Another Analysis of Trastuzumab for Only 9 Weeks: Not an Option

Alexander M. Castellino, PhD

October 30, 2018

MUNICH — Several trials have looked at a shorter duration of therapy with trastuzumab (Herceptin, Roche) for HER2+ breast cancer to reduce cardiotoxicity associated with the drug.

The Italian Short-HER study explored a 9-week course of trastuzumab combined with chemotherapy in the adjuvant setting compared with standard 1-year treatment, and as reported previously, overall failed to meet the primary endpoint of noninferiority.

Now researchers have reported a further exploratory analysis which shows that the shorter 9-week course of trastuzumab provides the same disease-free survival (DFS) as the standard 1-year course of treatment for women with low- and intermediate-risk HER+ early stage breast cancer and was associated with less cardiotoxicity.  

However, for high-risk women DFS was worse with the shorter treatment time.

The researchers conclude that the benefit–risk ratio is clearly in favor of 1-year trastuzumab for patients with high-risk disease.

"For patients at low to intermediate risk for relapse, the issue of treatment de-escalation is still an open one based on the DFS," they concluded in a poster presentation (191P) here at the European Society for Medical Oncology (ESMO) 2018 Congress.

However, breast cancer experts emphasize that 1 year of trastuzumab remains the current standard of care.  

"There is no patient for whom I would try 9 weeks of trastuzumab," ESMO expert Carmen Criscitiello, MD, PhD, of the European Institute of Oncology, Milan, Italy, told Medscape Medical News.

Details of the Short-HER Study

The phase 3 Italian Short-HER study randomized 1254 patients to receive de-escalation therapy of a shorter 9-week course of trastuzumab (short group) or standard 1-year course (long group).

The study did not meet its primary endpoint of noninferiority for the shorter 9-week course. At a median 6 years of follow-up, the hazard ratio (HR) for DFS was 1.13 (90% CI, 0.89 - 1.42), as previously reported.

For the current analysis, patients at low-, intermediate-, or high-risk were defined as follows:

  • Low risk (n = 467): Tumors ≤ 2 cm and node-negative disease (N0).

  • Intermediate risk (n = 586): Tumors ≤ 2 cm and 0-3 positive lymph nodes, or tumors > 2 cm and 0-3 positive lymph nodes.

  • High risk (n = 191): Tumors of any size but more than 4 positive lymph nodes.

For the low-risk group, 5-year DFS was 91% for the long group and 92% for the short group (HR, 0.96; 95% CI, 0.56 - 1.66). For the intermediate-risk group, corresponding 5-year DFS was 87% and 88% (95% CI, 0.56 - 1.36). But for the high-risk group, 5-year DFS was 82% for the long group and 64% for the short group (HR, 1.99; 95% CI, 1.18 - 3.36).

In the low-risk group, grade 2, 3, and 4 cardiac events occurred in 30, four, and zero patients on the long-group compared with 10, two, and zero patients in the short group. Relative risk (RR) for a cardiac event was higher for patients in the long group (RR, 2.85; 95% CI, 1.51 - 5.36).

In the intermediate-risk group, grade 2, 3, and 4 cardiac events occurred in 28, six, and zero patients in the long-group compared with 10, two, and zero patients in the short group (RR, 2.79; 95% CI, 1.48 - 5.25).

In the high-risk group, grade 2, 3, and 4 cardiac events occurred in 10, two, and one patient in the long group compared with two, one, and zero patients in the short group (RR, 4.29; 95% CI, 1.26 - 14.57).

What the Experts Are Saying

Regardless of the DFS benefit seen with the exploratory analysis for low- and intermediate-risk patients, the experts say that 1-year trastuzumab is still the standard of care for patients with early stage HER+ breast cancer.

During a discussion of the poster, Véronique Diéras, MD, of the Curie Institute, Paris, France, provided a rationale for the Short-HER study. A previous small study had shown the same magnitude of benefits of a shortened 9-week course of trastuzumab compared with the standard 1-year course, she noted. Real-world patients also tend to be at lower risk for relapse (node-negative, smaller tumors) and at high risk for cardiotoxicity (for example, older patients are likely to have comorbidities).

She then highlighted data from the recently published SOLD randomized study led by Finnish investigators (JAMA Oncol. 2018;4:1199-1206). In that study, noninferiority of administering trastuzumab for 9 weeks could not be demonstrated. In addition, a subgroup analysis did not identify any subgroup of patients who might benefit from a short course of trastuzumab based on relapse risk.

In a side-by-side comparison, Diéras showed that patients in the Short-HER and Fin-HER studies were remarkably similar. She indicated that an individual patient meta-analysis may better identify patients who may be candidates for therapy.

In the meantime, 1-year trastuzumab is still the standard of care for patients with stage I HER2+ breast cancer, she said.

Criscitiello said in an interview that she would not use the shorter 9-weeks trastuzumab course in any patient.  

However, for patients who experience cardiac toxicity or side effects of treatment, these data suggest that a shorter duration of treatment may not be detrimental, she added. In patients with small tumors and no nodal involvement who experience severe cardiac toxicity treatment may be stopped, she suggested.

She elaborated that there are many trials trying to de-escalate therapy for patients with breast cancer. The Fin-HER (9-weeks vs 1-year trastuzumab) and PERSEPHONE (6-months vs 1-year trastuzumab) studies tried to do this by shortening the duration of trastuzumab therapy.

The APT study has successfully de-escalated therapy by reducing the chemotherapy backbone, with trastuzumab given for 1 year (N Engl J Med. 2015;272:134-141). Three-year DFS was 98.5% and long-term follow-up showed a 7-year DFS of 93.3%.

Based on these observations, paclitaxel with 1-year trastuzumab is an effective regimen for stage I breast cancer with a low rate of recurrence, Criscitiello said.

She also pointed out that attempts to de-escalate therapy have also been undertaken in the neoadjuvant and metastatic breast cancer setting. For example, in the metastatic setting, the PERTAIN (J Clin Oncol. 2018;36:2826-2835) and ALTERNATIVE (J Clin Oncol. 2018;36:741-748) trials spared patients chemotherapy and instead provided endocrine therapy and anti-HER2 therapy. The results are encouraging and should provide options for patients who need to avoid the cardiotoxicity seen with chemotherapy regimens typically used with 1-year trastuzumab, Criscitiello noted.

With any de-escalation strategy it is important to identify patients who may be safely de-escalated without compromising the benefits of therapy, Criscitiello told Medscape Medical News. 

Currently we have no biomarkers that will help us identify patients who may benefit from a shorter course with trastuzumab, she added.

Conte and Guarneri have reported receiving research funding from Roche. Guarneri has reported being on the speakers bureau for Roche/Genentech.

European Society for Medical Oncology (ESMO) 2018 Congress. Abstract 191PD.

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