9 WEEKS OF ADJUVANT HERCEPTIN?

Nine weeks of treatment with trastuzumab (multiple brands) fell short of being noninferior to 1 year of treatment in a randomized controlled trial in early-stage HER2-positive breast cancer, according to findings reported here at the San Antonio Breast Cancer Symposium (SABCS) 2017.

It fell short by only a small margin. The 5-year rate of disease-free survival (DFS), which was the primary outcome, was 90.5% for the 1-year arm vs 88% for the 9-week arm (hazard ratio [HR], 1.39; 90% confidence interval [CI], 1.12 - 1.72).

All of the patients had received trastuzumab in addition to chemotherapy.

Lead investigator Heikki Joensuu, MD, of the University of Helsinki in Finland, was clear about the meaning of the results: "Chemotherapy plus 1 year of anti-HER2 therapy should remain the standard."

Chemotherapy plus 1 year of anti-HER2 therapy should remain the standard. Dr Heikki Joensuu

Dr Joensuu was speaking here at a press briefing for the SABCS. He presented these results from the Synergism or Long Duration Trial (SOLD)

He noted that there was less cardiac toxicity in the group that received trastuzumab for 9 weeks compared to the 1-year group (cardiac adverse events: 2% vs 3.9%, P = .01; congestive heart failure: 1.9% vs 3.3%, P = .04). For patients with underlying heart disease, "9 weeks may be an option," he said.

That comment was supported by Carlos Arteaga, MD, of the Harold Simmons Comprehensive Cancer Center at the UT Southwester Medical Center in Dallas, Texas, who moderated the press conference: "Patient safety is first."

Bishal Gyawali, MD, of the Institute of Cancer Policy, King's College London, United Kingdom, who was not involved in the trial, repeated the study conclusion. "As of now, 12 months of trastuzumab should remain the standard of care, where affordability is not a concern."

But Dr Gyawali told Medscape Medical News that cost is a concern with the longer schedule, especially in low- to middle-income countries.

Dr Joensuu agreed, saying that in "many countries," 1 year of treatment with trastuzumab was "too expensive."

Dr Gyawali, who also practices in his native Nepal, a low- to middle-income country, observed that 9 weeks of treament with the drug there would cost around $3000, which is much less than the 12-month price tag of $18,000 and is "within the affordability range for many patients."

Dr Joensuu agreed, saying that in "many countries," 1 year of trastuzumab therapy was "too expensive."

He also pointed out that "there was...not much difference between the groups in two other important clinical endpoints, distant disease-free survival [DDFS] and overall survival [OS], which were secondary endpoints in the trial."

For the 9-week and 1-year groups, the 5-year DDFS was 93.2% vs 94.2% (HR, 1.24; 90% CI, 0.93 - 1.65), and the 5-year OS was 94.7% vs 95.9% (HR, 1.36; 90% CI, 0.98 - 1.89).

Dr Gyawali observed that the absolute difference in the 5-year OS rates is 1.2%, which is small, not statistically significant, and "doesn't seem very clinically relevant." He also explained that noninferiority was not an issue with the secondary endpoint of OS.

"The power calculations were revised midway, and the design changed to noninferiority for the primary endpoint of DFS but not OS," he pointed out.

The sum of findings gives clinicians a lot to think about, he suggested.

"The interpretation of this trial is intriguing: if you look at DFS alone, the 12-month arm looks better, but there is no difference in OS or DDFS. So, probably the difference in DFS is primarily due to local recurrence, which can still be treated with curative intent, thus leading to the similar OS," he commented.

Dr Gyawali plans on using the findings in the clinic with appropriate patients.

"We can now counsel our patients that 9 weeks of trastuzumab would be much better than no trastuzumab at all and could provide nearly same survival as 1 year on trastuzumab with lower toxicities, although at a slightly higher risk of disease relapse," he said.

Dr Joensuu more or less agreed, saying 9 weeks of trastuzumab is "better than nothing."

Dr Gyawali said that SOLD must be seen in the context of similar trials in which 1 year of treatment with trastuzumab, which was an arbitrary duration created by the original investigators, was compared with therapy of shorter durations.

In a recent meta-analysis of four such trials with shorter-duration arms (ranging from 9 weeks to 6 months), Dr Gyawali and a colleague found that the 1-year treatment remained superior to the shorter regimens in terms of both DFS and OS, as reported by Medscape Medical News.

"It would be interesting to see if the addition of SOLD data would change that conclusion," he said.

For now, 12 months is still best, Dr Gyawali emphasized.

"In my practice, for patients who can afford 12 months of trastuzumab and can commute to the cancer center frequently, I would encourage 12-month therapy," he said.

SOLD Details

SOLD took place at 65 centers in Finland, Sweden, the United Kingdom, Belgium, New Zealand, Iceland, and Serbia; 2174 patients were enrolled from 2008 to 2014. All patients in the trials had histologically confirmed node-negative or node-positive HER2+ breast cancer; for patients with node-negative disease, the primary tumor diameter was >5 mm.

Exclusion criteria included distant metastases, inflammatory cancer, clinically significant cardiac disease, left ventricular ejection fraction (LVEF) <50 and="" estrogen="" health="" organization="" performance="" receptor="" status="" unknown="" world="">1. Patients were also excluded if they had received previous neoadjuvant systemic cancer therapy.

The two-arm design consisted of an identical 9-week initial systemic treatment schedule ― three cycles of docetaxel plus trastuzumab three times a week followed by three cycles of fluorouracil, epirubicin, and cyclophosphamide.

Thereafter, patients in the 9-week arm received no further treatment, whereas those in the 1-year arm received trastuzumab three times a week for 14 cycles for a period of 1 year.

Radiation therapy and endocrine therapy (for patients with ER+ cancer) were given according to the institutional practice; the minimum scheduled duration of endocrine therapy was 5 years.

Notably, the docetaxel dose was either 80 mg/m² or 100 mg/m² (prespecified for each center). The dose of docetaxel may have influenced the DFS outcome, said Dr Joensuu.

He noted that among patients who received the lower does (80 mg/m ²) of docetaxel, 1 year of treatment with trastuzumab provided superior DFS compared with 9 weeks, but this was not the case in patients who received the higher dose of docetaxel. This finding warrants further study, said Dr Joensuu.

LVEF was measured before initiation of therapy and throughout treatment. LVEF was higher in patients in the 9-week arm than for those in the 1-year arm. LVEF values "mostly" returned to baseline within 3 years after the time of randomization, said Dr Joensuu.

The study was sponsored by the Finnish Breast Cancer Group. Dr Joensuu and Dr Gawayli have disclosed no relevant financial relationships. Dr Arteaga has relationships with multiple companies, including Roche, a manufacturer of trastuzumab. 

San Antonio Breast Cancer Symposium (SABCS) 2017: Abstract GS3-04, presented December 7, 2017.