pCR Put Forth as a Surrogate Marker for Improved Survival in Early HER2+ Breast Cancer

Paolo Nuciforo, MD, PhD

Women with early-stage HER2-positive breast cancer who achieved a pathologic complete response (pCR) to neoadjuvant HER2-directed therapy experienced prolonged event-free survival (EFS) and overall survival (OS) versus those who did not, according to final results from the phase 3 NeoALTTO trial.¹

At a median follow-up of 9.7 years, 77% of patients who achieved a pCR were event free at 9 years versus 61% of those who did not. Moreover, 88% of patients who achieved a pCR were alive at 9 years compared with 72% of those who did not. The likelihood of achieving a pCR was the highest among patients who received the combination of lapatinib (Tykerb) and trastuzumab (Herceptin), at 51% versus 27.1% in patients who received trastuzumab or lapatinib alone.

“The results from this analysis show that patients who achieve pCR are significantly more likely to survive for longer than those who do not achieve pCR. This validates pCR as an early indicator of long-term outcome for HER2-positive disease and could help doctors decide on the best treatment,” said Paolo Nuciforo, MD, PhD, head of the molecular oncology group at Vall d’Hebron Institute of Oncology in Barcelona, Spain.¹

Final results from the study also demonstrated that the combination of lapatinib and trastuzumab led to superior EFS and OS versus trastuzumab or lapatinib alone in women with early-stage HER2-positive breast cancer, but were not found to be statistically significant.

The EFS rate was 69% in the combination arm, 65% in the trastuzumab-alone arm, and 63% in the lapatinib-alone arm. The OS rates were 80%, 76%, and 77%, respectively.

In the NeoALTTO study, 455 women with invasive, operable HER2-positive cancer with tumors larger than 2 cm were randomized to receive 1 of 3 neoadjuvant treatments for 6 weeks: intravenous trastuzumab, with a 4 mg/kg loading dose followed by 2 mg/kg weekly (n = 149); 1500 mg of lapatinib (n = 154); or 1000 mg of lapatinib daily plus the same trastuzumab regimen that was given in the trastuzumab-alone arm (n = 152). All patients received 80 mg/m² of paclitaxel starting at week 6 and continued on neoadjuvant therapy for another 6 weeks.

Following surgery, patients received 34 weeks of adjuvant therapy according to their initial randomization to complete 1 year of HER2-targeted therapy.

Initial results of the trial, which were presented in 2010, demonstrated a pCR rate of 51.3% in the combination arm versus 24.7% in the trastuzumab-alone arm (P = .0001) and 19.5% in the lapatinib-alone arm. The pCR rate did not differ significantly between the lapatinib- and trastuzumab-alone arms.²

After a median follow-up of 6.7 years, patients who achieved a pCR were found to have a significantly higher 6-year EFS rate, at 77% versus 65% in those who did not achieve a pCR. The 6-year OS rates also favored those who achieved a pCR, at 89% versus 77% of patients who did not achieve a pCR.

Additionally, the 6-year EFS rates were 74% with the combination, 67% with trastuzumab alone, and 67% and lapatinib alone (lapatinib vs trastuzumab: HR, 0.98; 95% CI, 0.64-1.51; P = .93; the combination vs trastuzumab: HR, 0.81; 95% CI, 0.52-1.26; P = .35). The 6-year OS rates were 85%, 79%, and 82%, respectively (lapatinib vs trastuzumab: HR, 0.85; 95% CI, 0.49-1.46; P = .56; the combination vs trastuzumab: HR, 0.72; 95% CI, 0.41-1.27; P = .26).³

“This trial has the longest follow-up of randomized clinical trials looking at HER2-positive breast cancer and shows how important it is to follow patients for as long as possible to fully understand how drug combinations and other factors can affect survival,” concluded Emiel Rutgers, MD, a surgical oncologist at the Netherlands Cancer Institute who commented on the findings.¹

References:

1. HER2+ breast cancer patients live longer if drugs given before surgery eradicate tumor. News release. European Organisation for Research and Treatment of Cancer. October 3, 2020. Accessed October 7, 2020. https://bit.ly/30Kl3Nd
2. Baselga J, Bradbury I, Eidtmann H, et al. First results of the NeoALTTO trial (BIG 01-06/ EGF 106903): a phase III, randomized, open label, neoadjuvant study of lapatinib, trastuzumab, and their combination plus paclitaxel in women with HER2-positive primary breast cancer. Cancer Research. 2010;70(24). doi:10.1158/0008-5472.SABCS10-S3-3
3. Huober J, Holmes E, Baselga J, et al. Survival outcomes of the NeoALTTO study (BIG 1–06): updated resylts of a randomized multicenter phase III neoadjuvant clinical trial in patients with HER2-positive primary breast cancer. Eur J Cancer. 2019;118:169-177. doi:10.1016/j.ejca.2019.04.038