CIN: Implications of the PROTECTIVE-2 Study

Hope S. Rugo, MD, FASCO: The next thing is the idea of combining plinabulin. The question is, can you give a new drug, unless it’s superior to what we already have? We talked about being comfortable with pegfilgrastim and filgrastim. The next study, which used the name PROTECTIVE-2, looked at the combination of plinabulin with pegfilgrastim. What was the rationale for using this combination, and what would be a benefit there? Maybe you could tell us a little bit about the updated data from PROTECTIVE-2 presented at ASCO [American Society of Clinical Oncology annual meeting] this year, Tiffany?

Tiffany A. Traina, MD: The rationale that was interesting and observed in PROTECTIVE-1 was that the benefit in the timing of plinabulin protection appeared to be from day 1 through day 10. Our experience with pegfilgrastim is it kicks in a bit later in its protection against neutropenia. We still get that nadir and then we get quicker recovery.

One rationale for putting these 2 agents together, plinabulin plus pegfilgrastim, would be more of the continuous protection against neutropenia throughout that intercycle duration. PROTECTIVE-2 was designed for patients with breast cancer. It was a randomized study with about 200 patients receiving TAC [docetaxel,doxorubicin,cyclophosphamide] chemotherapy, so not a regimen we use often, but polychemotherapy and a high risk of neutropenia. The patients received either TAC with pegfilgrastim, or TAC with pegfilgrastim plus plinabulin. Here the primary end point was designed as superiority. It sounds like a bunch of double negatives, but lack of grade 4 neutropenia was that primary end point. The study met that primary end point, where the plinabulin plus pegfilgrastim arm came in at about 32% of patients not experiencing grade 4 neutropenia. The pegfilgrastim arm was about 14%. So it definitely met that superiority primary end point.

Again, not unlike PROTECTIVE-1, looking at those clinically meaningful end points that are resonating for us and our patients, febrile neutropenia was significantly lower in the combination arm of both plinabulin and pegfilgrastim, with about 4% vs 14%. They had an end point of profound neutropenia, measured as an ANC [absolute neutrophil count] of 100 per μL, which was much lower with the plinabulin plus pegfilgrastim arm, about 21% vs 46%, and hospitalization due to febrile neutropenia was significantly lower. All of those efficacy end points favored the doublet of plinabulin plus pegfilgrastim. Then building on that early signal of less bone pain really translated in PROTECTIVE-2 as well. Bone pain with the combination was only 6% as opposed to 28% with pegfilgrastim. So it’s certainly more comfortable for our patients.

The last piece I’ll share, which I’m not quite sure why this occurred, but overall looking at grade 4 adverse events between these 2 arms, plinabulin plus pegfilgrastim had 20% lower grade 4 adverse events with TAC compared to TAC plus pegfilgrastim. It seems to be having an impact beyond just affecting the neutrophil count.

Hope S. Rugo, MD, FASCO: It’s very interesting, and the mechanisms for understanding that I think are also fascinating. There was also a little bit of data on quality of life as well in patients who had received this. I don’t know if you want to mention anything about that Rita, the quality of life data, and how that affects our ability to keep patients on treatment, particularly in the early stage setting.

Rita Nanda, MD: To see an agent that not only has all of these positive effects but at the same time improves the quality of life for patients who are on a very aggressive chemotherapy regimen is very important. It’s been many years since I’ve used TAC, but it’s a very challenging regimen to give and to tolerate. I think an improvement in quality of life in addition to the reduction of adverse events and chemotherapy-induced neutropenia and febrile neutropenia is a home run.

Hope S. Rugo, MD, FASCO: Based on data like this, would you consider using it for other regimens where we use pegfilgrastim? For example, I think AC [doxorubicin, cyclophosphamide] dose-dense, and docetaxel, carboplatin are probably the 2 main reasons. Docetaxel, cyclophosphamide doesn’t need quite as much, we just use them because it’s convenient.

Rita Nanda, MD: I think that’s a great question. I think as we’re looking into triple-negative breast cancer and incorporating more chemotherapy into our early stage treatment, we’ve got data that carboplatin by itself improves event-free survival, and adding pembrolizumab into the mix. It’s a very challenging chemotherapy regimen in the early stage triple-negative setting. Quality of life is important, and obviously, cytopenias increase when we’re adding yet another chemotherapy regimen into the mix. I think this data around the potential to augment dendritic cell activation, and antigen presentation, as well as the activation of T cells when adding immunotherapy into the mix, it’s interesting. I think there are a lot of opportunities for investigation in the context of other regimens that we use for breast cancer, in particular early stage triple-negative disease.

Hope S. Rugo, MD, FASCO: We talked a little bit about an immunomodulatory effect. There has been the DUBLIN-3 trial, looking at non–small cell lung cancer and efficacy, which was presented at ESMO [European Society for Medical Oncology Congress] this year. We don’t need to go into detail about the data, but what did you think about that? They showed an improvement in overall survival and some of the other efficacy endpoints.Rita Nanda, MD: I think that’s interesting, and the differences that were presented were modest, but to see an agent that not only prevents neutropenia, but also has anticancer properties is pretty exciting. It is certainly worthy of additional investigation, particularly as we’re moving immunotherapy into the early stage setting.

Hope S. Rugo, MD, FASCO: There are some approaches using plinabulin to augment immune checkpoint inhibitors that are being worked on, both with radiation therapy and a combination of nivolumab and ipilimumab. I think that where that ends up with breast cancer of course remains to be seen, but we can certainly use help in using checkpoint inhibitors in patients with breast cancer because even with our survival benefits in the metastatic setting, survival is still reasonably short. It will be interesting to see. I think this is a whole other area of investigation.

Transcript edited for clarity.