastases were eligible if they were clinically stable for at least 3 months after the discontinuation of corticosteroid and anticonvulsant therapy. Women with preexisting heart disease or conditions that could affect gastrointestinal absorption were ineligible.

The institutional review board for each participating institution approved the study protocol. All patients gave written informed consent.

STUDY DESIGN

In this open-label study, women were randomly assigned in a 1:1 ratio to receive lapatinib plus capecitabine or capecitabine alone. Randomization in permuted blocks of six women was performed within strata defined according to disease stage and the presence or absence of visceral disease. The combination regimen consisted of lapatinib at a dose of 1250 mg daily, 1 hour before or after breakfast, on a continuous basis, and capecitabine at a dose of 2000 mg per square meter of body-surface area in two divided doses on days 1 through 14 of a 21-day cycle. Since lapatinib is predominantly metabolized by cytochrome P-450 enzymes (CYP3A4), medications that inhibit or induce CYP3A4 were prohibited (Table 1 of the Supplementary Appendix, available with the full text of this article at http://www.nejm.org). Capecitabine monotherapy was administered at a dose of 2500 mg per square meter of body-surface area in two divided doses on days 1 through 14 of a 21-day cycle.

Standard recommendations for capecitabine dosage modifications were followed for the management of adverse events.15 Lapatinib was withheld for up to 14 days for grade 2 hematologic toxicity or any grade 3 or 4 toxicity. Lapatinib was permanently discontinued if grade 3 or 4 interstitial pneumonitis or cardiac dysfunction occurred. It was also permanently discontinued if improvement (a change to grade 0 or 1) did not occur within 14 days. After recovery from grade 2 hematologic toxicity or grade 3 toxicity, lapatinib was to be resumed at a dose of 1250 mg daily, although the site investigators could reduce the dose to 1000 mg daily after grade 3 toxicity if doing so was thought to be in the woman’s interest. Resumption of lapatinib administration after grade 4 toxicity was optional but required a dose reduction to 1000 mg daily.

Women were assessed every 6 weeks for the first 24 weeks, then every 12 weeks while they were receiving the study treatment. Women without progressive disease for whom the study treatment was withdrawn were assessed every 12 weeks until the commencement of alternative anticancer treatment, disease progression, or death. Efficacy was defined according to RECIST criteria, modified to include lesions that were 15 to 19 mm in diameter as assessed by methods other than spiral CT.14 Adverse events were assessed according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE, version 3.0), which grades events as mild (grade 1), moderate (grade 2), severe (grade 3), life-threatening or disabling (grade 4), or fatal (grade 5). Treatment continued until the investigator identified disease progression or unacceptable toxic effects.

The primary end point was the time to progression, defined as the time from randomization to disease progression or death due to breast cancer. Secondary end points were progression-free survival, defined as the time from randomization to disease progression or death due to any cause; overall survival; the overall response rate; the rate of clinical benefit, defined as a complete response, partial response, or stable disease for at least 6 months; and safety.

For analyses of the time to progression, progression-free survival, the overall response rate, and the clinical benefit rate, copies of serial radiographs and photographs of visible lesions used for efficacy determinations were collected for independent assessment under blinded conditions. Supportive analyses of these end points were conducted with the use of investigator-reported assessments.

CARDIAC EVALUATION

Evaluation of the LVEF by means of echocardiography or multiple gated acquisition scanning was performed at the time of the efficacy assessments with the use of the same technique for the duration of the study. A cardiac event was defined as a decline in the LVEF that was symptomatic, regardless of the degree of decline or was asymptomatic but with a relative decrease of 20% or more from baseline to a level below the institution’s lower limit of the normal range. Lapatinib was discontinued in patients with symptomatic cardiac events (CTCAE grade 3 or 4). For asymptomatic events, lapatinib was withheld and could be resumed at a dose of 1000 mg per day if the LVEF 2 to 3 weeks later was at or above the institution’s lower limit of the normal range.

STATISTICAL ANALYSIS

We calculated that a total of 266 time-to-progression events would be required to achieve a statistical power of 90%, with a two-sided, 5% type I error, to detect a 50% increase in the median time to progression (from an estimated 3 months in the group receiving capecitabine alone to 4.5 months in the group receiving lapatinib plus capecitabine). An analysis of overall survival was to be performed after 457 deaths had occurred, giving a statistical power of 80% to detect a 30% increase in median survival (from 8 months in the monotherapy group to 10.4 months in the combination-therapy group). To meet both of these requirements, an enrollment of 528 women was planned.

The intention-to-treat population, comprising all women who underwent randomization, was used for the analyses of efficacy data. Log-rank tests stratified according to the stage of disease and the presence or absence of visceral disease were used to analyze time-to-event end points, and Fisher’s exact tests were used for tumor-response rates. To account for the risk of death that was not related to breast cancer, cumulative incidence curves were used to summarize the time to progression. Kaplan–Meier curves were used to summarize progression-free survival and overall survival.

An independent data and safety monitoring committee reviewed the safety and efficacy data. A planned interim analysis of disease progression was to be conducted after approximately 133 independently assessed events. The date of the data lock to initiate the independent review and interim analysis was to be determined by the number of events reported by the investigators. To adjust for differences between the assessments by the independent reviewers and the investigators’ assessments, the date for the interim-analysis data lock was set to allow investigator-reported events to be approximately 10% higher than 133. The final analysis would occur after 266 independently assessed disease-progression events had occurred. For patients in whom progressive disease was not confirmed by independent review or who did not die, the time to progression was censored at the date of the last independent assessment and before the initiation of alternative anticancer therapy. Reporting of the data would be considered at the time of the interim analysis if the P value from a stratified log-rank test for the time to progression was below a prespecified level. One-sided O’Brien–Fleming boundaries16 at a 2.5% significance level were to be used to assess the superiority or futility of combination therapy as compared with that of capecitabine alone. The study would continue until the final analysis if a stopping boundary was not crossed at the interim analysis.

The study was funded and conducted by GlaxoSmithKline. It was designed by two of the authors, who are employees of the sponsor, with input from participating academic investigators. The interim analyses were conducted by an independent statistician and presented to the data and safety monitoring committee without disclosure to the academic investigators or the sponsor. After the committee’s recommendation to close accrual and report the results, complete analyses were supervised by an employee of the sponsor and reviewed along with the raw data by both academic investigators and employees of the sponsor. The authors vouch for the completeness and accuracy of the results. All of the authors reviewed the results of the analyses and contributed to the writing of the manuscript.

Results

Enrollment began on March 29, 2004, and on the basis of investigator-reported disease-progression events, November 15, 2005, was chosen for the data lock. As of this latter date, 146 disease-progression events had been reported in 324 patients. Vital status and disease assessments for 274 patients were available for independent evaluation, which documented 114 disease-progression events. The first assessments for response had yet to be performed for 39 women who had been receiving therapy for less than 6 weeks. The assessments of 11 women were unavailable. Corresponding one-sided O’Brien–Fleming boundaries were calculated on the basis of 114 disease-progression events for the log-rank test; the superiority boundary was P≤0.0014 and the futility boundary was P≥0.4516. After a review on March 20, 2006, the data and safety monitoring committee recommended reporting the study results, notifying women of the results, and offering lapatinib with capecitabine to women in the monotherapy group. To ensure that all relevant data up to the November 15, 2005, cutoff date were included, a data-validation process was conducted, and the analyses were repeated. We report the results of these analyses.

PATIENT POPULATION

Figure 1 shows the numbers of women who received the assigned study treatment, the numbers for whom assessment data were available, and the numbers of disease-progression events. Seven unreported deaths due to breast cancer occurred before the data lock and were not included in the review by the monitoring committee. With these deaths included, 121 independently assessed disease-progression events had occurred by the time of the data lock. These events form the basis of the analyses presented here.

FIGURE 1

Study Design, Randomization, and Assessment of Disease-Progression Events.

The baseline characteristics of the women were similar in the two treatment groups (Table 1). Most of the women (96%) had metastatic disease, 97% had received an anthracycline, and 97% had received a taxane. Trastuzumab had been administered to 97% of women (as treatment for metastatic disease in 91% and only as adjuvant or neoadjuvant treatment in 5%). The median time from discontinuation of trastuzumab to randomization was 5.3 weeks in the combination-therapy group and 6.0 weeks in the monotherapy group. The median duration of previous treatment with trastuzumab was 42 weeks in the combination-therapy group and 44 weeks in the monotherapy group.

TABLE 1

Baseline Characteristics of the 324 Women Included in the Analysis.

DELIVERED THERAPY AND COMPLIANCE WITH DISEASE ASSESSMENT SCHEDULE

A total of 155 of 163 women in the combination-therapy group (95%) and 145 of 161 women in the monotherapy group (90%) received the randomly assigned treatment. The median daily doses of administered capecitabine per cycle were 2000 mg per square meter of body-surface area in the combination-therapy group and 2377 mg per square meter in the monotherapy group. The median daily dose of lapatinib in the combination-therapy group was 1250 mg. Compliance with the timing of the assessment schedule was similar in the two groups (Figure 1 of the Supplementary Appendix).

INTERIM ANALYSIS OF DISEASE-PROGRESSION EVENTS

On March 20, 2006, the data and safety monitoring committee reviewed the interim analysis based on 114 disease-progression events. Forty-five disease-progression events occurred in the combination-therapy group and 69 occurred in the monotherapy group (hazard ratio for disease progression, 0.51; 95% confidence interval [CI], 0.35 to 0.74; P<0.001). The one-sided P value of 0.00016 ensured that the superiority boundary (P=0.0014), recalculated for 114 events, was crossed.

PRIMARY END-POINT ANALYSIS AFTER DATA VALIDATION

After the data validation, the analyses were repeated on the basis of the 121 disease-progression events assessed by the independent reviewers. Progressive disease accounted for 101 of the events; 20 were breast cancer–related deaths. Forty-nine disease-progression events occurred in the combination-therapy group, and 72 occurred in the monotherapy group (hazard ratio, 0.49; 95% CI, 0.34 to 0.71; P<0.001) (Figure 2A). The one-sided P value of 0.00004 showed that the superiority boundary that was recalculated for 121 events (P=0.0019) had also been crossed. The median time to progression was 8.4 months with combination therapy and 4.4 months with monotherapy. A Cox regression model indicated that the only significant effect on time to progression was the treatment assignment. Although the assumption of proportional hazards was not met, the model indicated that the average hazard ratio for the combination therapy as compared with capecitabine alone was 0.47 (95% CI, 0.32 to 0.68; P<0.001).

FIGURE 2

Cumulative Incidence of Disease Progression or Death from Breast Cancer According to the Assessment of the Independent Review Committee (Panel A), Kaplan–Meier Estimates of Overall Survival (Panel B), and Cumulative Incidence of Disease Progression or Death from Breast Cancer According to the Site Investigators’ Assessments (Panel C).

SECONDARY END POINTS

The overall response rate was 22% (95% CI, 16 to 29) in the combination-therapy group and 14% (95% CI, 9 to 21) in the monotherapy group (P=0.09). The corresponding clinical-benefit rates were 27% for the combination-therapy group and 18% for the monotherapy group (Table 2). Forty-nine events (disease progression or death from any cause) occurred in the combination-therapy group, and 76 occurred in the monotherapy group (hazard ratio for disease progression or death from any cause in the combination-therapy group, 0.47; 95% CI, 0.33 to 0.67; P<0.001). Thirty-six deaths occurred in the combination-therapy group, and 35 occurred in the monotherapy group (hazard ratio, 0.92; 95% CI, 0.58 to 1.46; P=0.72) (Figure 2B).

TABLE 2

Efficacy End Points in the Intention-to-Treat Population.

CNS AS THE SITE OF FIRST PROGRESSION

In the monotherapy group, 11 women had progressive CNS metastases, as compared with 4 women in the combination-therapy group. This difference was not statistically significant (P=0.10 by Fisher’s exact test).

SUPPORTIVE ANALYSES

An analysis of the investigator-assessed time to progression, based on the date of disease progression or death due to breast cancer, was conducted for the first 133 of the 146 reported disease-progression events. The subsequent 13 events were censored for this analysis. Investigators reported 59 disease-progression events in the combination-therapy group and 74 in the monotherapy group (hazard ratio for disease progression in the combination-therapy group, 0.59; 95% CI, 0.42 to 0.84; P=0.002) (Figure 2C). The median time to progression was 5.9 months in the combination-therapy group and 4.3 months in the monotherapy group. Investigator-assessed response rates were 29% (95% CI, 23 to 37) in the combination-therapy group and 17% (95% CI, 11 to 24) in the monotherapy group (P=0.01).

Table 2 of the Supplementary Appendix shows a 75% concordance between the assessments of time to progression that were made by the independent reviewers and the assessments made by the investigators. The primary reasons for differences were alternative interpretations of lesions and selection of different lesions by reviewers. In a sensitivity analysis with the use of the earliest disease-progression event assessed by the investigator or by the independent reviewers, there were 167 events: 74 in the combination-therapy group and 93 in the monotherapy group (hazard ratio for progression, 0.59; 95% CI, 0.43 to 0.80; P<0.001).

ADVERSE EVENTS

Table 3 shows adverse events through November 15, 2005, according to the treatment received. The most common adverse events were diarrhea, the hand–foot syndrome, nausea, vomiting, fatigue, and rash that was distinct from the hand–foot syndrome. Most adverse events were grade 1, 2, or 3. Grade 4 diarrhea occurred in two women in the combination-therapy group (1%). One case each of grade 4 fatigue, headache, and dizziness was reported in the monotherapy group. Diarrhea, dyspepsia, and rash occurred more often in the group of women who received combination therapy. Five women had a fatal adverse event: two in the combination-therapy group and three in the monotherapy group. The death of one woman in the monotherapy group, who had diarrhea, vomiting, and small-bowel obstruction, was deemed by the investigator to be related to drug toxicity. Adverse events led to discontinuation of treatment in 22 women in the combination-therapy group (13%) and in 18 women in the monotherapy group (12%).

TABLE 3

Adverse Events.

CARDIAC SAFETY

Asymptomatic cardiac events were identified in four women in the combination-therapy group and in one woman in the monotherapy group. All of these events in the combination-therapy group were considered to be related to treatment, and all women had an LVEF value that was at or above the lower limit of the normal range on subsequent assessment. Prinzmetal’s angina developed in one of the four women. It resolved when the study treatment was permanently discontinued, but there was a subsequent drop in the LVEF. An asymptomatic cardiac event occurred in one of the four women after tumor progression, and in the remaining two women, treatment with lapatinib was resumed at a dose of 1000 mg daily without recurrence of a cardiac event. The cardiac event in the monotherapy group was deemed to be unrelated to treatment and did not resolve. There were no symptomatic cardiac events, and lapatinib was not discontinued because of a decrease in the LVEF. There were no differences in the mean LVEF values between the two groups at scheduled assessments (Figure 2 of the Supplementary Appendix).

Discussion

This phase 3, randomized study compared lapatinib plus capecitabine with capecitabine alone in women with advanced, progressive HER2-positive breast cancer who had received multiple previous treatments. The interim analysis showed that the addition of lapatinib to capecitabine was associated with a 51% reduction in the risk of disease progression. The early reporting boundary for superiority was crossed. The median time to progression was 8.4 months in the combination-therapy group and 4.4 months in the monotherapy group. On the basis of the efficacy analysis and the absence of concern about safety, the data and safety monitoring committee recommended terminating enrollment and reporting the results.

To minimize ascertainment bias, the determination of the primary end point (time to progression) was based on an assessment of disease status by independent reviewers under blinded conditions. This design is consistent with the guidelines of the Food and Drug Administration.17 The independent reviewers identified different and fewer disease-progression events than did the investigators, but the rates of discordance were similar for the two treatment groups, and despite the differences, there was a consistent, statistically significant reduction in disease-progression events with lapatinib plus capecitabine. The sensitivity analysis provides support for the strength of the findings.

As compared with capecitabine alone, lapatinib plus capecitabine was not associated with an increase in either serious toxic effects or rates of discontinuation related to adverse events. There were no withdrawals from treatment due to declines in LVEF, no cases of congestive heart failure, and no decreases in the mean LVEF values in the group receiving lapatinib. There was a bias, because we selected women for this study who had normal cardiac function after they had received therapies that included trastuzumab. Also, since the duration of observation was limited, the possibility of late events cannot be excluded. Nevertheless, the low incidence of adverse cardiac effects of lapatinib is reassuring.

The development of CNS metastases is an important clinical problem occurring in approximately one third of women with metastatic breast cancer who receive trastuzumab.18,19 Although CNS disease developed in a small number of women during this study, it occurred in fewer women in the combination-therapy group than in the monotherapy group (4 vs. 11); the difference was not statistically significant.

This trial shows that lapatinib, a small-molecule, tyrosine kinase inhibitor that blocks downstream signaling pathways of HER2 and EGFR through inhibition of the autophosphorylation sites on the receptors,10,12,20 has clinical activity in HER2-positive breast cancer. The results provide support for the use of lapatinib and capecitabine in women with progression of HER2-positive breast cancer after treatment with trastuzumab. The findings also warrant evaluation of the role of lapatinib, which has a mechanism of action distinct from that of trastuzumab, earlier in the treatment of HER2-positive breast cancer.

Perils of the Pathologic Complete Response

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In May 2012, the US Food and Drug Administration (FDA) announced a fundamental shift in the accelerated approval process by supporting the use of the pathologic complete response (pCR) as a surrogate end point.1 The underlying assumption is that improvements in pCR are “reasonably likely to predict clinical benefit,” which the FDA defines as clinically and statistically significant improvement in event-free survival (EFS), disease-free survival (DFS), or overall survival (OS).1 Shortly afterward, the FDA approved the anti-human epidermal growth factor receptor 2 (HER2) antibody pertuzumab on the basis of the phase II NeoSphere randomized trial that showed a significant improvement in the pCR rate from 21.5% to 39.3%.2,3 To date, there have been no data that suggest pertuzumab improves EFS, DFS, or OS in the neoadjuvant setting.

The potential of the pCR to expedite the testing of cancer therapies is undeniable. The effect size on the pCR can be quite large, which substantially reduces the required sample size. The event is almost immediately observable, which dramatically reduces the time required until trial completion. Furthermore, improvement in the pCR rate objectively demonstrates efficacy of the agent against the primary tumor.

Despite the potential as a surrogate end point, the results seen with lapatinib sound a cautionary note. In the NeoALTTO (Lapatinib With Trastuzumab for HER2-Positive Early Breast Cancer) study, lapatinib and trastuzumab were compared with trastuzumab alone in the neoadjuvant setting.4 The pCR rate was increased from 29.5% to 51.3%, a larger absolute difference than in the NeoSphere (Efficacy and Safety of Neoadjuvant Pertuzumab and Trastuzumab in Women With Locally Advanced, Inflammatory, or Early HER2-Positive Breast Cancer) trial. Nonetheless, the first report of the subsequent ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization) randomized trial, which included 8,381 women with HER2-positive breast cancer showed that the addition of lapatinib to trastuzumab did not lead to any improvement in DFS (4-year DFS: 88% v 86%) or OS (4-year OS: 95% v94%) in the adjuvant setting.5

We would argue that an increase in pCR that failed to lead to improved survival is actually not surprising. Despite the desire for an effective surrogate end point, there is little evidence that trial-level pCR is an effective surrogate for survival.

 Correlation Between pCR and Outcomes

In 1998, the National Surgical Adjuvant Breast and Bowel Project (NSABP) began enrollment of the B-18 trial, which randomly assigned women to four cycles of doxorubicin and cyclophosphamide given either pre- or postoperatively.6 OS was not improved, but the effects of chemotherapy on the primary tumor were intriguing. pCR in the breast was seen in 13% of women treated preoperatively, and these women seemed to have improved outcomes (DFS hazard ratio [HR], 0.47; OS HR, 0.32). Subsequent studies have confirmed the correlation between pCR and favorable outcomes in many cancer types including breast,7,8 rectal,9 esophageal,10 and bladder cancers.11

In light of the strong individual-level association between pCR and survival, many have inferred that improvement in the pCR rate could be considered a surrogate for improvement in survival at the trial level. Unfortunately, a substantial body of literature calls into question the ability of the pCR to fulfill the conditions required to establish a preliminary end point as a surrogate for the final end point.

pCR Rate as a Surrogate End Point

It is a maxim of statistics that correlation does not necessarily imply causation. Similarly, correlation does not necessarily imply surrogacy. In both causation and surrogacy, the relationship must be proven by additional conditions. Prentice12 stated that the effect of a treatment on a surrogate end point should fully capture any effect on the final end point. A robust method to quantitatively establish the degree to which the effect on the proposed surrogate end point is reflected in changes in the final end point was proposed by Buyse et al.13 This method entailed a meta-analysis of multiple trials in which the effects of a treatment on the presumptive surrogate end point were compared with the effect of the treatment on the final end point through regression analysis. The coefficient of determination (R2) provides a quantitative estimate of how well changes in the presumptive surrogate end point predict changes in the final end point. For reference, an R2 of 0 indicates no association and an R2 of 1 is a perfect association. An R2 of 0.75 is often considered to be an acceptable level to determine surrogacy.14

To evaluate the surrogacy of pCR, Cortazar et al,8 with the support of the FDA, performed a meta-analysis of individual patient data for almost 9,440 women with breast cancer from 10 randomized trials who were treated with neoadjuvant therapy followed by surgery. The authors found that the R2 values for pCR as a surrogate for EFS and OS were extremely low at 0.03 (95% CI, 0.00 to 0.25) and 0.24 (95% CI, 0.00 to 0.70), respectively. Furthermore, the positive slope of the regression lines implies that treatments with a larger effect on pCR actually correlated with worse survival!

Berruti et al15 subsequently performed a meta-regression of 29 trials that included 14,641 women treated with neoadjuvant therapy before surgery. Again, minimal association between the effect of the treatment on pCR and the effect on EFS (R2, 0.08; 95% CI, 0.00 to 0.47) or OS (R2, 0.09; 95% CI, 0.01 to 0.41) was observed. The implications for approving therapies based on an improvement in pCR can be can be seen by looking at the individual studies in which the experimental therapy improved the pCR rate by at least a factor of two (odds ratio ≥ 2, the approximate effect seen in the NeoALTTO and NeoSphere trials) or improved survival by 20% (HR < 0.8, the improvement the ALTTO study was powered to detect) (Table 1). Of the 10 trials with improvement in pCR, four failed to show improvement in OS leading to a false-positive rate of 40%. In addition, three of nine experimental therapies that improved OS > 20% would have been falsely assumed to be ineffective for a false-negative rate of 33%.

Surrogacy of pCR for OS Among Breast Cancer Studies in Which the Experimental Therapy Improved the pCR Rate or Improved Survival

 

Proposed Explanations for the Lack of Surrogacy

Some have argued that the pCR rate might be an effective surrogate in certain breast cancer subtypes, including HER2-positive and triple-negative breast cancers.8,15,31The I-SPY 1 (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis) trial found that the association between pCR and relapse-free survival was stronger when analyzing the subsets separately.31 This is likely because hormone receptor–positive patients are less likely to achieve pCR but have more favorable outcomes in general. It is true that the correlation between pCR and outcome is stronger within the HER2-positive and triple-negative subgroups. However, the Cortazar et al8 study specifically analyzed these subgroups and found that despite the strong correlation, there is no evidence of surrogacy within the HER2-positive or triple-negative subgroups.

Berry and Hudis32 proposed some statistical considerations that merit discussion. First, they state that the Cortazar et al8 study lacked the power to rule out the possibility of surrogacy. In fact, the upper 95% CIs of the R2 for surrogacy of pCR on EFS in the Cortazar et al8 and Berruti et al15 studies were 0.25 and 0.47, respectively, far short of the 0.75 required to establish surrogacy. They also propose that treatments with a larger impact on pCR might translate to improvements in OS. This is possible. However, it is worth noting that the NeoALTTO study showed one of the largest absolute improvements in pCR, larger even than the NeoSphere trial. Nonetheless, no impact on survival was noted in a trial of more than 8,000 women.5

Lack of Surrogacy in Neoadjuvant Rectal Cancer Trials

The lack of surrogacy is seen in most settings in which the surrogacy of pCR is tested.33–36 Bonnetain et al33 analyzed pooled individual patient data from two randomized rectal cancer trials evaluating the effect of chemoradiation versus radiation alone before surgery on pCR and OS. pCR was increased from 3.7% to 11.2% (P < .001). However, there was no improvement in OS (5-year OS: 65.9% v66.3%). To test pCR as a surrogate for OS, patients were grouped into trial units and the effect on pCR was compared with the effect on OS in the trial units. For reference, the R2 of progression-free survival as a surrogate for OS was 0.88 (95% CI, 0.77 to 1). In contrast, the R2 of the pCR as a surrogate for OS was 0.11 (95% CI, 0.0 to 0.44) indicating poor surrogacy.

The Radiation Therapy Oncology Group (RTOG) 0247 (A Randomized, Phase 2 Study of Neoadjuvant Radiation Therapy Plus Concurrent Capecitabine and Irinotecan or Capecitabine and Oxaliplatin for Patients With Locally Advanced Rectal Cancer) study was a randomized phase II trial of preoperative radiation and capecitabine with irinotecan or oxaliplatin for patients with rectal cancer. Owing to a lower pCR rate, the irinotecan arm was rejected.34 Although not powered to detect a statistical difference, further follow-up showed that the irinotecan arm actually had a numerically superior survival (4-year OS: 85% v 75%; P > .05).35 Determining future studies on the basis of pCR would have led to the mistaken decision to reject the capecitabine/irinotecan regimen from further study, because longer follow-up showed this regimen was at least equivalent to capecitabine/oxaliplatin in terms of survival.

Paradox of the pCR

Patients who achieve a pCR have more favorable outcomes than those who do not; it would therefore seem logical that a therapy that increases the number of patients with a pCR should lead to more patients being cured of their disease. However, high-quality evidence suggests that this is not necessarily true. Although it is not entirely clear why improvements in pCR fail to translate into improvements in OS, we propose three clear limitations of the pCR that may lead to the poor surrogacy demonstrated in multiple studies.

First, the pCR measures the effect of a therapy only on the primary tumor. Cancer is not simply the primary tumor, but is also the potential micrometastatic systemic disease. The effect of a therapy on micrometastases outside the local tumor is likely to be the primary driver of improved outcomes. These residual clonogenic cells may be phenotypically or genotypically different from most cells in the primary tumor37,38and may not respond to therapies that are effective against the primary tumor.39

Second, effective therapies may not necessarily lead to pCR. The clearest example is the low rate of pCR after hormonal therapy despite the dramatic impact on survival. Breakthrough medications of the future may work by affecting circulating tumor cells, premetastatic niches, immune activation, or other mechanisms not measured by the effect on the primary tumor.

Third, the additional pCRs that are achieved from an investigational therapy may simply occur in patients who would have been cured by the standard therapy alone. An investigational therapy that increases the rate of pCR in the group of patients who are likely to have been cured with standard therapy alone will lead to a strong association between pCR and improved survival at the individual level. It may not, however, lead to improved cancer outcomes.

Pertuzumab and other therapies that improve the pCR rate may in fact become effective medications. However, a higher standard should be expected before exposing patients to the risk of severe or fatal toxicities40–42 and increased costs43from experimental therapies, or abandoning potentially effective therapies.34,35Unfortunately, the allure of quicker results is driving a major shift in the design of clinical trials. Our analysis of the trials listed on ClinicalTrials.gov44 found that pCR is the primary end point of approximately 50% of the currently enrolling phase II rectal cancer trials and 45% of the phase III breast cancer trials of preoperative therapy. Effectively, many ongoing clinical trials could be compromised by the choice to use the pCR as a primary end point despite strong evidence that it does not function as an effective surrogate for survival.

In summary, pCR is a favorable prognostic factor for individual patients undergoing treatment. Within the context of a clinical trial, clinicians may be able to reduce the intensity of subsequent therapy for patients who achieve a pCR. However, a substantial body of data suggests that improvements in the pCR from an experimental therapy cannot be considered a surrogate for improved EFS or OS at the trial level. Promoting therapies on the basis of an increase in the pCR rate may lead to approval of therapies that increase toxicity without improving survival. Conversely, rejecting a therapy on the basis of a failure to improve the pCR may lead to the abandonment of therapies that could have resulted in favorable survival outcomes.

Dual anti-HER2 therapy shows early tumour shrinkage in breast cancer study

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Rapid tumour shrinkage seen with lapatinib/trastuzumab combination therapy in patients with operable, newly-diagnosed HER2-positive breast cancer is raising the hope that clinicians will be able to identify patients who can be spared from chemotherapy in the future.

In the EPPHOS-B study, about a quarter of patients who received the lapatinib/trastuzumab combination as neoadjuvant therapy achieved early pathological complete response (pCR) in the breast or minimal residual disease (MRD, defined as <5 mm invasive tumour) after 11 days of treatment. [European Breast Cancer Conference 2016, abstract 6LBA]

“The early and significant tumour regression seen with dual anti-HER2 therapy suggests that we may be able to identify patients who can avoid subsequent chemotherapy on the basis of early response,” said lead investigator Dr. Nigel Bundred of the University Hospital of South Manchester NHS Foundation Trust, Manchester, UK.

EPPHOS-B is a multi-centre, two-part study designed to measure the effect of 10-12 days of neoadjuvant anti-HER2 therapy on tumour cell proliferation and apoptosis in patients with newly-diagnosed HER2-positive breast cancer. In part 1 of the study, 130 patients were randomized to receive no neoadjuvant treatment (n=22), trastuzumab only (n=57), or lapatinib only (n=51).

“Emerging evidence on the efficacy of combination anti-HER2 therapy led to amendment to the design of part 2, where patients were randomized to receive no neoadjuvant treatment [n=29], trastuzumab only [n=32], or lapatinib in combination with trastuzumab [n=66],” said Bundred.

“Among patients treated with the lapatinib/trastuzumab combination, 16.7 percent achieved MRD, while 10.6 percent achieved pCR in the breast,” he reported. “In contrast, the rate of MRD in the trastuzumab group was 3.1 percent. None of the patients treated with trastuzumab alone achieved pCR in the breast. Similarly, no patient in the control group achieved MRD or pCR in the breast.”

The investigators, however, urge caution in interpreting the study’s results. “We have no evidence that the lapatinib/trastuzumab combination would be effective for any patient other than those with newly-diagnosed HER2-positive breast tumours. In addition, we do not yet know what effect the treatment will have on long-term survival,” they wrote in a statement. “Further trials will be needed before we can confirm these results, even in HER2-positive patients.”

Breast cancer study finds ‘astonishing’ drug combination that gives results .

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Using Herceptin in combination with another drug can shrink tumours in less than two weeks, study finds.

The findings could potentially lead to fewer women needing chemotherapy, researchers say.

Using Herceptin in combination with another drug before surgery shrinks and may even destroy tumours in women with an aggressive form of breast cancer in less than two weeks, an “astonishing” study suggests.

The results of the Cancer Research UK-funded trial, presented at the 10th European Breast Cancer Conference in Amsterdam, could – if successfully replicated – lead to fewer women needing chemotherapy.

Around a quarter of 66 women with HER2 positive breast cancer treated for 11 days with both trastuzumab (the generic name for Herceptin) and lapatinib saw their tumours rapidly shrink significantly or even disappear.

Prof Nigel Bundred, from the University of Manchester and the University Hospital of South Manchester NHS foundation trust, who presented the data, said: “This has groundbreaking potential because it allows us to identify a group of patients who, within 11 days, have had their tumours disappear with anti-HER2 therapy alone and who potentially may not require subsequent chemotherapy.

“This offers the opportunity to tailor treatment for each individual woman.”

Samia al Qadhi, chief executive at Breast Cancer Care, said: “The astonishing findings in this study show that combining these two drugs has the potential to shrink HER2 positive breast cancer in just 11 days.

“For some HER2 positive breast cancer patients the effect of this drug combination will be amazing and mean they can avoid chemotherapy and its gruelling side effects completely. For others, their tumours may not shrink, but doctors will know either way very quickly, giving them the ability to rapidly decide on further treatment.

“Although an early study, this has game changing potential. Yet before this can be made available we need to see more evidence. Particularly because, at present, trastuzumab’s (Herceptin) licensing means it is only available to be used alongside chemotherapy and not alone. All cancer patients deserve access to clinically effective treatments.”

Trial co-leader Prof Judith Bliss, director of the clinical trials and statistics unit at the Institute of Cancer Research, London, said: “It was unexpected to see quite such dramatic responses to the trastuzumab and lapatinib within 11 days.

“Our results are a strong foundation on which to build further trials of combination anti-HER2 therapies prior to surgery – which could reduce the number of women who require subsequent chemotherapy, which is also very effective but can lead to long-term side effects.”

The trial, led by researchers from Manchester University, the University Hospital of South Manchester NHS foundation trust and the Institute of Cancer Research, studied 257 women with HER2 positive breast cancer in the short gap between their initial diagnosis and surgery to remove their tumours.

Initially women were randomised to receive either trastuzamab or lapatinib or no treatment. Halfway through the trial, after evidence from other trials of the effectiveness of the combination, the design was changed so that additional women allocated to the lapatinib group were also prescribed trastuzumab.

Of the women receiving both, 17% had only minimal residual disease – defined as an invasive tumour smaller than 5mm in size – and 11% had no biological sign of invasive tumour in the breast. Of the women treated with trastuzumab only, 3% had residual disease or complete response.

HER2 positive breast cancer is more likely to come back after treatment than some other types of breast cancer. It is generally treated with surgery, chemotherapy, endocrine therapy and targeted anti-HER2 drugs.

Current treatments are effective, and complete response is common after three to four months, but observing a disease response so quickly took the researchers by surprise.

In the UK, around 53,000 women a year are diagnosed with invasive breast cancer, and in 10% to 15% of these cases it is HER2 positive breast cancer. Around 11,500 women die from the disease every year.

Herceptin was approved by the National Institute for Health and Care Excellence (Nice) 10 years ago after pressure from patients. Lapatinib has not been approved and so is not routinely available on the NHS due to its expense.

According to Cancer Research UK, current treatments are effective, and women often experience a complete response after three to four months. Nevertheless, researchers said the 11-day response was very surprising.

Prof Arnie Purushotham, senior clinical adviser at Cancer Research UK, said: “These results are very promising if they stand up in the long run and could be the starting step of finding a new way to treat HER2 positive breast cancers.

“This could mean some women can avoid chemotherapy after their surgery – sparing them the side-effects and giving them a better quality of life.”

Neoadjuvant Trastuzumab or Lapatinib With Standard Chemotherapy for HER2+ Breast Cancer.

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ABSTRACT

BACKGROUND

The addition of trastuzumab (T) and lapatinib (L) to neoadjuvant chemotherapy increases the pathological complete response (pCR) rate in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. We investigated the efficacy of T or L with neoadjuvant chemotherapy and specific efficacy biomarkers.

METHODS

Patients with stages I–III (including inflammatory) HER2-positive breast cancer were randomised to receive epirubicin (E) plus cyclophosphamide (C) × 4 cycles followed by docetaxel (D) plus either T (EC-DT) or L (EC-DL). End points included pCR (primary), clinical response, toxicity, and pCR-predictive biomarkers.

RESULTS

We randomised 102 patients to EC-DT (50) and EC-DL (52). Median age was 48, 56% were premenopausal and 58% had oestrogen receptor (ER)-positive tumours. Pathological complete response in breast was 52.1% (95% CI:38.0–66.2%) for EC-DT and 25.5% (95% CI:13.5–37.5%) for EC-DL (P=0.0065). Pathological complete response in breast and axilla was 47.9% for EC-DT and 23.5% for EC-DL (P=0.011). Grade 3–4 toxicity did not differ across treatments, except for diarrhoea (2% in EC-DT vs 13.5% in EC-DL, P=0.030). Multivariate analyses showed that treatment (P=0.036) and ER (P=0.014) were the only predictors of pCR in both groups.

CONCLUSION

EC-DT exhibited higher efficacy and lower toxicity than EC-DL. Of the different biomarkers studied, only the absence of ER expression was associated with increased pCR.

Systemic Treatment for Brain Metastases from HER2-Positive Breast Cancer.

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Two thirds of patients achieved a partial response; half experienced grade 3 or 4 adverse effects.

As new targeted agents have improved outcomes in HER2-positive breast cancer, studies have suggested that survivors might have a longer time to be at risk for developing brain metastases. Radiation therapy is the mainstay for treatment of breast-cancer brain metastases, but it causes adverse effects, and whole-brain radiotherapy (WBRT) impairs cognitive function. Alternatively, systemic therapy seems to have relatively little penetration into the central nervous system (CNS), and evidence of it producing a CNS antitumor effect is lacking. However, recent studies have shown that the oral tyrosine kinase inhibitor lapatinib — administered as monotherapy or in combination with capecitabine — might be an effective treatment. To determine whether this approach could delay radiation therapy, French investigators conducted an industry-funded, single-arm, open-label, phase II (LANDSCAPE) trial of lapatinib and capecitabine involving 44 evaluable patients with HER2-positive breast cancer who had not received whole brain radiotherapy (WBRT).

Treatment was administered in 21-day cycles: patients received oral lapatinib (1250 mg) daily and oral capecitabine (2 gm/m2) on days 1 to 14. Clinical assessments of toxicity and neurological effects were conducted every 3 weeks. Patients underwent computed tomography and magnetic resonance imaging studies to detect CNS lesions every 6 weeks. More than 90% of patients had received prior trastuzumab, 57% had neurological signs and symptoms at enrollment, and 84% had extra-CNS sites of disease, most commonly in bone, liver, and lung. The primary end point of the study was the rate of objective CNS response, defined as a 50% volumetric reduction in CNS lesions without progression of symptoms, extra-CNS disease, or use of steroids.

At median follow-up of 21.2 months, 66% of patients achieved objective CNS responses, all of which were partial responses. Patients were equally likely to attain CNS response whether previously treated with trastuzumab or not. Median time to CNS progression was 5.5 months, and median time to radiotherapy was 8.3 months. The majority of patients (78%) had CNS as the first site of disease progression. Nearly 50% of patients had at least one grade 3 or 4 adverse event, most commonly diarrhea or hand-foot syndrome.

Comment: Brain metastases remain a significant therapeutic challenge, and patients who have a relatively long survival after WBRT might experience some of the well-described cognitive and functional deficits. The LANDSCAPE trial offers patients with HER2-positive brain metastases the potential to delay radiation therapy. However, the combination of lapatinib and capecitabine has the potential to produce substantial adverse effects, which can also negatively affect quality of life.

Source: Journal Watch Oncology and Hematology