Also full of hope and gratitude...

[chrisy]

combined with my brains leaking out of my ears because of information overload!

There was so much great information again this year at SABCS. This year the symposium was also sponsored by the AACR (the cancer researchers group) so there was an increased focus on the "basic science" aspects - which I can best explain as research gaining understanding of the "how" and "why" cells function as they do.

Generally, there is again a growing trend and discussion on learning how to identify the factors which contribute to a specific cancer's behavior, then use that knowledge to find ways to "personalize" therapy based on each individual's situation. The main goal of this is to select treatments that you know will WORK for a person - thus not wasting energy, money, hair, and anxiety throwing one size fits all therapy at people.

The most talked about application of this was a presentation by Jenny Chang, looking at the differences in how herceptin and tykerb work - they both target her2 but via different mechanisms. The conclusion of her study:

Conclusions: Activation of PI3 kinase pathway is associated with trastuzumab but not lapatinib resistance. Lapatinib may affect signalling through the Ras/Raf/MAPK/ERK pathway, inhibiting cell division. Low PTEN expression was not associated with lapatinib resistance, and may explain the clinical efficacy of lapatinib in trastuzumab-resistant patients, supporting clinical trials for the combination of both agents.

The implication of this is that they will be someday be able to determine who will benefit from which drug, and target herceptin to some, lapatinib to others. There will be head to head trials of lapatinib vs. herceptin in adjuvant settings coming soon to validate this.

[chrisy]

Early results from the trastuzumab dm1 trial were also presented - and this study was also the talk of the town!

There is much excitement about this, and we heard about this trial in the general session, several satellite symposia, and the Genentech advocates briefing.

The abstract has been posted elsewhere here, but here it is again:
[33] A phase II study of trastuzumab-DM1, a first-in-class HER2 antibody-drug conjugate, in patients with HER2+ metastatic breast cancer.

Vukelja S, Rugo H, Vogel C, Borson R, Tan-Chiu E, Birkner M, Holden SN, Klencke B, O'Shaughnessy J, Burris HA Tyler Cancer Center, Tyler; UCSF Comprehensive Cancer Center, San Francisco; Lynn Cancer Institute, Boca Raton; St. Louis Cancer & Breast Institute, St. Louis; Florida Cancer Care, Tamarac; Genentech, Inc., South San Francisco; Baylor-Sammons Cancer Center, Dallas; Sarah Cannon Cancer Center, Nashville

Background
Trastuzumab-DM1 (T-DM1), an antibody drug conjugate (ADC) designed to combine the biological activity of trastuzumab with the targeted delivery of a highly potent anti-microtubule agent (DM1) to HER2-expressing cells, has demonstrated activity in a Phase I study. The maximally tolerated dose (MTD) for T-DM1 given every 3 wks was 3.6 mg/kg.
Methods
This is a multi-institutional, open-label, single-arm, Phase II study of T-DM1, 3.6 mg/kg administered by IV infusion every 3 wks, to pts with HER2+ MBC; 100 efficacy-evaluable pts who have progressed on prior T and chemotherapy given in the metastatic setting will be enrolled. The primary objective is to assess objective response rate (ORR) and safety and tolerability in this patient population. Key secondary objectives include measurement of duration of objective response and progression-free survival; to characterize the pharmacokinetics of this T-DM1 regimen; and to assess the formation of antibodies to T-DM1. A preplanned, protocol specified interim analysis of efficacy data was performed after the first 30 efficacy evaluable pts had completed 4 cycles (12 wks) of treatment. A final analysis will be conducted 26 wks after the last patient has been enrolled.
Results
As of June 6, 2008, 92/100 pts have been enrolled. Demographic data from the first 31 enrolled pts include: median age 57 (range 38-79); PS 0-1, 29; PS 2, 2; median number prior metastatic chemo agents 2 (range 1-9); median duration of prior T is 76.1 wks (range 12-379); 13 pts (42%) received prior lapatinib. Of the 31 pts, 30 were evaluable for efficacy per protocol. Based on investigator assessments, 12/30 (40%) pts have had a partial (11) or complete (1) response reported. The IRF has reported a partial response in 9/30 (30%) pts to date. To date, these 31 pts have received a median of 4 T-DM1cycles (range 1-11). Gr2 adverse events (AEs) include thrombocytopenia (10%), fatigue (13%), nausea/vomiting (10%), infusion reaction/fever/chills (10%). Gr3 thrombocytopenia occurred in 10% of pts and Gr4 AEs occurred in 2 (6%) pts (thrombocytopenia and transaminase elevation). Sixteen (52%) pts have discontinued therapy, 11 for progressive disease.
Conclusions
T-DM1 has shown single-agent clinical activity in pts who have progressed on prior HER2-directed therapy. The safety profile of T-DM1 appears tolerable at the recommended dose. To date, preliminary data show a 40% investigator-determined response rate and a 30% IRF-reported response rate. Updated results for the entire study population will be presented.

It was noted by many that this was very early data - which accounted for the large difference in observed response rate and CONFIRMED response rate (lower by about 10%). It was explained that confirmed meant that there had been a response noted on a scan, then it had been confirmed by the next scan. Since this was such early data, many of the participants had only had one scan so far. So the lack of "confirmation" does not mean the initial evaluation was incorrect, only that there has not been a subsequent scan to verify.

There was much buzz about how the "heavily treated" patients, and that it worked well in some patients who had had tykerb as well as herceptin both fail.

[chrisy]

Hope I spelled that one right. This is another new agent targeting the HER family:

[37] Neratinib (HKI-272), an irreversible pan erbB receptor tyrosine kinase inhibitor: phase 2 results in patients with advanced HER2+ breast cancer.

Burstein HJ, Sun Y, Tan AR, Dirix L, Vermette JJ, Powell C, Zacharchuk C, Badwe RA Dana Farber Cancer Institute, Boston, MA; Cancer Institute and Hospital, Chinese Acadeny of Medical Sciences, China; Cancer Institute of New Jersey, New Brunswick, NJ; Oncology Center AZ St-Augustinus, Antwerp, Belgium; Wyeth Research, Cambridge, MA; Tata Memorial Hospital, Mumbai, India

Background: Neratinib (HKI-272) irreversibly inhibits the tyrosine kinase receptors, erbB1 (EGFR) and erbB2 (HER2). In a phase 1 study, neratinib was tolerable and demonstrated antitumor activity in patients (pts) with solid tumors, including 8 of 25 evaluable pts with erbB2-positive advanced breast cancer. In this open-label, 2-arm phase 2 study, pts with stage IIIB, IIIC or IV erbB2-positive advanced breast cancer were evaluated to further characterize the safety and efficacy of neratinib.
Methods: ErbB2 gene amplification in tumor tissue, by FISH was a requirement for study entry. Pts were assigned to arm A if they had prior treatment with trastuzumab and to arm B if they had no prior treatment with trastuzumab or other erbB2-targeted drug. All pts received oral doses of 240 mg of neratinib daily. The primary endpoint was progression-free (PFS) survival rate at 16 weeks (wks).
Results: Enrollment of 136 pts (arm A: 66 pts; arm B: 70 pts; median age 50 years [range 31-83 years]) was completed in November 2007. Common neratinib-related adverse events (AEs), any grade, were diarrhea (89%), nausea (29%), vomiting (23%), fatigue (16%), and anorexia (15%). Diarrhea was the only grade 3 AE that occurred in 5% of pts, 26/136 (19%) total pts, 27% in arm A and 11% in arm B. Dose reductions occurred in 27% total pts, 36% in arm A and 19% in arm B, most commonly because of diarrhea. The main reasons for discontinuation of the study were disease progression (arm A: 74%, arm B: 43%), and AEs (arm A: 8%, arm B: 4%).
124 pts (arm A: 61 pts, arm B: 63 pts) were evaluable for efficacy based on independent assessment and 131 pts (arm A: 65 pts, arm B: 66 pts) were evaluable based on investigator assessment. The objective response rates (complete or partial response) were 26% (95% CI 16%, 39%) in arm A, 51% (95% CI: 38%, 64%) in arm B for independent assessment and 34% (95% CI: 23%, 47%) in arm A, 62% (95% CI: 49%, 74%) in arm B for investigator assessment. The 16-wk PFS rates were 61% in arm A, 75% in arm B (independent); 57% in arm A, and 78% in arm B (investigator). The median PFS for independent [and investigator assessment] was 23 [22] wks in arm A and 40 [35] wks in arm B.
Discussion: Neratinib demonstrates robust antitumor activity in pts with erbB2-positive advanced breast cancer, with objective response rates of 26% in pts who had prior treatment with trastuzumab and 51% in pts who had no prior treatment with trastuzumab. Additional updated efficacy and safety data will be presented.

The main adverse side effect of this drug is diarreah (I still can't spell that word -maybe I just don't want to think about it!). Such that it would replace tykerb as the diva drug of rest area stops. It worked really really well against the cancer but as Dr. Slamon pointedly asked, would it really be appropriate for a patient who was a schoolteacher! Despite the nearly 100% reporting of this side effect, there were almost no discontinuations due to this, so apparently the problem decreased over time or people were able to manage it. There will be more to come on this one for sure...

[chrisy]

I loved hearing the researchers discuss their work and the various things they heard. Some of the highlights heard or overheard:

"ooooh those will be great targets"

"these survival mechanisms are the achilles heel"

"I said 5 years ago we would cure Her2+cancer - and we will"

"we love it when the patient is involved! our job is to give you the best information and options...so you can decide what is the right treatment"

"in my country (switzerland), patients are not allowed at a meeting such as this" She didn't say if she thought that was a good idea or not, but she was very nice, so I think she probably appreciated having us there!

"patients don't fail drugs, drugs fail the patients" this last one was actually directed AT the researcher reporting the DM1 trial. I spoke to her later that day and after I told her I was in that trial, she started apologizing and beating herself up about using the phrase "patient failed" - for you Harry Potter fans, it reminded me of a house elf banging it's head against the wall after saying something bad about their wizard!

She was so wonderful - I just loved her and assured her that, from my perspective at least, that little semantic faux pas did not negate ANY of her great work, and to keep pushing!

I think one of the main benefits of having advocates come to meetings such as this is that we get to be face to face with each other - the patients, doctors, researchers - and get to see each other as the beautiful, dedicated people we are.

I think that everyone goes home from this event with renewed energy (after a nap, that is), renewed passion, renewed hope.

[chrisy]

But I'm SOOOOO glad I was able to come to San Antonio! Thanks, Joe and Christine!

[Soccermom]

Chrisy,
I so heartily agree w yuour assessment! They see our faces and we see theirs (the researchers) ..I once told a research scientist from Australia, that whenever he should grow weary and frustrated with finding that elusive magic bullet for us he should remember my face (hairless and sickly at the time)...and the photo of my daughter..and that we would revive in him the passion and the RESOLVE to help us find that CURE!
So jealous of you all being able to be at San Antonio....perhaps next year I will be able to make it.
Thank you all for being my eyes and ears!
Hugs and Love,
Marcia

[schoonder]

Did SABCS abstract #33 get garbled?


The interim data reported were from the T-DM1 Phase II trial that began in July 2007. The trial is designed to evaluate T-DM1, administered at 3.6 mg/kg every 3 weeks, in approximately 100 efficacy-evaluable patients with HER2-positive metastatic breast cancer that progressed on treatment with HER2-directed therapy plus chemotherapy. It was reported today that 112 patients were enrolled in this study, and that 107 of these patients were efficacy evaluable. At the time of data cut-off for presentation (8/29/08), the patients had a median follow up of 4.4 months (19 weeks). Final results are expected to be available in 2009 when all patients have at least 6 months of follow-up.
Baseline demographic, disease characteristics and prior therapy information were reported for the 112 patients enrolled. All of these patients had metastatic disease, with 68.7% having at least 3 distinct metastatic sites. They all had previously been treated with trastuzumab (Herceptin) plus chemotherapy, with a median time on trastuzumab of 76.6 weeks. Additionally, 55.4% of these patients also had received lapatinib (Tykerb) plus chemotherapy. The median duration of treatment with lapatinib among the patients who had received it was 26.3 weeks. Approximately two-thirds (67.9%) of the patients had received prior anthracycline therapy.
At the time of data cut-off for presentation, the 112 patients had received a median of 5.0 cycles of T-DM1. Two patients discontinued treatment due to adverse events considered to be possibly related to the study drug. Three of the 112 patients were dose-reduced from 3.6 mg/kg to 3.0 mg/kg for tolerability reasons, and these three patients were still receiving T-DM1 at the time of data cut-off.
The efficacy section of the presentation reported two types of findings: the overall objective response rate (Overall ORR) and the confirmed objective response rate (Confirmed ORR). The Overall ORR includes all complete responses (CRs) and partial responses (PRs) reported, whereas the Confirmed ORR includes only those CRs and PRs that were able to be confirmed with two consecutive scans taken at least 4 weeks apart. (Reasons a response would not be confirmed include that the data cut-off occurred before it could be confirmed, that the patient withdrew from the study before it could be confirmed, and that it was not sustained long enough to be confirmed.)
Among the entire 107 efficacy evaluable patients, the Overall ORR was 39.3% and the Confirmed ORR was 27.1%, with an explanatory note included that these findings include 19 patients who only had one post-baseline tumor assessment (i.e., they had not had the absolute minimum number of assessments needed to confirm a response). Thus, results were also reported for just those patients who had either had at least 6 months of follow-up or had discontinued treatment prior to the data cut-off date. Among these 76 patients, the

Overall ORR was 43.4% and the Confirmed ORR was 38.2%. Other activity information presented was:
? Sixty of the efficacy evaluable patients previously were treated with lapatinib. The activity of T-DM1 in these patients was found to be consistent with that in the entire study population (Overall ORR of 38.3%; Confirmed ORR of 21.7%).
? One of the inclusion criteria for the study is that patients have metastatic breast cancer that is HER2-positive (FISH+ and/or IHC3+). However, among the 86 efficacy evaluable patients where HER2 expression could be confirmed centrally, it was found that only 74.4% were HER2-positive by these criteria. Among the 64 patients confirmed to be HER2-positive, the Overall ORR was 50.0% and the Confirmed ORR was 34.4%. The presentation conclusions include that T-DM1 shows single agent activity in patients with previously treated HER2-positive breast cancer, including patients previously treated with trastuzumab and with lapatinib, and appears to be well tolerated at the dose and schedule used.

[chrisy]

schoonder -
thanks, yes I did not post the entire abstract, just the recap that was in the program. Thanks for posting the detail!

[jones7676]

I am excited to hear this since my brain surgeon said the board that met recommended that I try to get enrolled in any research regarding it. Based on my health record they believe Tykerb would assist me in preventing more brain mets and it is one thing I will be working on soon. Thanks for all your info!

[Believe51]

Thanks Chrisy, cannot wait to get the complete low-down.>>Believe51

[RobinP]

Thanks, Chrisy, for the optimistic post. Yes, lots of nice new targeted therapies for her2. I like the high response stats for Neratinib.