This Penn Medicine news release describes two trials of experiemental breast cancer treatments, neratinib and veliparib with carboplatin, with potential to be used alongside chemotherapy to eradicate residual cancer cells before an operation to remove a breast cancer tumor for patients with aggressive HER2-positive or triple negative breast cancer.
While neglecting to mention alternative treatments already available, and some serious side-effects of neratinib treatment, the news release does a decent job of not over-claiming for the results of these phase 2 trials. The trials measured the likelihood that the treatments would be successful in larger phase 3 trials, and the news release comes close to claiming this research milestone has important implications for patients and doctors, which would have been unjustified.
The news release does a good job of highlighting why these potential new breast cancer treatments might be important, but should be weighted with the major proviso of waiting on the results of phase 3 trials.
These experimental drugs are part of the I-SPY 2 Trial (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging And moLecular Analysis 2), a heavily accelerated method of analyzing potential new drugs using fewer patient volunteers and at reduced cost, according to an interview with the principal investigator.
The drugs in the trial are aimed at more aggressive subtypes of breast cancers where HER2/neu (human epidermal growth factor receptor) is over-expressed and in triple negative breast cancers.
While response rates to chemotherapy can be excellent in these aggressive cancers, some tumors progress despite aggressive therapy. With 40,000 U.S. women dying every year due to metastatic breast cancer, patients and the general public are hanging on every new study that is published, waiting for some bit of news to offer hope, especially to those dying of the disease.
No mention is made of the costs of either neratinib or veliparib/carboplatin. Both treatments are experimental and so do not have a market price, but it should be possible to give a rough estimate of the price range of new cancer drugs when they gain regulatory approval. Although the trials detailed in the news release are too early stage to talk about impending approvals, given that the release raises the possibility of ‘promise for patients’ (in the headline), we think it’s not too early to consider how much patients would have to pay.
The news release doesn’t include any statistics on the benefits of the treatments but does make strong pitches on their effectiveness:
“Compared to standard therapies alone, the drugs tested in the trial substantially reduced the presence of residual disease in the breast tissue and lymph nodes (known as achieving pathological complete response, or “pCR”) when administered before surgery,” according to a co-investigator.
“… when added to standard, neoadjuvant chemotherapy, the combination of the molecularly targeted experimental drug veliparib plus carboplatin showed sufficient improvement to meet the pre-specified threshold for “graduation” from the trial, signifying a high likelihood for success in a modest, confirmatory phase 3 neoadjuvant trial in the triple negative subset. Likewise, the experimental drug neratinib was found to have sufficient improvement in the pCR rate for patients in the HER2-positive/HR-negative subset, that it too was “graduated” from the I-SPY 2 trial.”
This is a close call. These are small, phase 2 trials, and therefore not designed to provide clear data on drug efficacy. And had the release made that point explicitly, perhaps we’d be more inclined to rule this Satisfactory. However, we think that readers deserve to know what “substantially reduced” and “sufficient improvement” refer to, particularly when the researchers are making strong claims about potential efficacy. How many patients benefited? What is meant by “high likelihood of success” in a future trial? We wished for some numbers to make this clearer.
Although highlighted in the NEJM paper describing the neratinib trial, the news release doesn’t mention that 38% of patients receiving the drug experienced severe diarrhea, requiring a change to the trial protocol.
A related NEJM editorial also noted that a phase 3 trial including trastuzumab, pertuzumab and neratinib (compared to standard of care trastuzumab and pertuzumab) could result in significant side effects when added to chemotherapy, and they raise concerns of over-treatment of a large number of patients.
The news release doesn’t overclaim for the effectiveness of the two treatments. However, by presenting suggestive evidence that they might be successful in a phase 3 clinical trial as “new treatment options on the horizon,” the news release isn’t clear on how strong the evidence actually is.
It’s well known that the failure rate of phase 3 trials is high; between 25% and 75% depending on who you ask. This is often because data that looked significant in small phase 2 trials ends up being a statistical blip when tested in larger populations.
The related editorial in the NEJM describes how the favorable effects seen in the two trials could be from factors other than the effectiveness of the drugs themselves, and predicts potential problems with scaling up to phase 3 trials. The editorial notes that a significant benefit has already been seen in patients with triple negative breast cancer with the additional of platinum agents, and that the benefit in the triple negative patients in the I-SPY 2 study might have been from these agents, not the PARP inhibitor (targeted agent) veliparib.
However, the news release does explain why the I-SPY 2 trial design is optimized for identifying compounds which are most likely to be successful in phase 3 trials. Since this feature of trial design is the backbone of the NEJM papers described by the news release, it seems fair to give a satisfactory rating.
Aggressive subtypes of breast cancers are common, serious diseases with fewer treatment options and are highly worthy of public attention.
The sponsor of the trial is given as QuantumLeap Healthcare Collaborative, a non-profit set up by Silicon Valley entrepreneurs.
The manufacturers of neratinib and veliparib — Puma Biotechnology and Abbvie, respectively — are listed as “strategic partners” on the QuantumLeap Healthcare Collaborative website, suggesting potential financial involvement. That’s a financial tie that should have been noted in the news release as well.
Both NEJM papers explicitly state that the pharmaceutical companies had no direct involvement in the trials except to provide the drugs.
No alternatives are mentioned for treatment of either HER2-positive or triple negative breast cancer. This is a major oversight given that a variety of treatments, such as Herceptin, are available for HER2-positive breast cancer.
Both neratinib and veliptarib are described as “experimental” so it is clear that neither are currently available outside of clinical trials.
Both neratinib and veliptarib are described as new drugs in the news release, but they are talked about in the context of augmenting standard cancer therapy. No suggestion is made that these drugs are a sea change in how breast cancer is treated.
The phrases “‘promise for patients” and “treatments on the horizon” teeter towards unjustifiable language since the trials being described have produced data on how likely the treatments are to make it through a phase 3 trial, rather than being meaningful for patients and doctors. We don’t think the language is so sensationalistic as to warrant an unsatisfactory rating.
The release seems to be making the case that the trial design, rather than the drug data, is the cause for excitement.