CIN: Takeaways From the PROTECTIVE-1 Study

Hope S. Rugo, MD, FASCO: We talked about febrile neutropenia. If you have no neutrophils, you can’t protect your GI [gastrointestinal] tract and your mucosa from letting bacteria cross it. That’s related to immunity, but we’ve become much more interested in this other aspect of host immunity that’s incredibly complex and poorly understood. We have had trouble understanding what the immunity to COVID-19 is, for example, and how to test for it seems very unclear. That’s generated a huge amount of research.

There have been some clinical trials looking at plinabulin, primarily as a myeloprotective agent. Tiffany, there were some studies both in breast cancer as well as non–small cell lung cancer?

Tiffany A. Traina, MD: Yes, that’s right. One of the first studies was called PROTECTIVE-1 and was just reported at ASCO [American Society of Clinical Oncology annual meeting] 2021. This was a phase 2/3 study of about 100 patients who had either non–small cell lung cancer, hormone-refractory prostate cancer, or breast cancer, and they were receiving treatment with docetaxel. There was randomization to either get pegfilgrastim the day after their docetaxel infusion, or receive docetaxel and same-day plinabulin.

The small study was designed as a noninferiority trial to look at days of severe neutropenia, and built into the trial were almost daily CBCs [complete blood counts] and tracking of neutrophil count. The study met its primary end point in terms of seeing significantly fewer days of severe neutropenia. Plinabulin in combination with docetaxel was noninferior to docetaxel with pegfilgrastim.

Some of the secondary end points were interesting as well. What we see as clinically meaningful, febrile neutropenia did not occur at all with the plinabulin arm but was about 2% with pegfilgrastim. Looking at infections rates, they were about half; the plinabulin arm was 7% vs around 15% with pegfilgrastim. Hospitalizations looked a little bit higher with plinabulin, 4% vs 2%. But when you looked at discontinuation of chemotherapy due to neutropenia, something that would be a meaningful end point as well, it was half, seen in only 13% of the plinabulin arm vs about 26% with pegfilgrastim.

From a mechanism of action point around supporting neutrophil count and adverse events associated with neutropenia, the plinabulin combination with docetaxel seemed encouraging and noninferior. The other advantage seen in terms of toxicity was that the plinabulin arm was associated with significantly less bone pain and less thrombocytopenia. I don’t know if that was anticipated, but it was observed.

Hope S. Rugo, MD, FASCO: You mentioned there’s less bone pain, which is interesting. Plinabulin is given intravenously on the same day as the chemotherapy, right? That’s huge for us in terms of timing, if it turns out that this is something we want to be considering. What other adverse events do you see with this drug?

Tiffany A. Traina, MD: Plinabulin is about a 30-minute infusion given the day of treatment, which is convenient. There was some low-grade risk of infusion reaction, such as GI [gastrointestinal] toxicity, a bit of nausea, diarrhea, and fatigue. It can be potentially hard to tease out what’s docetaxel related, given that both arms are receiving backbone chemotherapy there, but it did appear well tolerated.

Hope S. Rugo, MD, FASCO: Before we move on to discussing the PROTECTIVE-2 trial, I want to get feedback from Rita and Bill about what they think about the PROTECTIVE-1 data—noninferiority, a drug that can be given intravenously the same day, and with less bone pain.

Rita Nanda, MD: It’s quite convenient for patients, they’re already there for treatment and they don’t have to self-administer growth factors at home. I thought it was exciting to hear, from the data that Tiffany just shared, the lower degree of thrombocytopenia that was observed versus with growth factors.

We think about platinum agents and our therapies, we’re increasingly using platinum in our armamentarium of drugs. We use platinum in the early stage setting and now for triple-negative breast cancer, and it is widely used in the advanced cancer setting, particularly for triple-negative disease. That can become an issue, in addition to neutropenia. I think that was the part of the preliminary data from the study that was quite appealing, and then obviously the bone pain that patients didn’t experience, which can certainly be debilitating for a small segment of patients who get growth factor.

William J. Gradishar, MD: When we talk about drugs, we’re usually worried about the pleiotropic effect, or the off-target effect. Basically, what we’re describing here is the drug is pretty well tolerated, easy to give, and the off-target effects are favorable for the patient, regarding neutropenia and a potential anticancer effect. Right now it looks like a very favorable kind of drug to be using.

Transcript edited for clarity.