Promising new breast cancer therapies in the pipeline

ASCO—The future of breast cancer therapies will involve agents targeting multiple aspects of the signaling pathway. At ASCO 2007, investigators reported encouraging preliminary activity for numerous agents in the pipeline.

Alvespimycin

In an effort to treat HER2-positive patients who progress after trastuzumab (Herceptin)—and, in general, to find effective alternatives to trastuzumab in this patient subset—investigators are evaluating a number of HER2-targeted agents.

One of these is a second-generation heat shock protein 90 inhibitor, alvespimycin (Kosan Biosciences). The drug can disrupt the activity of multiple oncogenes and cell signaling pathways implicated in tumor growth, including HER2.

In a phase I trial (abstract 1115), 25 very heavily pretreated patients with HER2-positive metastatic disease received 1-hour weekly infusions of alvespimycin plus trastuzumab. The median number of prior regimens excluding hormone therapy was 6.5; the median prior trastuzumab-containing regimens was 4.

Clinical benefit was observed in 35% of patients; 5 patients had prolonged stabilization for 4, 5, 6+, 11+, and 12 months.

One patient, who had 13 prior regimens, including progression on single-agent lapatinib (Tykerb) and 3 prior trastuzumab-containing regimens, had almost complete resolution of lung me-tastases. One patient with 11 prior regimens showed a 10% reduction in tumor mass and a decrease in two tumor markers, and is continuing on the study.

One ovarian cancer patient with 13 prior regimens remained on study for over 16 months and had a near complete resolution of ascites and left pleural effusion, and an 83% decrease in CA125.

Toxicities were mainly grade 1 and 2: diarrhea, fatigue, headache, arthralgia, and nausea.

Senior author Clifford Hudis, MD, of Memorial Sloan-Kettering Cancer Center, commented, "This compound has the potential to work additively or synergistically with standard chemotherapy; this would make it an important addition to the treatment options for these tumors."

Studies of alvespimycin in combination with trastuzumab and as mono-
therapy in patients without prior trastuzumab therapy are underway. A larger, international phase II-III trial of alvespimycin plus trastuzumab in patients with HER2-positive metastatic breast cancer will be initiated later in 2007.

Pertuzumab

Another HER2-targeted agent is the monoclonal antibody pertuzumab (Roche), a HER dimerization inhibitor. Jose Baselga, MD, of Vall d'Hebron University Hospital, Barcelona, presented phase II data on pertuzumab plus trastuzumab in 33 HER2-positive metastatic breast cancer patients who progressed on trastuzumab (abstract 1004).

The combination was active and well tolerated, with six responses (18%), including one complete response; seven patients (21%) achieved stable disease.

There are now 57 patients in this ongoing trial, and another study is evaluating the single-agent activity of pertuzumab in HER2-positive patients.

Vinflunine

Vinflunine (Bristol-Myers-Squibb), a microtubule inhibitor of the vinca alkaloid class, was combined with trastuzu-mab in several studies reported at ASCO. In a trial from the Sarah Cannon Cancer Institute (abstract 1043), the doublet used as first-line treatment of metastatic breast cancer produced a 47% response rate and 35% stabilization rate in 17 evaluable patients. Ten patients are progression free at a median follow-up of 8 months.

Tolerability was very good; the most frequent grade 3-4 toxicity was neutropenia in 24% of patients.

In a French study (abstract 1058), response rate was 76% and the disease control rate reached 95%, with good tolerability in spite of an 89% dose intensity.

Both of these groups are starting phase III trials of vinflunine plus trastuzumab.

Trastuzumab-DM1

T-DM1 (Genentech) combines the anti-tumor activity of trastuzumab with targeted delivery into the tumor cell of the highly potent agent DM1, an inhibitor of tubulin polymerization (abstract 1042, see Oncology NEWS International, August 2007, page 19). This approach increases the efficacy of trastuzumab and reduces the toxicity of DM-1, said Murali Beeram, MD, of the Institute for Drug Development, San Antonio.

Dr. Beerman presented a phase I study in 18 HER2-positive metastatic patients who progressed after trastuzumab. Four of these heavily pretreated patients had a partial response, several quite durable, including a response in one patient that has continued for more than 1 year.

RAD001

Through mTOR inhibition, RAD001 (everolimus, Novartis) exerts antiproliferative and antiangiogenic effects. It works by disrupting an inhibitory mechanism impinging on the PI3K signaling pathway, resulting in sustained activation of the IGF-1R pathway.

Susan Ellard, MD, of the National Cancer Institute of Canada, reported that daily oral RAD001 (10 mg/d) was marginally active in 32 metastatic patients (abstract 3513), with 2 confirmed partial responses and stable disease in 17 patients. One has remained on treatment for over 1 year, Dr. Ellard reported.

Grade 3-4 toxicities included diarrhea, cough, neutropenia, and pneumonitis. Investigators expressed some concern about the unexpected pneumonitis, which was mostly manageable and readily reversible, Dr. Ellard said, but four patients discontinued because of this complication.

Axitinib

Axitinib (Pfizer), an oral TKI targeting VEGF receptors being evaluated in several solid tumor types (see Oncology NEWS International, August 2007, page 4), was studied in combination with docetaxel (Taxotere) as first-line treatment in 168 metastatic breast cancer patients (abstract 1003).

Hope Rugo, MD, of the University of California, San Francisco, reported that the combination produced responses in 40% of patients vs 23% with docetaxel alone (P = .038). There was also a strong trend (P = .052) for improved time to progression (8.2 months vs 7.0 months).

In a predefined subgroup analysis, adding axitinib to docetaxel resulted in marked improvement in response in patients who had received prior adjuvant chemotherapy (from 13% to 45%, P = .0003), but not in patients who were chemotherapy nave (35% vs 34%). The same pattern was seen in time to progression, which increased from 6 to 9 months with axitinib in those with prior adjuvant chemotherapy (HR 0.54, P = .012)

Dr. Rugo said, "We believe that in chemotherapy-nave patients, docetaxel is very effective; therefore, in this small trial, the addition of an antiangiogenic drug did not have an effect. Our hypothesis is that this treatment may have its most potency in reversing chemotherapy resistance."

Adecatumumab

Patients who express high levels of the epithelial cell adhesion molecule (EpCAM) benefited from adecatumumab (Merck Serono), an IgG1 antibody with a binding specificity for EpCAM. Overexpression of EpCAM has been shown to promote the proliferation, migration, and invasiveness of breast cancer cells and is associated with decreased survival.

In a study of 108 metastatic breast cancer patients (abstract 3588), the primary endpoint (greater than 25% clinical benefit rate at week 24) was not met in any dose group. However, time to progression was significantly improved in the high-dose group, and patients with high EpCAM expression achieved stable disease. High-dose adecatumumab will be evaluated in patients with strong EpCAM expression and is currently being studied in combination with docetaxel in the metastatic setting as well.