CHICAGO – Combining trastuzumab emtansine (T-DM1) and pertuzumab (P) reduced grade 3+ toxicity in patients with HER2-positive stage I-III breast cancer in the KRISTINE trial, but led to lower event-free survival (EFS) and pathological complete response (pCR) rates vs. standard chemotherapy plus dual HER2 blockade, according to the preplanned 3-year final data analysis.
The EFS rate among participants in the randomized, phase 3 study who completed follow-up was 94.2% in 189 patients who received neoadjuvant T-DM1+P treatment and 85.3% in 196 patients who received docetaxel, carboplatin, and trastuzumab (TCH) plus pertuzumab (hazard ratio, 2.61). The difference was due to more locoregional progression events before surgery (15 [6.7%] vs. 0 in the groups, respectively),, reported at the annual meeting of the American Association of Clinical Oncology.
The curves separated early, prior to surgery, without much change after surgery, noted Dr. Hurvitz, a medical oncologist at the University of California, Los Angeles, where she also serves as director of the Breast Cancer Clinical Trials Program.
Additional analysis showed that low HER2 expression by mRNA or immunohistochemistry (IHC), and HER2 heterogeneity “tended to correlate with locoregional progression.”
Invasive disease-free survival (IDFS) risk, however, was similar with the two treatments (93% and 92%, respectively; HR, 1.11), and, as has been shown “many times over,” experiencing a pCR was associated with reduced risk of an IDFS event (HR, 0.24), regardless of treatment arm, Dr. Hurvitz said.
The previously reportedof the study, which failed to reach its primary endpoint, showed a pCR of 44% vs. 56% in 223 women who received TDM-1+P and 221 who received TCH+P, respectively. (Lancet Oncol. 2018 Jan;19:115-126. doi: 10.1016/S1470-204530716-7).
Of note, additional data reported in aat the 2016 San Antonio Breast Cancer Symposium showed that pCR rates “were higher with TCH+P in those tumors with IHC2+ HER2 staining (20% vs. 7% in the T-DM1 arm), or IHC3+ HER2 staining (61% vs. 50%),” she said (SABCS 2016 P6-07-09).
“During neoadjuvant treatment, however, it’s not surprising that the T-DM1+P arm had a more favorable safety profile with a lower incidence of grade 3-4 events, lower incidence of [serious adverse events], and lower incidence of AEs leading to treatment discontinuation,” she said.
The overall rate of grade 3 or greater AEs was 31.8% vs. 67.6% with T-DM1+P vs. TCH+P, but the T-DM1 regimen was associated with more grade 3+ AEs during adjuvant treatment (24.5% vs. 9.9%), and with more adverse events leading to treatment discontinuation – both overall (20.2% vs. 11.0%) and during adjuvant therapy (18.4% vs. 3.8%), said Dr. Hurvitz, noting, however, that 50 patients in the T-DM1+P arm received cytotoxic chemotherapy in the adjuvant phase as allowed by study protocol.
Patient-reported outcomes favored T-DM1+P during the neoadjuvant phase, but were similar in the two groups during the adjuvant phase.
Adverse events occurring substantially more often with TCH+P (2% or greater difference in incidence between the groups) mainly included neutropenia, diarrhea, febrile neutropenia, and anemia, but peripheral neuropathy was a bit higher in the T-DM1 arm, she said.
“Standard-of-care neoadjuvant therapy for HER2-positive breast cancer is chemotherapy plus dual HER2 blockade with trastuzumab and pertuzumab, followed by continued HER2 blockade in the adjuvant setting,” Dr. Hurvitz said, noting that rates of pCR, which is associated with prolonged survival, range from 46% to 62%. “Despite the good outcomes ... 15% of patients will relapse or die; moreover, our standard cytotoxic approaches are associated with systemic toxicity, so there still is a need for effective, less toxic therapies.”
The antibody drug conjugate (ADC) T-DM1 is associated with a lower incidence of AEs typically associated with cytotoxic chemotherapy due to its targeted nature, and in the Germanit has shown of efficacy as monotherapy or with endocrine therapy in the neoadjuvant setting in HER2-positive, hormone receptor-positive breast cancer.
“So when we designed this clinical trial we thought that combining T-DM1 with pertuzumab might be an efficacious therapy that would provide patients with a less toxic regimen,” she said.
Participants had centrally-confirmed HER2-positive breast cancer over 2 cm and were randomly assigned 1:1 to T-DM1+P or TCH+P every 3 weeks for six cycles prior to surgery. Those who received T-DM1+P continued adjuvant T-DM1+P for 12 cycles, and those who received TCH+P received adjuvant trastuzumab plus pertuzumab for 12 cycles.
Those in the T-DM1 arm were allowed to receive standard adjuvant chemotherapy at physician discretion – and were encouraged to do so if they had residual disease in the breast greater than 1 cm or lymph node-positive disease. They then went on to receive T-DM1+P for 12 cycles, she said.
“We know that patients who achieve a pathologic complete response have a very good 3-year [IDFS], and for our study, for either arm, it was around 97%. Patients with residual disease have a lower 3-year IDFS in the mid [80% range] representing an unmet need,” she said.
In addition, the similar overall risk of an IDFS event with T-DM1+P and TCH+P in this study suggests that systemic chemotherapy might be unnecessary for some patients.
“But, of course, identification of these patients is going to be critical in determining who can have a deescalation approach, and the clinical utility of chemotherapy-sparing regimens must be confirmed in prospective studies, hopefully using biomarkers,” she concluded.
In a companion article published June 3 in the Journal of Clinical Oncology, Dr. Hurvitz and her colleagues further noted that “the role of T-DM1 in early HER2-positive breast cancer is evolving, with two trials evaluating this agent in the adjuvant setting.”
These include the, which showed a lower risk of invasive breast cancer recurrence or death with adjuvant T-DM1 vs. adjuvant trastuzumab in patients with residual disease after neoadjuvant systemic chemotherapy plus single or dual HER-directed therapy (HR, 0.50), and the ongoing , which is comparing T-DM1+P with taxane plus trastuzumab after anthracyclines as adjuvant therapy in patients who have not received prior neoadjuvant therapy.
“Data from KAITLIN will further define the clinical utility of adjuvant T-DM1+P in patients with HER2-positive early breast cancer,” they wrote.
During a discussion of the KRISTINE study findings and other related data presented at ASCO 2019,, a medical oncologist and professor at Stanford (Calif.) University, said that T-DM1-based neoadjuvant regimens appear, based on peer-reviewed published data from KRISTINE and other studies (such as the Swedish , which was also discussed during the session), to be clinically active and well tolerated in HER2-positive early breast cancer.
“Early adopters may consider neoadjuvant T-DM1 in patients who are perhaps not candidates for chemotherapy due to comorbidities, age, et cetera, or those patients who frankly refuse chemotherapy, of which we all have a few,” said Dr. Pegram, who also is the first director of the Breast Cancer Oncology Program at Stanford Women’s Cancer Center. “The burden is on us to identify molecular, genetic, or perhaps imaging markers to identify patients who are most suitable for consideration of deescalation strategies with T-DM1 or newer HER2 antibody drug conjugates [in development].”
Dr. Pegram also highlighted the KRISTINE EFS finding on locoregional progression prior to surgery.
“Sara showed you that the ... event-free survival outcomes that are deleterious happen prior to surgery, which is, I think, fascinating, and if we could identify those patients prospectively, it could be very powerful in maximally exploiting the potential of deescalation with T-DM1 or T-DM1-based regimens,” he said. “But we’re not there yet, obviously.”
The KRISTINE study was funded by F. Hoffmann-La Roche and Genentech. Dr. Hurvitz reported research funding to her institution from Ambryx, Amgen, Bayer, Biomarin, Boehringer Ingelheim, Cascadian Therapeutics, Daiichi Sankyo, Dignitana, Genentech/Roche, GlaxoSmithKline, Lilly, Macrogenics, Medivation, Merrimack, Novartis, OBI Pharma, Pfizer, Puma Biotechnology, Sanofi, and Seattle Genetics, and travel/accommodations/expenses from Lilly, Novartis, and OBI Pharma. Dr. Pegram reported relationships (honoraria; consulting/advisory roles) with Daiichi Sankyo, Genentech/Roche, Macrogenics, and Seattle Genetics.
SOURCE: Hurvitz S et al. ASCO 2019: .