Nab-Paclitaxel More Effective Than Paclitaxel in Neoadjuvant Breast Cancer Trial

Photo Courtesy © SABCS/Todd Buchanan 2014

Nab-paclitaxel (Abraxane) proved markedly more effective than conventional paclitaxel as part of a neoadjuvant regimen for patients with high-risk early breast cancer in a large German study presented at the 2014 San Antonio Breast Cancer Symposium.

The GeparSepto study found that 38% of patients who receivednab-paclitaxel during the randomized phase III trial achieved a pathologic complete response (pCR), compared with 29% of participants who were given conventional paclitaxel, according to results announced by the German Breast Group (GBG).¹The 9% absolute improvement is statistically significant (P<.001) and clinically meaningful, the group said.

The results are particularly noteworthy because pCR rates were &ldquo;strongly increased by replacing a key component of the standard neoadjuvant chemotherapy instead of just adding additional agents to it,&rdquo; Gunter von Minckwitz, MD, PhD, chairman and managing director of GBG, said in a statement.

Von Minckwitz, who also served as co-chair of the GeparSepto trial, said it was the first time that substituting a single agent in a drug regimen had made such an impact in 18 years of collaboration on neoadjuvant breast cancer studies involving the GBG and the German Gynecological Oncology Working Group-Breast (AGO-B).

He noted that &ldquo;long-term outcome data have to be awaited to confirm that this short-term benefit to patients is maintained.&rdquo;

Other GBG researchers also were enthusiastic about the impact ofnab-paclitaxel as part of the neoadjuvant repertoire.

&ldquo;The phase III study provided a head-to-head comparison of weeklynab-paclitaxel with weekly conventional paclitaxel followed by epirubicin/cyclophosphamide in both arms before surgery. Our findings clearly demonstratenab-paclitaxel is superior to paclitaxel in achieving pCRs in early high-risk breast cancer,&rdquo; coordinating investigator Michael Untch, MD, PhD, of Helios Klinikum Berlin-Buch, who presented the study results at the symposium Wednesday, said in the GBG statement.

Differences in the Two Drugs

Nab-paclitaxel is an albumin-encapsulated nanoparticle formulation of the taxane paclitaxel that delivers &ldquo;higher dosing with shorter infusion duration and produces higher tumor drug concentration&rdquo; to the tumor site than conventional paclitaxel, the GBG investigators said in the clinical trial protocol.²

Moreover,nab-paclitaxel is solvent-free, resulting in an improved safety profile compared with the solvent-based paclitaxel and eliminating the need for premedication to prevent hypersensitivity reactions, the researchers noted.

Nab-paclitaxel is approved by the FDA for the treatment of patients with metastatic breast cancer whose disease has progressed after combination chemotherapy or who have relapsed within 6 months of adjuvant chemotherapy.

Head-to-Head Comparison

The GeparSepto trial testednab-paclitaxel in the neoadjuvant setting, where conventional paclitaxel has been incorporated into standard chemotherapy regimens.

The study recruited 1204 patients with untreated cT2-cT4d carcinoma and no clinically relevant cardiovascular or other comorbidities. The overall median age was 49 years, 33% of participants had HER2-positive tumors, and 23% had triple-negative breast cancer.

The participants were randomized 1:1 to receive eithernab-paclitaxel (125 mg/m²) or paclitaxel (80 mg/m²) weekly for 12 weeks followed by 4 cycles of conventionally dosed epirubicin (90 mg/m²) plus cyclophosphamide (600 mg/m²). Patients with HER2-positive disease also received trastuzumab and pertuzumab. &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;

Investigators said they started the trial with a higher dosage ofnab-paclitaxel (150 mg/m²), but that was reduced after an interim safety analysis. The lower dosage &ldquo;delivered 56% more chemotherapy to the tumor than conventional paclitaxel,&rdquo; researchers said.

The primary endpoint was pCR, defined as ypT0 ypN0, with no microscopic evidence of residual invasive or noninvasive viable tumor cells in all resected specimens of the breast and axilla.³The pCR measure serves as a surrogate marker for long-term efficacy.

Overall, 265 patients reported serious adverse events, including 146 patients in thenab-paclitaxel arm and 119 in the paclitaxel group. Four patients died on the study, with three deaths on thenab-paclitaxel arm (accident at home, multiorgan failure, sepsis) and one death on the paclitaxel arm (cardiac decompensation).

While the differences in some adverse events such as grade 3/4 fatigue, diarrhea, and rash were not statistically significant between the two treatment arms, the incidence of peripheral sensory neuropathy was higher in thenab-paclitaxel cohort compared with the conventional paclitaxel group for any grade (84.3% vs 65.2%, respectively) and for grades 3/4 (10.2% vs 2.7%).

More patients in thenab-paclitaxel group discontinued treatment due to toxicities compared with the paclitaxel group (17% vs 6.2%), investigators said. However, there were fewer instances of local disease progression withnab-paclitaxel as opposed to paclitaxel (1.7% vs 5%).

The advantage among patients who received nab-paclitaxel held true among subgroups, notably among participants with triple-negative disease (n = 275). The pCR rate among these patients was 48.2% in thenab-paclitaxel group compared with 25.7% for conventional paclitaxel (P<.001).

&ldquo;We observed the superior effect ofnab-paclitaxel in patients with triple-negative disease, where the pCR almost doubled withnab-paclitaxel. This is a very important finding, as we know that pCR is most prognostic for outcome in this specific high-risk subtype, which comprises about 15% of all breast cancers,&rdquo; said Sibylle Loibl, MD, co-chair of the GBG, in the group&rsquo;s statement.

The GBG disclosed that Celgene, which manufacturesnab-paclitaxel, and Roche supported the GeparSepto study with unrestricted grants and the provision of medication.

References

1. Untch M, Jackisch C, Schneewei&szlig; A, et al. A randomized phase III trial comparing neoadjuvant chemotherapy with weekly nanoparticle-based paclitaxel with
2. solvent-based paclitaxel followed by anthracyline/cyclophosphamide for patients with early breast cancer (GeparSepto); GBG 69. Paper presented at: 2014 San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, TX. Abstract S2-07.
3. A randomized phase III trial comparing nanoparticle-based paclitaxel with solvent-based paclitaxel as part of neoadjuvant chemotherapy for patients
4. with early breast cancer (GeparSepto). German Breast Group website. http://www.germanbreastgroup.de/images/stories/GeparSepto/GBG_69_-_Gepar7__Protocol_Synopsis_Version_08.03.2012.pdf. Accessed December 10, 2104.
5. NIH Clinical trials Registry. ClinicalTrials.gov website. Identifier: NCT01583426.

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