Toxicity Without Benefit With Paclitaxel Plus Everolimus

Neil Osterweil

December 12, 2011

December 12, 2011 (San Antonio, Texas) — It seemed like a good idea at the time, but including everolimus (Afinitor, Novartis) in a neoadjuvant chemotherapy regimen with paclitaxel (Taxol, Bristol-Myers Squibb) added nothing but toxicity to the treatment of women with primary HER2-negative breast cancers, according to data presented here at the 34th Annual San Antonio Breast Cancer Symposium.

Among 403 women who had no response after 4 cycles of initial chemotherapy with epirubicin and cyclophosphamide, with or without bevacizumab, those who were later randomized to weekly paclitaxel plus daily everolimus had lower pathologic complete response (pCR) rates and lower clinical response rates at surgery than patients treated with paclitaxel alone, reported Jens Huober, MD, from the Kantonsspital St. Gallen in Switzerland.

"We could see that toxicity was higher in the group treated with [everolimus] in addition to paclitaxel. However, the pCR might not be the appropriate end point in this patient population. Thus, before drawing definite conclusions, disease-free survival and overall survival results" are needed, said Dr. Huober, who presented data from the nonresponder group of the GeparQuinto trial (A Phase 3 Trials Program Exploring the Integration of Bevacizumab, Everolimus [RAD001], and Lapatinib Into Current Neoadjuvant Chemotherapy Regimes for Primary Breast Cancer).

Primary results from the trial were presented at the symposium last year.

Everolimus selectively binds to and inhibits the mammalian target of rapamycin (mTOR), a protein kinase that controls cellular proliferation of activated T-lymphocytes and neoplastic cells. It has been show to have synergistic activity with some chemotherapy drugs, including exemestane and paclitaxel, Dr. Huober said.

Dr. Huober and colleagues looked at women with either unilateral or bilateral primary HER2-negative breast carcinoma with lesions 2 cm or greater on palpation or 1 cm or greater on ultrasound and no metastases, with tumor stage cT4 or cT3, stage cT2 if hormone-receptor negative or cN+, or stage cT1 if hormone-receptor negative or pNSLN+.

Those who had no response (less than 50% tumor reduction) after 4 cycles of epirubicin and cyclophosphamide with or without bevacizumab were then randomized to receive either paclitaxel 80 mg/m² weekly for 12 weeks (201 patients), or the same schedule of paclitaxel plus everolimus starting at 2.5 mg every other day and escalating to 5 mg per day at day 13 (202 patients).

In all, 11.6% of patients in the paclitaxel group discontinued chemotherapy (2.5% because of adverse events, 5.1% based on the investigator's decision, 2.5% based on the patient's decision, and 1.5% because of progressive disease). In the paclitaxel plus everolimus group, 22.1% dropped out (6.2% because of adverse events, 6.2% based on the investigator's decision, 5.1% based on the patient's decision, 4.1% because of progressive disease, and for 0.5% other reasons). Additionally, 7.2% of the latter group dropped everolimus but stayed on paclitaxel.

Adverse events that were significantly higher in the paclitaxel plus everolimus group than in the paclitaxel group were grade 3 to 4 neutropenia (17.8% vs 9.5%; = .023); thrombocytopenia of any grade (15.9% vs 5.1%; = .001); grade 1 or higher liver enzyme elevation (47.6% vs 32.2%; = .003); any grade fever (13.8% vs 3.6%; < .001); any grade diarrhea (32.7% vs 16.3%; < .001); any grade infection (38.3% vs 23.0%, P=.001); any grade stomatitis, mucositis, and/or esophagitis (66.8% vs 54.1%; = .013); any grade acneiform skin rash (37.2% vs 18.4%; < .001); any grade allergic reactions (16.3% vs 6.1%; = .002); and any grade bleeding (25.5% vs 12.8%; = .002).

An analysis of pCR results for the 395 patients with data available showed that 5.6% of the paclitaxel group had a pCR (defined as invasive or noninvasive residuals in breast and nodes), compared with 3.6% of the paclitaxel plus everolimus group (= .476).

Similarly, using a pCR definition of no invasive residuals in breast and nodes (defined by investigators at the University of Texas M.D. Anderson Cancer Center in Houston), the rate was 6.1% in the paclitaxel group, compared with 5.1% in the paclitaxel plus everolimus group (= .836)

Using the National Surgical Adjuvant Breast and Bowel Project definition of pCR (no invasive residuals in the breast), the respective rates were 7.1% and 6.6% (= .689).

Combined clinical complete and partial responses at the time of surgery in 379 patients were seen in 62.1% of the paclitaxel group, compared with 52.2% the paclitaxel plus everolimus group (= .061).

A subgroup analysis showed no differences in pCR by age, stage, grade, or hormone-receptor status, Dr. Huober said.

In the BOLERO (Breast Cancer Trials of Oral Everolimus BOLERO)-2 trial, everolimus was successfully combined with endocrine therapy, which has mechanisms of cross-talk with the platelet-factor 3 kinase pathway, said Steven J. Isakoff, MD, PhD, from the Massachusetts General Hospital Cancer Center in Boston. Dr. Isakoff, who was not involved with either of these everolimus trials, explained that these mechanisms are not present between everolimus and chemotherapy.

"The analysis from this trial was limited to the nonresponders, so it's already selecting out a group of tumors that have declared themselves as less responsive to chemotherapy. It's entirely possible that in this particular subgroup, this particular targeted agent isn't sufficient to make paclitaxel better, but we don't know whether the pathologic complete response rate in the responding population might be enhanced with this agent," Dr. Isakoff told Medscape Medical News.

The study was supported by Novartis. Dr. Huober reports receiving grant/research support from GlaxoSmithKline; being a consultant for Novartis, Roche, Amgen, and GlaxoSmithKline; and receiving financial or material support from Novartis and Roche. Dr. Isakoff has disclosed no relevant financial relationships.

34th Annual San Antonio Breast Cancer Symposium (SABCS): Abstract S3-6. Presented December 8, 2011.

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