This article describes the early results from a preliminary study of a novel compound for the treatment of a form of metastatic breast cancer. It provides solid background regarding the components in the compound and how it works. However, the article provides inadequate context, misinterprets a key result, and does not provide balance regarding potential serious harms and the lack of data for overall survival. We also question the sole outside source being an investigator who receives funding from the same drug company that funded this study.
Patients with metastatic breast cancer have a poor prognosis, and there is a need for new effective treatments.
Costs are not mentioned in the article. As the expense of Herceptin (trastuzumab) alone has come up in public discourse, such as in this Atlantic article, it stands to reason that a novel compound including trastuzumab would have economic considerations.
While the article does present numbers for the outcomes, it does not mention the number of subjects in the study, a key piece of information needed to put the outcomes in perspective. There are further concerns about the language used to describe the results. Most importantly, the article claims that "Women remained cancer-free for an average of seven months." This sentence appears to be a significant misinterpretation of the data because the Dana Farber press release states that the median time to progression was 7.3 months. That doesn’t mean the cancer vanished in these subjects for 7 months: it was there but it just didn’t progress. The study abstract from the conference does not provide the relevant data, and thus we cannot confirm the numbers and metrics presented by the author. If, however, this was a misinterpretation, it’s significant because a reduction in tumor size (only observed in one third of women) is not the same as being cancer free.
There are several other points of critique regarding how potential benefits are described. The key result that "Tumors shrank in one-third of women with metastatic breast cancer given T-DM1" fails to mention that this population was a minority subset of metastatic breast cancer: those with HER2-positive disease. Perhaps readers would infer this caveat from the discussion of HER2 prevalence in the article’s second section, but it should have been stated much earlier, at the very least when the study population was described. Otherwise it overstates the potential applicability of the benefits.
The title of the article "drug shrinks tumors" is an exaggeration: tumors only shrunk in one third of subjects. Growth was stable in another 12% of subjects, which means that the other half of subjects progressed during the study.
The editorial definition of the term "refractory" as "sick" is overly simplistic and perhaps misleading.
The article does mention that all the women experienced side effects. It left out some potential harms and didn’t quantify any specific adverse events, simply noting that side effects were "typically the fatigue and nausea often seen with chemotherapy." The Genentech press release mentions and quantifies severe adverse events that were not mentioned here, including low platelet levels in about 6% of patients.
The article does describe a death that occurred during the trial, although see the "sources" criterion for a comment about the outside source that provided the interpretation. Especially because it doesn’t present how many women were enrolled in the trial, the article needs a truly outside expert’s interpretation of this death. In general, more discussion and quantification of the harms would have matched the quantified benefits.
Also not noted are the potential risks associated with Herceptin, a component of T-DM1. For instance, this drug is associated with cardiac toxicity; while the risk of heart failure may at present not be a dominant concern in the treatment of metastatic breast cancer, the risk could become more relevant if T-DM1 were truly able to increase lifespan. Other black box warnings of Herception not mentioned include the potential for serious infusion reactions, sometimes fatal.
The article doesn’t mention that these are early results from the study, nor that the study was a Phase II trial. It also doesn’t provide the number of subjects enrolled. And it’s not explained that because these results were presented at a conference, they have not been published and undergone the same peer review as a published article.
Also, the article never mentions the lack of overall survival data, even though it may be forthcoming as further results from the study become available. Context on progression-free data would have been helpful because such data can’t tell us whether the women actually lived longer or with a better quality of life or burden of symptoms. Especially in metastatic disease, many agents that produce progression-free periods ultimately have no effect on overall survival.
The article doesn’t exaggerate the burden of metastatic breast cancer or underestimate the options for patients with refractory disease. It also points out that only a subset of patients with the disease are HER2-positive; although not explicit, it’s implied that only this subset would be eligible for the investigational treatment.
The article includes dramatic quotes from the investigator, that the results were "unheard of" and "as good as we’ve ever seen" in this population. While a source presumably unrelated to the study was used and confirmed that the results were "exceptional," Edith Perez has received grant funding from Genentech, a sponsor of the Krop study. (Dr. Perez is also the lead author on a Genentech-supported study of trastuzumab presented at the same conference.) Acknowledging this connection, or citing another or an additional specialist without ties to the sponsor, would have added more balance, or at least the appearance of balance, to the claims of efficacy and tolerability, including the interpretation of the death that occurred during the study.
This topic is not addressed directly. The nature of the study design implies that perhaps there are no alternatives, given that subjects are described as having "refractory" breast cancers, and given that there are baseline data regarding a median of 7 other therapies for metastatic disease. However, the abstract states that the range of prior therapies was as low as 1, so the role of possible alternatives is not clear. Because the end of the article mentions other trials that are comparing T-DM1 to other therapies, it would seem that a more explicit discussion of alternatives — or that there were no alternatives for these subjects — would clarify the potential treatment role of T-DM1.
By not mentioning that this was a Phase II trial — an early stage, uncontrolled, non-randomized study — and that the compound is still investigational, the article is unclear about T-DM1’s development status and prospects for becoming available in the future. In addition, some of the results are preliminary, or "immature" according to Genentech press release, with final results to be presented at a future meeting. The fact that these are early data is also not mentioned.
The article does mention that other studies of T-DM1 are ongoing and are comparing T-DM1 to other treatments. However, the key explanation is missing that the other ongoing trial is Phase III, and comparisons of T-DM1 to other treatments is the key to its FDA approval for use in patients.
The article describes the novelty of the compound as a combination of an existing drug and a derivation of an older, abandoned drug. It also describes that there are other ongoing studies of T-DM1.
The article does not appear to have overly relied on a news release. The investigator and specialist quotes were "as told to WebMD."
Systematic, Criteria-Driven
The tale of two “negative” studies. Or, how spin is applied to make research findings look more impressive. A must read. https://johnmandrola.substack.com/p/the-tale-of-two-negative-studies
The @nytimes chose to interview one of the editors of the @AnnalsofIM (publisher of this paper) who "gushed with extraordinary glee: It’s huge! There are very few things that reduce your mortality by 30%."
Turns out coffee is not one of those few things despite all that glee. https://twitter.com/garyschwitzer/status/1533202075928215558
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