December 10, 2010
By Lindsey Collins, BCA Board Member
While sitting in Friday morning’s panel, Barbara forwarded us a press release from Genentech on NEOSPHERE, their phase II trial on the combined use of Herceptin (trastuzumab) and pertuzumab with chemotherapy for early-stage HER2-positive breast cancers. The press release celebrated the results, and cited the presentation at San Antonio. Not quite: the Genentech/Roche people hadn’t presented yet. Dr. Neil Spector from Duke University was still talking about therapies that target HER2 positive breast cancers, and the problem of women developing resistance to HER2 drugs such as trastuzumab. Spector suggested that adding lapatinib (Tykerb) and pertuzumab to Herceptin could have good effects even after women become Herceptin resistant, which often happens after 12 months. Spector asked, if women become resistant to trastuzumab (Herceptin), how can we block HER2 and make it affordable and accessible to women? To paraphrase, Spector asked, “If only four women can afford this therapy, then we have to ask what the hell we’re doing.” What the hell, indeed. Herceptin can cost patients anywhere between $42,000 and $65,000 a year.
This was an interesting transition into Luca Gianni’s presentation for Genentech. Gianni, the Director of Medical Oncology at the National Cancer Institute in Milan, Italy, and principal investigator for the NEOSPHERE trial, neglected to mention the cost of a combined trastuzumab and pertuzumab therapy, which could easily top $100,000 a year (given that Herceptin alone can cost this much). The study recommends that the trial proceed to phase III due to findings in animal models that pertuzumab enhances the antitumor activity of trastuzumab in early inflammatory, locally advanced or HER2-positive cancer. The study’s endpoint is pathological complete response (pCR), or complete tumor disappearance at the time of surgery, and found that the addition of pertuzumab and docetaxel (chemotherapy) achieved a pCR rate of 45.8%. The pCR for just Herceptin (trastuzumab) and pertuzumab was 16.8%. The study asserts that “a proportion” of HER2-positive tumors can be eradicated without chemotherapy with the trastuzumab-pertuzumab therapy. The study also finds that there is no added toxicity and that “tolerability is good” for this combination. In other words, you’ll still probably have a reduced white blood cell count and diarrhea, and you may have some frightening heart problems, too, but not a whole lot more. It’s important to note, too, that the study didn’t look at long-term outcomes, only tumor reduction until the time of surgery. There’s no data on whether this therapy works 12 months after surgery and beyond. The press release identifies side effects for Herceptin, which include diarrhea, fever, vomiting, heart problems, reduced blood cell counts, and infusion reactions, but neglects to elaborate on side effects of the Herceptin-pertuzumab combination or this combination and chemotherapy, other than the brief explanation in Gianni’s presentation about “no significant additional toxicity.” Unfortunately, lack of detail doesn’t mean lack of side effects.
Up next was Jose Baselga, associate director of the Massachusetts General Hospital Cancer Center. Baselga’s study, conducted in Barcelona, Spain, the phase III Neo-ALLTO trial, looked at Herceptin and Tykerb (lapatinib) together, and this combination plus the chemotherapy drug paclitaxel, in early-stage HER2-positive cancers. The Neo-ALLTO study’s primary endpoint was pCR (pathological complete response), defined as “no invasive cancer in the breast or only non-invasive in-situ cancer,” with secondary endpoints of overall survival (OS), disease-free survival (DFS), the rate of conversion to breast conserving surgery, and the rate of conversion to breast surgery in patients who initially had inoperable disease before the treatment (a sidenote here: the study’s key inclusion criteria lists “women with operable invasive breast cancer greater than 2 cm.” If the study’s criteria includes women with operable breast cancer, then why is the study’s goal to see how many women with inoperable disease convert to operable disease? Hasn’t the criteria already been met by the study’s design, thus making this secondary goal unmeasurable in the study?) The study found that when the experimental combination of lapatinib-trastuzumab-paclitaxel was given, 51.3% of women showed no signs of invasive cancer at surgery, compared to 24.7% of women given only lapatinib and 29.5% in women given only trastuzumab. pCR was even higher in women with HER2-negative cancers (again, I’m not sure how this works: if the study focused on HER2-positive women only, then where does this finding come from?). The study doesn’t seem to result in a statistically significant group of women having breast conservative surgery after the experimental treatments, and although the study mentioned DFS (disease-free survival) and OS (overall survival) as secondary goals, I didn’t see any relevant data. Toxicity increased with lapatinib, both alone and in combination with trastuzumab, and included effects like diarrhea and disturbed liver enzymes. Dr. Baselga called the added toxicity “manageable,” but neglected to say how. Tykerb (lapatinib) costs $5000-$6000 a month, and Herceptin costs $4000 a month plus infusion fees.
For more details, follow the link to an AP report.