Since I began writing here at Forbes, it’s become harder to keep up with new oncology drugs. So many medicines are being tested, who can keep track of them all?
Days ago, investigators reported results of a multinational trial of an immune drug, combined with chemotherapy, in patients with advanced triple negative breast cancer (TNBC), an aggressive form. Roche sponsored the study. Dr. Peter Schmid presented the findings at the annual ESMO meeting. Patients received nab-paclitaxel (a chemo agent sold as Abraxane, Celgene) with or without atezolizumab (a PDL-1 antibody approved for use in bladder and lung cancer, sold as Tecentriq, Genentech). The trial is called “Impassion130.”
A press release touted “success.” You may have read of terrific findings in The New York Times: “Women with an aggressive type of breast cancer lived longer if they received immunotherapy plus chemotherapy, rather than chemo alone.” Researchers called the study “a long-awaited breakthrough for immunotherapy in breast cancer” or “a gamechanger,” it reported. “Immunotherapy-chemo combo extends life,” CNN stated. A Roche executive told Bloomberg the data are “stunning.” A more cautious take came from the AP, beneath a positive (“big win”) headline.
Unfortunately, the IMpassion130 results don’t quite match the spin. As reported, progression-free survival (PFS) was 7.2 months for patients on atezolizumab with nab-paclitaxel vs. 5.5 months for those on placebo with chemo, with median follow-up just over a year. This small difference was deemed meaningful from a statistical perspective based on the p-value.
The wow with atezolizumab—a trend toward improved overall survival in patients with advanced TNBC—came only after some statistical shenanigans with addition of a second trial endpoint and enrollment of more patients, as described. At the data cut-off date, more patients in the placebo arm of the IMpassion130 trial had died; overall survival was 21.3 months for the immune drug vs. 17.6 months for the placebo, all with chemo (nab-paclitaxel). This finding was not statistically significant, but it came close (p=0.8).
Greater buzz came by way of a subset analysis, and that’s where I think this paper gets dark and fuzzy. Investigators defined as “PD-L1 positive” as cases in which the pathology showed “expression on tumor infiltrating immune cells of 1% or more.” Then they looked at 369 PD-L1 positive TNBC patients, divided equally between the immune drug and placebo arms, and reported that the drug benefited the PD-L1 positive subgroup. In that subset, the drug extended overall survival to 25 months, from 15.5 months.
Previously I’ve covered atezolizumab in a smaller trial of TNBC, also by Dr. Peter Schmid, who at the 2017 AACR meeting reported companion studies of PD-L1 staining by immunohistochemistry. This kind of test for PD-L1 is a notoriously unreliable biomarker. Perhaps in the future we’ll have computers analyzing millions of cells stained and objectively assessing the degree of PD-L1 positivity in TNBC pathology specimens, but that didn’t’ happen in this trial. How a pathologist or machine might quantify “tumor infiltrating immune cells,” or TILs, can be a tricky business in itself, and it underlies the PD-L1 readout.
Atezolizumab is 1 of 6 immune oncology drugs called checkpoint inhibitors, approved by the FDA for other malignancies, that interfere with the programmed death (PD) receptor or its ligands. These antibodies, given intravenously, have potential to unleash a person’s immune system against a tumor. That’s an appealing concept. These are expensive, sometimes toxic and sometimes life-extending drugs. There’s been little evidence, until now, to support their use in breast cancer.
Triple negative breast cancer represents a particularly hard-to-treat form; by definition, the malignant cells lack estrogen receptors, progesterone receptors or Her2+; patients with TNBC aren’t eligible for drugs targeting those hormones or Her2. Some 12% of all breast cancer pathology is triple negative. This subtype tends to grow faster and be more lethal, relative to hormone-sensitive cases; it affects younger women and African Americans disproportionately. For sure, there’s an unmet need; many patients, thousands, are desperate for something that has a good probability of helping them to live longer.
The improved results appear to apply to a large fraction of some of the most desperate breast cancer patients: Some 369 of 902 in this trial of advanced TNBC, or around 40%, were deemed PD-L1 positive. Already Roche is sponsoring several other, ongoing studies trials of atezolizumab in TNBC. IMpassion030 would recruit 2300 patients with stage 2 or 3 TNBC. IMpassion131 aims to recruit 540 patients with advanced TNBC. After the latest news, I fear a run on slots! Which is concerning, and sad, among other reasons because most patients enrolled in the IMpassion130 trial died within 2 years.
I don't attribute the hype only to the October press release, or to investors' eagerness. Many doctors, patients and even journalists want there to be good news for patients living with advanced TNBC. This is a condition for which FDA-approved treatments are few, and effective treatments may be fewer. We’ve heard about new immune drugs helping other cancer patients; wouldn’t it be great if these agents delivered remissions in patients with metastatic breast cancer who, it is reported, have a median life expectancy of less than 3 years? For those with TNBC, estimates for median survival fall under 18 months. I wish the data for atezolizumab in TNBC were more convincing.
For now, as an advocate, I’d say I’m encouraged. It’s evident that some patients with advanced TNBC benefit from this immune drug given with chemo. Based on all of the above, and largeness of the multinational Roche-sponsored trials, I have no doubt that many patients with breast cancer will “volunteer” to participate in studies of atezolizumab. A question for each patient should be: Does this medicine offer the best shot at improving survival or quality-of-life, among all drugs approved or available in clinical trials, in my case?
In an upcoming post, I plan to consider these findings in context of other types of drugs for advanced breast cancer. Meanwhile, for those curious or wanting additional perspective, there’s interesting commentary about these results on Reddit.