First results from the phase III ALTTO trial (BIG 2-06; NCCTG [Alliance] N063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (T→L), or their combination (T+L) in the adjuvant treatment of HER2-positive early breast cancer (EBC).

Purpose: We conducted a randomized phase III study to determine whether patients with early breast cancer would benefit from the addition of capecitabine (X) to a standard regimen of doxorubicin (A) plus cyclophosphamide (C) followed by docetaxel (T).Experimental Design: Treatment comprised eight cycles of AC!T (T dose: 100 mg/m 2 on day 1) or AC!XT (X dose: 825 mg/m 2 twice daily, days 1-14; T dose: 75 mg/m 2 on day 1). The primary endpoint was 5-year disease-free survival (DFS).Results: Of 2,611 women, 1,304 were randomly assigned to receive AC!T and 1,307 to receive AC!XT. After a median follow-up of 5 years, the study failed to meet its primary endpoint [HR, 0.84; 95% confidence interval (CI), 0.67-1.05; P ¼ 0.125]. A significant improvement in overall survival, a secondary endpoint, was seen with AC!XT versus AC!T (HR, 0.68; 95% CI, 0.51-0.92; P ¼ 0.011). There were no unexpected adverse events. Of patients with estrogen receptor (ER)-positive/HER2-negative disease, 70% of whom were node-positive, 26% and 59% had tumors with a centrally assessed Ki-67 score of <10% or <20%, respectively, and only 17 (2%) and 53 (6%) DFS events, respectively, occurred in these groups at 7 years.Conclusions: The very low event rate in patients with ERpositive, low Ki-67 cancers, regardless of nodal status, strongly suggests that these patients should not be enrolled in adjuvant trials that assess 5-year DFS rates and that central Ki-67 analyses can identify these patients.

Section: Discussionmentioning

confidence: 91%

Patients with Slowly Proliferative Early Breast Cancer Have Low Five-Year Recurrence Rates in a Phase III Adjuvant Trial of Capecitabine

O’Shaughnessy

Koeppen²,

Xiao³

et al. 2015

“…The FDAled meta-analysis of 12 neoadjuvant clinical trials (CTNeoBC) confirmed the patient-level prognostic value of pCR, but it could not demonstrate a significant correlation between pCR OR and event-free survival HR at the trial level across the studies (16). More recently, the ALTTO adjuvant trial (n ¼ 6,281) that compared 1 year of anti-HER2 therapy with lapatinib alone, trastuzumab alone, or the combination of the two drugs concomitant with or after chemotherapy in HER2-positive early breast cancer also failed to show statistically significant improvement in survival (17), despite a significant improvement in pCR rate (51% vs. 29% and 24%) with the dual HER2 blockade in the neoadjuvant NeoALTTO trial (18). Clearly, substantial and statistically significant improvements in pCR rate can translate in minor, nonsignificant improvements in patient survival in large trials.…”

Section: Introductionmentioning

confidence: 93%

Relationship between Complete Pathologic Response to Neoadjuvant Chemotherapy and Survival in Triple-Negative Breast Cancer

Symmans

Zhang

Gould

et al. 2016

Purpose: Pathologic complete response (pCR) to neoadjuvant chemotherapy reflects the cytotoxic efficacy of a drug, but patient survival is influenced by many other factors. The purpose of this study was to assess the relationship between increased pCR rate and trial-level survival benefit in triple-negative breast cancer (TNBC).Experimental Design: We used bootstrap resampling from a neoadjuvant trial to simulate trials with different pCR rates. We used estimates from Adjuvant!Online to simulate trial populations with different baseline prognosis and estimated survival improvements associated with changes in pCR rate.Results: Assuming that survival is similar for patients with pCR regardless of treatment arm, a linear relationship exists between increasing pCR rate and increasing recurrence-free survival (RFS). The slope is equal to the difference in survival between those with pCR and residual disease, which in turn is influenced by (i) the baseline prognosis of the trial population, (ii) interactions between prognostic variables and pCR, and (iii) the efficacy of the postneoadjuvant therapies. For example, if the pCR rates are 30% and 60% (OR ¼ 3.5) and the 10-year RFS of the control arm is 0.74, the trial would require 3,550 patients per arm, whereas if the RFS is 0.54, the trial would require only 425 patients per arm to detect significant survival benefit.Conclusions: We provide a framework for understanding the relationship between pCR and overall survival benefit that can help inform the design of neoadjuvant trials aiming to demonstrate improved survival from a regimen that results in higher pCR rate.

“…Following early combinatorial trials in the metastatic HER2 setting, investigators rapidly moved this combination into thesome and a disappointment to all: a small, non-statistically improved disease-free survival (compared with trastuzumab) accompanied by substantial toxicity (9). However, it is important to note that just 555 disease-free events had occurred at 4.5 years, which fell far short of the 850 that were needed to achieve the desired power in the statistical plan.…”

mentioning

confidence: 99%

“Vertical” Inhibition of HER2 Yields Horizontal Gains in the Clinic

Sledge

Pegram

2015

HER2-targeted therapy has moved beyond trastuzumab to include other monoclonals targeting the cell surface, receptor tyrosine kinase inhibitors of HER2, and antibody-drug conjugates. Afatinib, a small molecule receptor tyrosine kinase inhibitor, now joins the ranks of HER2-targeting agents in combination with trastuzumab. The combination brings new opportunities and challenges. Clin Cancer Res; 21(12); 2663-5. Ó2015 AACR.See related article by Ring et al., p. 2737 In this issue of Clinical Cancer Research (CCR), Ring and colleagues (1) present clinical data for the combination of trastuzumab with afatininib, a combination that demonstrates both the challenges and promises of combination vertical blockade of HER2.Following the initial proof-of-concept studies with trastuzumab, investigators confronted the reality that although HER2-targeted monotherapy significantly improved outcome, it did not eliminate HER2-driven breast cancer. Indeed, an increasing understanding of HER2 biology has led to multiple new avenues of attack beyond trastuzumab. Given the evidence of trastuzumab's manifest efficacy in the adjuvant and metastatic settings (2), these new approaches regularly involved "combinations" with trastuzumab.These included drugs targeting the tyrosine kinase moiety of the HER2 molecule (e.g., lapatinib and neratinib), drugs preventing HER2 dimerization (e.g., pertuzumab), antibody-drug conjugates (e.g., T-DM1), and drugs targeting downstream pathway molecules (e.g., PI3K/AKT/mTOR; see Fig. 1). Afatanib now joins the list of agents combined with trastuzumab, as described in the phase I trial presented by in this issue of CCR.Afatinib is an irreversible, oral, 4-anilinoquinazoline small molecule that binds to the kinase domains of EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4), as well as selected EGFR exon 19 deletion mutations, or exon 21 L858R mutations, to inhibit their tyrosine kinase activity. It was FDA approved in 2013 as firstline monotherapy for patients with metastatic non-small cell lung cancer whose tumors have detectable EGFR exon 19 deletions or exon 21 (L858R) substitution mutations. In that setting, common toxicities (20%; 40 mg, once daily dose) include diarrhea, rash, stomatitis, paronychia, dry skin, decreased appetite, and pruritus (3).Ring and colleagues combined afatinib with trastuzumab in a phase I trial using a standard 3þ3 dose escalation. Trastuzumab was used in its standard weekly dosing of 4 mg/kg for 1 week, then 2 mg/kg weekly thereafter. Afatinib ultimately was tested at just two dose levels, 20 mg and 30 mg once daily, with dose-limiting toxicity (DLT), namely grade 3 diarrhea, being common at both dose levels (4/13 and 2/2, respectively). In contrast, afatinib monotherapy is administered at a higher dose of 40 mg daily.This experience mimics that seen previously with lapatinib, where full doses of the oral kinase inhibitor could not be administered with trastuzumab, due to DLT events defined by grade 3 fatigue and diarrhea, as well as nausea and vomiting (4). Whether this neces...