Negative ALTTO Results Reverberate for Lapatinib, Novel Clinical Trials

Edith A. Perez, MD

A dual HER2-blockade strategy that added lapatinib to trastuzumab for the adjuvant treatment of women with early breast cancer failed to demonstrate a significant improvement in disease-free survival (DFS) over the standard therapy with trastuzumab alone, according to findings from a major clinical trial released Sunday.¹

The combination faltered in the phase III ALTTO trial despite positive signals in an earlier study that suggested pathologic complete response (pCR) to the dual agents when used as neoadjuvant therapy could serve as a surrogate marker for long-term treatment impact.

As a result, the findings may deal a blow to an emerging movement to establish pCR as a clinical trial endpoint in earlier disease settings not only in breast cancer but also in other malignancies, experts said.

The ALTTO trial, which enrolled more than 8000 women in 44 countries, is the largest adjuvant clinical trial ever conducted in women with HER2-positive breast cancer and the findings were eagerly anticipated in the oncology community.

Released at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting, the findings indicated that treatment with lapatinib plus trastuzumab, either sequentially or concurrently, was associated with a high rate of DFS but that combining the drugs did not produce a statistically significant advantage over trastuzumab alone.

At a median follow-up of 4.5 years, the DFS rates were 86% for patients who received trastuzumab alone; 88% for participants treated with trastuzumab and lapatinib concurrently; and 87% for patients who received trastuzumab followed by lapatinib. All patients also received chemotherapy.

The results proved to be a disappointment to researchers pursuing a new approach for reducing the risk of relapse for women treated after surgery with trastuzumab and chemotherapy. Approximately 20% of patients relapse within 10 years, and usually develop metastatic disease, according to ASCO.

Findings from the NeoALTTO study,² released in December 2013, showed that patients who achieved a pCR after receiving the two drugs as neoadjuvant therapy displayed a significantly higher rate of 3-year event-free survival, raising hopes that ALTTO would confirm those results.

However, senior study author Edith A. Perez, MD, said during the press briefing that ALTTO did not corroborate the theory that pCR could be used as a surrogate marker in a smaller trial, making large trials such as ALTTO unnecessary. The findings are “important for the breast cancer field overall,” said Perez, who is deputy director at large at the Mayo Clinic Cancer Center in Jacksonville, Florida.

“From a practical point of view, this is the kind of study that, if positive, would have changed practice tomorrow morning because these drugs are available and the adjuvant setting is one where there is a tremendous drive to reduce recurrence and prevent early death,” said Clifford A. Hudis, MD, president of ASCO, who served as moderator during the press briefing.

He said that the results also have “tremendous potential implications” for getting drugs to patients preoperatively based on pCR rates studied in smaller-scale clinical trials.

Clifford A. Hudis, MD

“This is going to cause a lot of high-level scientific discussion in terms of drug development,” said Hudis, who is chief of Breast Cancer Medicine Service at Memorial Sloan Kettering Cancer Center in New York City. “This is a really important study. It’s important because it has profound long-term implications right now in terms of drug development.”

Impetus for Launching ALTTO

Launched in January 2007, the ALTTO trial took international research cooperation to a new level, according to the National Cancer Institute (NCI).³ The global initiative was coordinated by two large academic research networks, the North American Breast Cancer Groups (NABCG), based in the United States, and the Breast International Group (BIG) in Brussels, Belgium. The NCI and GlaxoSmithKline, which markets lapatinib in the United States as Tykerb, sponsored the trial.

Researchers were seeking to determine whether combining the two drugs, which targeted HER2 in different ways, would prove more beneficial than trastuzumab alone and whether lapatinib would deliver similar benefits to trastuzumab in the adjuvant setting.

Lapatinib is a small-molecule inhibitor of EGFR and HER2 that is approved in combination with capecitabine for HER2-positive advanced or metastatic breast cancer after prior chemotherapy and trastuzumab, and in combination with letrozole for postmenopausal women with HER2-positive, hormone receptor-positive metastatic breast cancer.

Trastuzumab (Herceptin), an anti-HER2 monoclonal antibody, is indicated either as monotherapy or in combination with chemotherapy in both adjuvant and metastatic settings for patients with HER2-positive breast cancer.

In all, ALTTO enrolled 8381 women with HER2-positive, nonmetastatic, primary invasive breast cancer. The eligibility requirements included adequate tumor excision and axilla dissection for patients (if positive sentinel node), and patients with axillary node-positive or node-negative disease with tumor ≥1 cm.⁴

The trial, which accrued participants through July 2011, initially included 4 arms in which patients received trastuzumab, lapatinib, sequential trastuzumab and lapatninb, or concurrent trastuzumab and lapatinib. Patients also received chemotherapy either before the study treatments started, concurrently with the study drugs, or both before and during the study depending upon the type of chemotherapy.⁴

Perez Explains Findings

The lapatinib arm was discontinued in September 2011 after a planned interim analysis showed that the lapatinib-alone arm was not likely to demonstrate noninferiority to trastuzumab.⁵ Perez said results from that arm are scheduled to be presented later this year.Overall, patients who participated in ALTTO experienced better outcomes than investigators initially had anticipated, said Perez. She said the plan was to analyze results when 850 DFS events occurred or at 4.5 years, depending upon which occurred first. As it turned out, the trial reached 4.5 years with 555 DFS events.

DFS, the primary endpoint, was defined as whether there had been invasive breast cancer recurrence at any site, a second primary cancer including invasive contralateral breast cancer or a non-breast malignancy, or death from any cause as first event.

A P value of ≤.025 was required for statistical significance to test both the concurrent and sequential lapatinib with trastuzumab arms compared with the trastuzumab-alone group.

Among the 2093 patients in lapatinib plus trastuzumab arm, the DFS rate was 88%, with a hazard ratio (HR) of 0.84 (97.5% CI, 0.70-1.02) for a P value of .048. For the 2091 patients who received trastuzumab followed by lapatinib, the DFS was 87% with an HR of 0.96 (97.5% CI, 0.80-1.15) and a P value of 0.610. For the 2097 patients in the trastuzumab-alone arm, the DFS was 86%.

Similarly, the overall survival (OS) differences failed to cross the threshold for statistical significance. The OS for patients in the lapatinib plus trastuzumab arm was 95% with an HR of .080 (95% CI, 0.62-1.03) for a P value of .078 and 95% in the sequential arm for an HR of 0.91 (95% CI, 0.71-1.16) for a P value of .433. The OS for trastuzumab alone was 94%.

In terms of toxicities, patients who took lapatinib either concurrently or sequentially experienced higher rates of diarrhea, hepatobiliary effects, and rash or erythema.

Future of pCR

One important finding, Perez said, was the less than 1% incidence of primary cardiac events in all arms. Perez said this is significant because 97% of the participants had received anthracycline-based chemotherapy, and that cardiac events have been feared as an adverse event as a result of such agents.Excitement about the use of pCR as a surrogate marker that would help fast-track drug development grew in September 2013 when the FDA approved a new indication for pertuzumab (Perjeta) in combination with trastuzumab and docetaxel as neoadjuvant treatment for patients with HER2-positive, locally advanced inflammatory or early-stage breast cancer.

The approval was based on pCR, defined as the absence of invasive cancer in the breast and lymph nodes, under the FDA's accelerated approval program. The confirmatory phase III APHINITY trial is in progress and has enrolled more than 4,800 patients with HER2-positive early-stage breast cancer. This trial is comparing pertuzumab, trastuzumab, and chemotherapy with trastuzumab and chemotherapy as an adjuvant treatment. Further data on efficacy, safety, and long-term outcomes from this trial are expected in 2016.

Hudis noted that pCR might very well turn out to correlate with outcomes concerning pertuzumab. “The hope obviously is that by getting the drug into the market based on pCR we would ultimately save lives,” said Hudis. “That may turn out to be true for that drug [pertuzumab]. We’re going to have to wait for the results of that study.”

He indicated, however, that the ALTTO results raise broad questions. “Can we routinely use the preoperative setting and the improvement in pathologic complete response as a reliable surrogate for disease free and overall survival? Then the answer at least from ALTTO right now is maybe not.”

References

1. Piccart-Gebhart M, Holmes AP, Baselga J, et al. 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). Presented at: 2014 ASCO Annual Meeting Press Briefing; June 1, 2014; Chicago, IL. Abstract LBA4.
2. Piccart-Gebhart M, Holmes AP, de Azambuja E, et al. The association between event-free survival and pathological complete response to neoadjuvant lapatinib, trastuzumab, or their combination in HER2-positive breast cancer. Survival follow-up analysis of the NeoALTTO study. Presented at: the 36th Annual San Antonio Breast Cancer Symposium; December 10-14, 2013; San Antonio, TX. Abstract S1-01.
3. ALTTO: Optimizing Targeted Therapy for HER2 Breast Cancer. National Cancer Institute website. http://www.cancer.gov/clinicaltrials/noteworthy-trials/altto. Updated June 1, 2014. Accessed June 1, 2014.
4. Trial overview. ALTTO trial website. http://alttotrials.com/hcp.php. Accessed June 1, 2014.
5. Lapatinib clinical trial update [press release]. London, UK: GlaxoSmithKline. September 9, 2011. http://us.gsk.com/html/media-news/pressreleases/2011/2011-pressrelease-614856.htm. Accessed June 1, 2014.

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