Preserving Dose Intensity with Romiplostim Balances Bleeding Risk and GI Cancer Control in Patients With CIT

In the phase 3 RECITE trial (NCT03362177), the thrombopoietin receptor agonist (TPO-RA) romiplostim was found to significantly reduce chemotherapy dose delays and reductions over placebo in patients with gastrointestinal (GI) cancers who developed persistent chemotherapy-induced thrombocytopenia (CIT) during treatment.¹

By allowing chemotherapy dose intensity to be maintained, this approach could translate to long-term survival and disease control, potentially transforming how oncologists manage a notoriously difficult complication that currently lacks approved therapeutic options, according to Gerald Soff, MD.

"What we have shown in this study and other studies is that we can use romiplostim to keep the platelet counts adequate to continue chemotherapy at the full dose and on target,” Soff said in an interview with OncLive®. “The "holy grail" or "trillion-dollar question," is whether intervening to keep patients on full-dose chemotherapy results in an improvement in progression-free and overall survival. We do not have the answer yet.”

In addition to discussing these unanswered questions, Soff explained the concept of relative dose intensity and its importance in cancer treatment, shared topline efficacy and safety outcomes from RECITE, and emphasized the need for longer-term studies to assess the effect of romiplostim on survival outcomes.

Soff is a professor of clinical medicine in the Division of Hematology and chief of the Classical Hematology Section at the University of Miami Miller School of Medicine in Florida.

OncLive: How does chemotherapy impact blood cell production, and what is the role of TPO-RAs in GI malignancies?

Soff: In the cancer world, cancer-related treatments—particularly chemotherapy—suppress the bone marrow's production of blood cells, including white cells, red cells, and platelets. For 20 years or more, we have had a group of drugs, to treat low white cells that has been extremely effective, so the management of that area has been very established. For red blood cells, the management right now is simply transfusion support. There is a growth factor for red cells, but it is generally not safe in cancer patients. Therefore, what we are tackling is the third of these 3 areas, which is the platelets.

For many years, [my colleagues and I] have been working on a class of drugs called TPO-RAs, which are drugs that stimulate megakaryocytes to enhance platelet production. The drug class has been approved for several years for other reasons, classically for immune thrombocytopenia [ITP] and the pre-operative management of patients with liver disease and thrombocytopenia. In 2010, I started working on developing TPO-RAs for chemotherapy-induced thrombocytopenia [CIT], and our first paper came out around 2014. Since then, most of the work has been with an injectable TPO-RA called romiplostim.

What was the rationale for utilizing romiplostim to address CIT in GI cancer?

Romiplostim… [addresses] a very long-standing unmet need, which is the ability to treat CIT. [Prior to these investigations], the field was "dead in the water" for several years because nobody had previously gotten any of the TPO-RA drugs to work for CIT.

The first patient I treated was in 2010; romiplostim had just come out and was being used for ITP, and there was a patient with CIT whose platelets just were not coming back. There was really nothing to offer him, so I talked with the patient and his family and said, "Well, there is a new drug that boosts platelets." For several weeks, I treated [him] as if it were ITP, which is what romiplostim was first FDA-approved for. The patient responded fantastically; his platelets came up, he was able to continue chemotherapy for his colon cancer, and he lived for 3 years with excellent disease control. That [success] led to several other studies, including a [phase 2 study (NCT02052882)] published in the Journal of Clinical Oncology in 2019, which was the first randomized study [I conducted evaluating this agent for CIT]. Romiplostim has now become accepted into the National Comprehensive Cancer Network [NCCN] recommendations as a consideration for CIT.²

What was the outcome of the RECITE trial?

[RECITE was] a large phase 3 study [evaluating romiplostim] for this specific indication, and to keep it scientifically valid, we restricted it to a subpopulation of patients with GI cancer who received a particular type or group of chemotherapy regimens. [This was because] the more homogeneous the patients you treat [are], the easier it is to get clear statistical benefit. [Data from] the study were published [in March of] this year. The goal was to avoid modifications of the cancer regimen of the chemotherapy regimen because of recurrent CIT, and the [results] were quite dramatic.

[In total], 84% of [patients receiving romiplostim [n = 109] did not require dose modification to their chemotherapy regimens [vs] 36% in the placebo arm [n = 56], so it was highly significant [odds ratio, 10.16; 95% CI, 4.44-23.72; P < .001; risk ratio, 2.77; 95% CI, 1.78 to 4.30; P < .001].¹ We very clearly proved that romiplostim is effective. Of course, we already knew that because it's been published in smaller studies, but it's very good to have a large single study like this.

What should be known about the safety profile of romiplostim in patients with CIT?

The safety profile was good. Mostly, we care about the risk of thrombosis or blood clotting, and that has been a theoretical worry for a long time, but nobody has really shown that this class of drugs does indeed increase the risk of thrombosis in cancer patients. There was some evidence of blood clotting in the liver, though not in the cancer patients and not with romiplostim. We saw no significant difference in thrombosis and/or other adverse effects.

With romiplostim potentially allowing full-dose chemotherapy to be administered without dose delay or reduction, how could this translate to long-term outcomes and/or a shift in guidelines?

This is the critical question. There is a concept called relative dose intensity [RDI] and which means delivering the ideal amount of treatment—including the dose and the timing—for effectiveness against the cancer. If the dose must be reduced because of thrombocytopenia or other toxicities, we believe that could be harmful. If the doses must be delayed because of thrombocytopenia, that might also be harmful. We do know from other retrospective studies that if the RDI is reduced, then that is associated with poor outcomes. That has been shown in a few studies, but no one has shown that preventing the reduction in the RDI specifically because of thrombocytopenia is associated with that same adverse outcome.

The corollary is, if we keep the patients on a full dose because of the use of romiplostim to treat CIT, do they favorably improve outcomes? No one knows that yet because this study was only 3 cycles, and other studies have relatively short end points. How to get those data is tricky because it would require a multi-year study at best. We would have to conduct a similar study but not simply end it at 3 cycles. In other words, we would take [patients with GI cancer] who have CIT and [randomly assign] them to romiplostim or a placebo control to see how many stay on the full dose vs require reduced-dose chemotherapy and whether that translates into a benefit. I do not think that overall survival [OS] assessment is achievable, but progression-free survival [PFS] could be measured.

Current NCCN Guidelines for Hematopoietic Growth Factors indicate that possible use of romiplostim is a level 2A recommendation.² What are the advantages vs challenges created by this endorsement?

In a way, we have been handicapped by our own success, since the drug is available and NCCN-endorsed. Because of that earlier phase 2 study and because there are no alternative [treatment options for CIT management], the NCCN endorsed consideration of romiplostim in CIT. Although it is technically off-label and not FDA-approved, the NCCN endorsement means insurance companies will cover the costs, so patients get the drug all the time now.

[Therefore], if a patient has metastatic colon cancer and they are approached about going on a randomized study, their family will likely say, "Well, this is very interesting, Dr Soff, but what are the options if I don't go on the study?" I would [recommend that they] get romiplostim anyway because it is NCCN-endorsed. Then the patient would say, "Well, why would I go on a study where there is a chance I won't get the treatment when my very life depends on it?"

This means that a long-term study would be extremely hard [to conduct], as no rational person would go on that study and no IRB would ever authorize a study giving a placebo when the drug could already be dispensed.

In light of this, what are some more feasible next avenues for studying romiplostim going forward?

There are a couple of things we can do. Right now, the phase 3 study is only [evaluating romiplostim] in GI cancer, so we have to see data for other cancers. What I hope will happen is that people can conduct larger, more epidemiologically related studies. One could look at a large cancer population from the last 5 years and examine patients who had persistent CIT. We could compare those who received romiplostim for persistent CIT and those who did not to see if the drug was associated with better outcomes. Although you can never get a perfect match in the populations, one can get reasonable comparators to see if the drug is associated with improved OS and PFS.

References

1. Al-Samkari H, Muñoz C, Geredeli Ç, et al. Romiplostim versus placebo for chemotherapy-induced thrombocytopenia. N Engl J Med. 2026;394(11):1061-1073. doi:10.1056/NEJMoa2511882
2. Soff GA, Al-Samkari H, Leader A, et al. Romiplostim in chemotherapy-induced thrombocytopenia: a review of the literature. Cancer Med. 2024;13(15):e7429. doi:10.1002/cam4.7429