long-awaited results! Phase II trial of AI+herceptin in advanced bc pts

[Lani]

1: Breast Cancer Res Treat. 2006 Aug 8; [Epub ahead of print] Links
The combination of letrozole and trastuzumab as first or second-line biological therapy produces durable responses in a subset of HER2 positive and ER positive advanced breast cancers.

Marcom PK,
Isaacs C,
Harris L,
Wong ZW,
Kommarreddy A,
Novielli N,
Mann G,
Tao Y,
Ellis MJ.
Duke Comprehensive Cancer Center, Duke University, Durham, NC, USA.
BACKGROUND: Estrogen receptor (ER) and/or progesterone receptor expression occurs in approximately 50% HER2 positive (HER2+) breast cancers and cross-talk between the estrogen and HER2 pathways promotes endocrine therapy resistance. The efficacy of the aromatase inhibitor letrozole in combination with trastuzumab was therefore tested in a Phase 2 study. METHODS: Patients with ER+ and/or PgR+ and HER2+ (IHC 2+ or 3+ or FISH+) advanced breast cancer were treated with trastuzumab plus letrozole until disease progression or unacceptable toxicity. RESULTS: Thirty-three patients were enrolled, of which thirty one were considered evaluable. The majority of patients (82%) had received tamoxifen and 82% had HER2 FISH+ and/or IHC 3+ tumors. Eight patients responded (1 CR and 7 PR) for an overall response rate (ORR) of 26% and a clinical benefit rate (CBR) of 52%. The median time to progression (TTP) was 5.8 months and the median duration of response (DOR) was 20.6+ months. Excluding IHC 2+, FISH- tumors, the OR was 24%, CBR 44%, TTP 5.5 months and DOR 17+ months. The combination was well tolerated with only two toxicity events requiring termination of study medication. CONCLUSIONS: Combined trastuzumab and letrozole treatment for patients with HER2+ and ER+ advanced breast cancer produced durable responses consistently lasting at least 1 year in one quarter of the patients. While these data are promising for a subgroup, for half the patients, trastuzumab plus letrozole was inactive. This finding demonstrates ER+ HER2+ advanced disease is heterogeneous and additional agents will be required for optimal management based on targeted therapeutics alone.
PMID: 16897431 [PubMed - as supplied by publisher]

[Becky]

Thanks for the post Lani.

It is very interesting that the combo of Herceptin and Femara has a response rate of 50% which is the response rate of each drug separately (when looking at data of Herceptin in the adjuvant setting and Femara in the adjuvant setting). I realize that advanced or metastatic disease is different and the use of an AI with Herceptin in the adjuvant setting could be a bigger one-two punch but I was hoping for better than 50% (that the combo would be better). However, if memory serves me well (and 50% of the time it doesn't - heehee), I think in the advanced/metastatic setting, an AI or Herceptin only has a 25% response rate (I think Herceptin 26%) so... if this is correct, the combo is much better.

Thanks again and kind regards

Becky

[Lani]

1: J Clin Oncol. 2002 Feb 1;20(3):719-26. Links
Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer.

Vogel CL,
Cobleigh MA,
Tripathy D,
Gutheil JC,
Harris LN,
Fehrenbacher L,
Slamon DJ,
Murphy M,
Novotny WF,
Burchmore M,
Shak S,
Stewart SJ,
Press M.
University of Miami School of Medicine, Comprehensive Cancer Research Group Inc, and Columbia Cancer Research Network of Florida, Miami, FL, USA.
PURPOSE: To evaluate the efficacy and safety of first-line, single-agent trastuzumab in women with HER2-overexpressing metastatic breast cancer. PATIENTS AND METHODS: One hundred fourteen women with HER2-overexpressing metastatic breast cancer were randomized to receive first-line treatment with trastuzumab 4 mg/kg loading dose, followed by 2 mg/kg weekly, or a higher 8 mg/kg loading dose, followed by 4 mg/kg weekly. RESULTS: The objective response rate was 26% (95% confidence interval [CI], 18.2% to 34.4%), with seven complete and 23 partial responses. Response rates in 111 assessable patients with 3+ and 2+ HER2 overexpression by immunohistochemistry (IHC) were 35% (95% CI, 24.4% to 44.7%) and none (95% CI, 0% to 15.5%), respectively. The clinical benefit rates in assessable patients with 3+ and 2+ HER2 overexpression were 48% and 7%, respectively. The response rates in 108 assessable patients with and without HER2 gene amplification by fluorescence in situ hybridization (FISH) analysis were 34% (95% CI, 23.9% to 45.7%) and 7% (95% CI, 0.8% to 22.8%), respectively. Seventeen (57%) of 30 patients with an objective response and 22 (51%) of 43 patients with clinical benefit had not experienced disease progression at follow-up at 12 months or later. The most common treatment-related adverse events were chills (25% of patients), asthenia (23%), fever (22%), pain (18%), and nausea (14%). Cardiac dysfunction occurred in two patients (2%); both had histories of cardiac disease and did not require additional intervention after discontinuation of trastuzumab. There was no clear evidence of a dose-response relationship for response, survival, or adverse events. CONCLUSION: Single-agent trastuzumab is active and well tolerated as first-line treatment of women with metastatic breast cancer with HER2 3+ overexpression by IHC or gene amplification by FISH.
PMID: 11821453 [PubMed - indexed for MEDLINE]

So for her2 2+ and 3+ 35% had an objective response and of her2 + by FISH 34% had a response--but 48% had clinical benefit ie, not that the tumor(s) got smaller but that they didn't progress, I believe.

This is the only published study I believe on herceptin monotherapy ie, herceptin given without previous or concurrent chemo and was only done in the metastatic setting.

(Remember that IHC and FISH testing is not done equally well everywhere.)

IT seems about 50-60% of those who responded or got benefit (stayed stable) had a "long" lasting benefit ie, did no progress for the intervening 12 months at least.

Drs. Spector and Baccus have published articles implying that herceptin resistance can develop in double/triple/positives if an antihormonal of some type is not given. Dr. Dennis Slamon believes, theoretically at least, that fulvestrant should be the most effective in her2+ patients, but it is only available in the metastatic setting for those who have failed previous antihormonals

Hope this help!