[Joan M]

Here's the article from the link above, if you can't access it online. Joan

TDM-1 Is a Good Drug, But Better Than WHAT?
Steven Vogl, M.D.

American Society of Clinical Oncology (ASCO) 2012 saw the plenary presentation of the EMILIA trial comparing a new targeted therapy consisting of a HER2 antibody (trastuzumab; Herceptin, Genentech) conjugated to a very toxic chemotherapy drug (a maytansine analog called DM-1) with an “approved” (by the FDA) chemotherapy regimen of lapatinib and capecitabine. The results appeared quite favorable for the antibody conjugate, called TDM-1, which was tested in women whose tumor had worsened on prior therapy including trastuzumab (Table 1).

TDM-1 seems to be a “nice” drug. It causes no alopecia, little neutropenia and only moderate thrombocytopenia. It requires only a short infusion every three weeks, lacks cumulative toxicity and has a response rate as first-line chemotherapy that is about the same as that of docetaxel and trastuzumab with apparently longer remissions—median duration 14.2 versus 9.2 months as cited by Kimberly Blackwell, MD, in her ASCO plenary presentation (E. Perez, personal communication). It is indeed representative of a new class of very promising drug–antibody conjugates, of which brentuximab vedotin for Hodgkin’s lymphoma is a shining example.

How Do We Interpret the TDM-1 Phase III Trial?

We cannot interpret it, because all the data available in 2012 suggest that the control arm, lapatinib and capecitabine, is distinctly suboptimal and does not represent a standard of care. We do know that lapatinib-capecitabine is modestly superior to capecitabine alone in women whose tumor grew on other chemotherapy plus trastuzumab (Table 2).1 Alas, we still do not know if it is superior or even equal to capecitabine with continued trastuzumab in the same population. Perhaps it is even inferior to capecitabine plus lapatinib plus trastuzumab.

Stopping Trastuzumab for Even Six Weeks Costs Four Months In Median Survival in a Heavily Pretreated Population

Unfortunately, in 2012, we know very little about how and when to use lapatinib. Based on a study just published for the third time by Dr. Blackwell, all we know is how not to use it: We should not use it without trastuzumab.2 The authors of this paper, a very distinguished group indeed, concluded that their study showing the superiority of lapatinib plus trastuzumab over lapatinib alone supports the use of dual HER2 blockade (Table 3).

An attractive, simpler explanation is that it demonstrates the importance and value of continuing trastuzumab even after disease progression on multiple lines of trastuzumab-containing chemotherapy. The large deleterious effect on median survival of even a short hiatus off trastuzumab—4.5 months when prolongation of disease progression was just a few weeks (Table 2)—argues that continued trastuzumab has a major effect on disease progression that causes death even as disease continues to worsen on trastuzumab.


Several Points Remain

Choice of inferior comparators is common

It is common for pharmaceutical companies to choose inferior comparators in Phase III trials, as was done in EMILIA. Recent examples include using the “Mayo Clinic regimen” of low-dose 5-fluorouracil plus leucovorin as the comparator for adjuvant capecitabine for resected colon cancer and for capecitabine-oxaliplatin as chemotherapy for metastatic disease.

Roche similarly used docetaxel rather than vinorelbine as the drug partner for trastuzumab in the control arm of a Phase II trial of TDM-1 as first-line chemotherapy for metastatic breast cancer.4 It has long been obvious that vinorelbine is less toxic than docetaxel, and this has been recently documented in the published Phase III HERNATA (Herceptin Plus Navelbine or Taxotere) trial that found similar response rates but longer remissions with vinorelbine–trastuzumab, presumably because the chemotherapy partner could be given longer, with docetaxel having been stopped early more often because of toxicity. As Dr. Blackwell mentioned in her ASCO plenary presentation, in the Roche trial reported by Dr. Hurwitz at ESMO 2011, the advantage of TDM-1 was that remissions with TDM-1 seemed longer than those with the control arm of docetaxel-trastuzumab.

Drug companies choose to rely on marketing and sales skills, rather than convincing data, to sell their wares when their studies have weak or suboptimal control arms.

EMILIA was a very large study that proved little

It is really too bad that this study chose an inferior comparator because it is one of the largest studies of chemotherapy for metastatic HER2-positive breast cancer. With 991 patients, it is the largest trial I could identify for these women. The Genentech study proving a four-month increase in survival with trastuzumab had 469 patients randomized. EGF 104900, which looked at lapatinib plus trastuzumab, had 291 subjects; GBG 26 (capecitabine with or without trastuzumab) had 156; HERNATA (trastuzumab with docetaxel or vinorelbine) had 284; CLEOPATRA (CLinical Evaluation Of Pertuzumab And TRAstuzumab) had 808; MA.31 closed at 652; two studies looking at the addition of carboplatin to trastuzumab plus taxane had 196 and 263 each.

TDM-1 does not meet goals of a major advance

TDM-1, while subjectively well tolerated and low on serious toxicity, does not achieve the goals we really want to advance systemic therapy for metastatic breast cancer (Table 4). Data available to date suggest that TDM-1 provides at most a small incremental benefit without a major change in prognosis for these women.

TDM-1 likely to be very expensive

Roche likely will charge a steep premium for TDM-1 compared with trastuzumab plus chemotherapy. I predict that Roche will commission studies of cost-effectiveness based on lower administration costs and cheaper treatment for toxicity (although compared with unnecessarily toxic “standard treatments”). It is not fashionable to discuss costs at medical meetings or in journals, but drug companies were careful to pay their lobbyists to induce Congress to forbid Medicare from negotiating prices in the legislation authorizing Medicare Part D prescription plans. Drug prices now seem to be set at the estimated maximum the market will bear (with secret discounts to large customers in a position to negotiate on price).

A rational purchaser of chemotherapy who is morally conscientious but frugal could not use currently available data to support purchasing TDM-1 at a substantial cost premium over trastuzumab plus generic chemotherapy (like paclitaxel, docetaxel, cyclophosphamide, gemcitabine, cisplatin, carboplatin, fluorouracil and vinorelbine, alone or in combination) or capecitabine. American taxpayers and those who purchase health insurance, be they employers or individuals, unnecessarily spend a great deal of money because they have not insisted on rational control of medical charges. It is likely that TDM-1 will add to these costs. Hopefully we will one day have a government that can help us spend our resources wisely.

Pertuzumab is very active, making the role of TDM-1 uncertain

The CLEOPATRA study does indeed suggest that dual antibody therapy with pertuzumab plus trastuzumab in addition to docetaxel is preferable to trastuzumab alone for HER2-positive metastatic breast cancer, although survival data are not yet mature.5 Adding pertuzumab increased the response rate from 69% to 80%, increased median progression-free survival from 12.4 to 18.5 months, and appeared to decrease the early death rate. Whether pertuzumab should continue with trastuzumab for the lifetime of the patient as chemotherapy varies is unclear. It is also not clear whether trastuzumab is really necessary in addition to the pertuzumab, or whether pertuzumab should be added to TDM-1.

These are fruitful lines of study rendered difficult to interpret because HER2-positive metastatic breast cancer has become a chronic disease, because these constitute only 20% of breast cancer patients, and because most patients with localized or regional HER2-positive breast cancer are now being cured by adjuvant trastuzumab and chemotherapy, leaving very few who develop metastatic disease later. Like follicular lymphoma, all patients with metastatic disease will likely receive multiple lines of therapy containing many or all of the active agents, and studies will be assessing their order of administration, whether they should be administered singly or in combinations of two to four at a time, and their length of administration.


Should we give TDM-1 now?

Absent more data, will I be giving TDM-1 if it is approved in 2012? Perhaps, but I will favor it only if the price is right, and if payers restrict the use of pertuzumab to first-line therapy. Now that pertuzumab is approved for first-line therapy based on the very impressive CLEOPATRA results, the appropriate comparator for first-line therapy with TDM-1 alone is now chemotherapy—docetaxel or vinorelbine, with the latter favored because it is less toxic and produces longer time to disease progression—plus trastuzumab plus pertuzumab. Pertuzumab may well need to be included with trastuzumab in the comparators for later rounds of chemotherapy as well.

References

Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355:2733-2743, PMID: 17192538.
Blackwell KL, Burstein HJ, Storniolo AM, et al. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 study. J Clin Oncol. 2012;30:2585-2592, PMID: 22689807.
von Minckwitz G, du Bois A, Schmidt M, et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a german breast group 26/breast international group 03-05 study. J Clin Oncol. 2009;27:1999-2006, PMID: 19289619.
Andersson M, Lidbrink E, Bjerre K, et al. Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study. J Clin Oncol. 2011;29:264-271, PMID: 21149659.
Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-119, PMID: 22149875.