Data from the phase 2 trial ROCKstar clinical trial (NCT03640481) demonstrated that patients with chronic graft-versus-host-disease (GVHD) and were treated with belumosudil (Rezurock) experienced clinically meaningful, durable responses. These results were consistent among patients despite differences in prior treatments, severity of disease and number of organs affected, according to the published study in 

The best overall response rate (ORR) achieved with belumosudil at a once-daily dose of 200 mg was 74% (95% CI, 62%-84%) and 77% (95% CI, 65%-87%) when given at a twice-daily dose of 200 mg. High ORRs, ranging from 61% to 85%, were reported in all subgroups analyzed.

The efficacy demonstrated with belumosudil was maintained, regardless of previous treatment with ibrutinib (Imbruvica; n = 46) or ruxolitinib (Jakafi; n = 38). The ORRs in the ruxolitinib and ibrutinib subsets were 68% (95% CI, 51%-83%) and 74% (95% CI, 59%-86%), respectively.

Additionally, best ORR was observed across all affected organs. The ORRs observed in the skin, eyes, mouth, liver, lungs, joint/fascia, upper gastrointestinal (GI) tract, lower GI tract, and the esophagus at 37%, 42%, 55%, 39%, 26%, 71%, 52%, 69%, and 45%, respectively.

“Belumosudil is very effective in inducing responses across all organs affected by chronic GVHD and is safe and well tolerated. It is exciting to see the development of new interventions that can help patients,” study investigator Corey Cutler, MD, MPH, FRCPC, associate professor of medicine at Harvard Medical School and medical director of the Adult Stem Cell Transplantation Program at Dana-Farber Cancer Institute, stated in a press release.

An oral selective inhibitor of ROCK2, belumosudil was designed to reduce type 17 and follicular helper T cells through downregulation of STAT3 and to strengthen regulatory T cells through the upregulation of STAT5.

In July 2021, the FDA approved belumosudi

 for use in adult and pediatric patients aged 12 years and older with chronic GVHD following failure of at least 2 prior lines of systemic therapy.

The regulatory decision was supported by data from ROCKstar.

In the multicenter registration phase 2 trial, investigators examined 2 doses of belumosudil, at 200 mg daily (n = 66) and 200 mg twice daily (n = 66) in patients with chronic GVHD who had previously received 2 to 5 lines of treatment.

To be eligible for participation, patients needed to have received an allogeneic hematopoietic cell transplant, be at least 12 years of age, and have persistent chronic GVHD manifestations following 2 to 5 previous systemic lines of therapy. Patients needed to be on stable corticosteroids for 2 weeks before screening, and they needed to have a Karnofsky or Lansky Performance Status Scale score of 60 or higher.

If patients experienced a relapse of their underlying malignancy, had a National Institutes of Health (NIH) lung symptom score of 3, and had developed lymphoproliferative disease following transplant, they were excluded. Other exclusion criteria included liver transaminases greater than 3 times the upper limit of normal (ULN), a total bilirubin of more than 1.5 times the ULN for any reason, current receipt of ibrutinib.

Study participants received belumosudil at either once-daily 200 mg or twice-daily 200 mg in patients with chronic GVHD. Patients were stratified 1:1 by chronic GVHD severity and previous exposure to ibrutinib. Patients received belumosudil continuously until significant disease progression or intolerable toxicity.

The primary end point of the trial was best ORR at any time, and important secondary end points comprised duration of response (DOR), time to response (TTR), changes in Lee Symptom Scale (LSS), failure-free survival (FFS), corticosteroid dose reductions, overall survival, and safety.

A total of 132 patients were enrolled to the trial between October 2018 and August 2019. Baseline demographics and clinical characteristics were found to be comparable across the arms. The median age of participants was 56 years (range, 21-77), and the overall median time from diagnosis to enrollment was 28 months (range, 2-162).

At the time of screening, 31% of patients had moderate disease and 67% had severe disease. Moreover, 52% had involvement of 4 or more organs. Additionally, 36% of patients were found to have lung involvement at baseline; 38% of these patients had a NIH lung symptom score of 2. Patients received a median of 3 prior systemic lines of treatment. Additionally, 72% of patients had disease that was refractory to their last systemic line of treatment received, 34% had prior ibrutinib, 29% had prior ruxolitinib, and 72% had 3 or more prior lines of therapy. The median corticosteroid dose at baseline was 0.2 mg/kg/day of prednisone equivalent; the mean dose was 0.25 mg/kg/day.

At the time of the data analysis, 37% of patients were still on belumosudil treatment. Patients who discontinued treatment did so because of disease progression (n = 21), voluntary withdrawal (n = 13), toxicities (n = 16), physician decision (n = 11), progression of an underlying malignancy (n = 5), death because of an underlying malignancy or progression (n = 4), other (n = 7), and nonadherence to treatment (n = 3).

Additional data from the study showed that 7 patients experienced a complete response (CR) in all affected organs. Of 12 patients with lung responses based on normalization of FEV1, 3 achieved a CR and there were an additional 3 CRs based on a reduction in NIH lung symptom score from 1 to 0. Six additional patients achieved a partial response (PR).

Of the 41 patients who experienced skin responses, 11 were noted to have a decrease in sclerotic features, 15 had a decrease in body surface area (BSA) involvement, and 13 had improvements in both BSA involvement and sclerotic features.

Responses were found to occur rapidly. The median TTR was 5 weeks (range, 4-66). Within 6 months of treatment, 91% of patients experienced responses; the remaining 9% of patients experienced responses after 6 to 12 months of treatment. Notably, 59% of patients who responded to belumosudil continued to respond for 20 weeks or longer. The median DOR was 54 weeks in responders. The FFS rates achieved with the agent at 6 months and 12 months were 75% (95% CI, 66%-81%) and 56% (95% CI, 47%-64%), respectively.

With belumosudil, 65% of patients reduced their corticosteroid dose. The mean dose resulted in a 45% reduction in the modified intention-to-treat (mITT) population; the mean dose reduction was 54% in responders. Moreover, 21% of patients discontinued treatment with corticosteroids. Twenty-two percent of patients were able to discontinue treatment with calcineurin inhibitors; 20% discontinued sirolimus (Rapamune) and 21% discontinued mycophenolate mofetil.

Lastly, treatment with belumosudil at a daily-dose of 200 mg and a twice-daily dose of 200 mg improved the 7-day LSS summary score by 59% and 62%, respectively, from baseline in the mITT population. Among responders, the rates with the once-daily and twice-daily doses were 69% and 71%, respectively; in nonresponders, these rates were 29% and 33%, respectively.

Belumosudil was well tolerated, with toxicities consistent with those expected in patient with chronic GVHD who were receiving corticosteroid therapy. Thirty-eight percent of patients experienced 1 or more serious adverse effects (AEs), with pneumonia being the most frequently reported (7%). The most common grade 3 or 4 toxicities comprised pneumonia (8%), hypertension (6%), and hyperglycemia (5%).

Of 83 patients who discontinued treatment with belumosudil, 21% did so because of toxicity, 12% because of potential drug-related toxicities, 4% because of progression of underlying malignant disease, and 16% because of progression of chronic GVHD.

“Based on the similar efficacy and safety observed in this study, 200 mg once daily is the preferred dosage for the treatment of chronic GVHD. Although the 200-mg twice-daily dose showed higher responses in certain organs, such as the skin, and slightly fewer AEs, the difference compared with the 200-mg twice-daily dose was not deemed significant,” the studfy authors concluded. “Because of its unique mechanism of action, belumosudil may have broad therapeutic potential beyond chronic GVHD and is currently being studied in systemic sclerosis, with plans for additional studies in other immune disorders.”

Cutler CS, Lee SJ, Arai S, et al. Belumosudil for chronic graft-versus-host disease (cGVHD) after 2 or more prior lines of therapy: the ROCKstar study. 

. Published online July 15, 2021. doi:10.1182/blood.2021012021

Kadmon announces pivotal trial data published in the journal Blood for REZUROCK (belumosudil) in chronic graft-versus-host disease (cGVHD). News release. Kadmon Holdings, Inc. July 19, 2021. Accessed July 19, 2021. 

US FDA grants full approval of REZUROCK (TM) (belumosudil) for the treatment of patients with chronic graft-versus-host disease (cGVHD). News release. Kadmon Holdings, Inc. July 16, 2021. Accessed July 19, 2021. 

This article was originally published as 

“Belumosudil Represents Promising Newly-Approved Option for Chronic GVHD”

Articles

A recent study showed that belumosudil induced clinically meaningful, durable responses among a varied cohort of patients with chronic graft-versus-host-disease. 

Newly-Approved Belumosudil Yields High Overall Response Rate in Patients with Chronic Graft-Versus-Host-Disease

Belumosudil (Rezurock) has received the greenlight from the FDA for the treatment of adult and pediatric patients aged 12 years and older with chronic graft-versus-host disease following failure of at least 2 prior lines of systemic therapy, according to Kadmon, the manufacturer of the agent.1

The regulatory decision is based on safety and efficacy data from the phase 3 ROCKstar trial (KD025-213), which showed that the agent elicited an overall response rate of 75% (95% CI, 63%-85%) through cycle 7 day 1 of treatment; 6% of patients achieved a complete response and 69% experienced a partial response.

"[Belumosudil] represents a new treatment paradigm for thousands of cGVHD patients, including those with difficult-to-treat manifestations like fibrosis," Corey Cutler, MD, MPH, FRCPC, associate professor of medicine at Harvard Medical School and medical director, Adult Stem Cell Transplantation Program at the Dana-Farber Cancer Institute, stated in a press release. "[Belumosudil] has shown robust and durable responses across the spectrum of cGVHD and is safe and well tolerated, allowing patients to stay on therapy and achieve meaningful benefit from treatment."

The open-label, multicenter trial enrolled patients with chronic GVHD who had previously received 2 to 5 lines of systemic therapy. A total of 65 patients received treatment with oral belumosudil at a once-daily dose of 200 mg.

The median time from diagnosis of chronic GVHD was 25.3 months and just under half of patients (48%) had 4 or more organs involved. Notably, participants had received a median of 3 prior lines of systemic therapy and 78% were refractory to the last therapy they had received.

Additional data from the trial indicated that the median time to first response with belumosudil was 1.8 months. Moreover, 62% of those who responded to the agent did not need new systemic therapy for at least 1 year after their response. The median duration of response was 1.9 months.

Investigators also reported clinically meaningful improvements from baseline with regard to Lee Symptom Scale score in 52% of patients through cycle 7 day 1 of treatment with the drug.

"Patients receiving [belumosudil] reported significant improvements in chronic GVHD symptoms, showing that not only did treatment result in organ responses, but it also made people feel better. This is so important for a chronic disease with a high symptom burden," Stephanie Lee, MD, MPH, professor at the Fred Hutchinson Cancer Research Center and the University of Washington School of Medicine, and research director of the Long-Term Follow-Up Program at Fred Hutchinson, added in the release.

Regarding safety, belumosudil was found to be well tolerated and toxicities proved to be consistent with what had been expected in patients with advanced chronic GVHD who were receiving corticosteroids and/or other immunosuppressants.

1. US FDA grants full approval of REZUROCK (TM) (belumosudil) for the treatment of patients with chronic graft-versus-host disease (cGVHD). News release. Kadmon Holdings, Inc. July 16, 2021. Accessed July 16, 2021. https://bit.ly/3z14sTW

This article was originally published on OncLive as, "

FDA Grants Full Approval to Belumosudil for Chronic GVHD

The FDA has approved belumosudil for the treatment of patients aged 12 years and older with chronic graft-versus-host disease following failure of at least 2 prior lines of therapy.

Belumosudil Receives Full FDA Approval for Chronic Graft-Versus-Host Disease

Clinicians must consider factors like prophylactic medications and optimal fluid administration when they are administering the 4-drug treatment regimen of carfilzomib (Kyprolis), lenalidomide (Revlimid), dexamethasone, and daratumumab (Darzalex; KRd-D), according to C. Ola Landgren, MD, PhD. 

“[We need] to really be on [the top of our] game and know what is needed. If you are going to deliver these good drugs, you need to have the right supportive drugs,” Landgren underscored. “[It’s] the same thing [with fluid]. If you give half a liter of fluid before and after the infusions with carfilzomib, you are going to run [the risk of] congestive heart failure…You have to give the optimal fluid and have the right prophylactic medicine. Attention to [these details] is very important.”

In an interview with Oncology Nursing News' sister publication, 

®, Landgren, the inaugural leader of the Experimental Therapeutics Program at Sylvester Comprehensive Cancer Center, Miami Health System, discussed key safety considerations with a novel carfilzomib quadruplet regimen in patients with newly diagnosed multiple myeloma, the clinical implications of the phase 2 MANHATTAN trial (NCT03290950), and next steps for this research.

®: What was the tolerability of the 4-drug regimen examined in MANHATTAN and what factors should be considered to ensure the appropriate management of patients who receive it?

: One thing that is sometimes a little bit overlooked is the attention to detail [that is needed] for [optimal] clinical management; [this includes] how [drugs] are delivered and all the other surrounding [factors], such as the different types of prophylactic medications, as well as fluid administration, and careful assessment of patients. Many times, people tend to forget about this. The older drugs were less effective, but they were, at the same time, potentially a little bit easier to give. The newer drugs are more effective and better, but many of them [require] more attention. You have to have good anticoagulation if you are going to use good drugs.

Are any next steps planned for this research?

Yes. These results are the best we have ever seen in the newly diagnosed setting. Beyond the efficacy [observed], in terms of the high rates of minimal residual disease [MRD] negativity, we also did not see the high rate of peripheral neuropathy that you see with bortezomib [Velcade]. That is also one thing that we get used to; no one is hiding it [or] lying about it, because it happens all the time, but we kind of stop thinking about it. If you go back and look through the data, the bortezomib studies have been around for 15 years or so. Many patients who are treated with this therapy, maybe up to half, experience chronic peripheral neuropathy in [their] fingers and toes, which is something they will have to manage for the rest of their life; it impacts [them] every day. [Patients] have to be on medications and some even require a walker. Not every patient will experience this effect, but it is not a trivial proportion of patients [who] do.

With the regimen, you do not see that because carfilzomib does not cause peripheral neuropathy; that is important. For that reason, we felt that this [regimen] has to go forward to be validated and tested in a large study. We have already launched the large, randomized 2 ADVANCE study [NCT04268498]; this is open to newly diagnosed patients and compares this new therapy with the standard of care.

What are the clinical implications of the MANHATTAN trial? What should be taken away?

[These data] show that you can achieve very deep responses in patients with a modern therapy in the absence of a bone marrow transplantation. Once-a-week dosing is a very reasonable schedule for a defined period of time. I do not know that going forward every patient will need 8 cycles. If you look at the time to reaching MRD negativity, [some] patients reach negativity after just 1 to 6 cycles. The median time [to MRD negativity] is around 6 cycles. As such, thinking about getting an injection and infusion once a week—3-weeks-on and 1-week-off for this number of cycles—compared with other options like bone marrow transplantation and all the toxicities [that come with it], such as sustained peripheral neuropathy, [this approach is worth it]. If you look at the value proposition of receiving a modern 4-drug combination with such a high rate of MRD negativity, it really pushes the field forward and provides a new option for patients with newly diagnosed disease.

Data demonstrate that if you use the best drugs in every line of therapy, that means that you will lose fewer patients for the next line [of treatment]. If the disease relapses and comes back [because] patients were not treated properly, some will have so much disease that they will not make it to the next line [of therapy]. The emphasis on using optimal drugs in every line is there, and it starts with the first line.

The last thing I want to say is that this is not for every patient; unfortunately, [this regimen is] not for every doctor either. [To give this,] you must pay attention to detail. You have to be on top of the anticoagulation and the intravenous fluids. In my practice, I do an echocardiogram of the heart and an electrocardiogram for every patient before I start [my patients] on therapy. I would also assess the blood pressure and would adjust that, [if needed]; if it is too high, I would treat that. If there are any concerns, I would be more careful with these types of therapies. However, if you do not see [these issues], which is true for many patients, and no other underlying comorbidity [is observed], this is an excellent therapy.

This article originally appeared on OncLive as, "

Landgren Spotlights Safety Considerations for Carfilzomib Quadruplet in Newly Diagnosed Myeloma

Consider options like prophylactic medications and optimal fluid administration when giving a 4-drug regimen to treat patients with multiple myeloma, one expert says. 

Expert Talks Safety Considerations in 4-Drug Myeloma Regimen

While cabozantinib (Cabometyx) exposure was not a predictor of progression-free survival, it was related to high rate of palmar-plantar plantar erythrodysesthesia (PPE) and diarrhea in patients with advanced renal cell carcinoma (RCC) who are given frontline cabozantinib plus nivolumab (Opdivo). These findings, which were a part of an exposure-response analysis of the phase 3 CheckMate 9ER trial, were presented during the 2021 ASCO Annual Meeting.

“ER modeling predicts that appropriate dose modification of the 40-mg cabozantinib starting dose to manage AEs [adverse effects] will not adversely affect the efficacy of nivolumab plus cabozantinib in first-line advanced RCC,” lead study author Amishi Y. Shah, MD, an assistant professor in the Department of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center, and co-authors wrote in a poster of the data.

The CheckMate 9ER trial revealed that the frontline combination of nivolumab plus cabozantinib significantly improved PFS (HR, 0.51; 95% CI, 0.41-0.64; 

 < .001), overall survival (OS; HR, 0.60; 95% CI, 0.40-0.89; 

 < .001) compared with sunitinib (Sutent) in patients with advanced RCC.

In the study, patients with previously untreated RCC received 40 mg of cabozantinib daily in combination with 240 mg of nivolumab every 2 weeks.

The regimen was generally well tolerated among patients, with low rates of treatment-related discontinuations. Dose modifications appeared to successfully manage AEs and allow patients to tolerate the regimen.

Patients (n = 320) received a median average daily dose of 29.4 mg of cabozantinib in the CheckMate 9ER trial. First-level dose reductions of cabozantinib to 20 mg daily because of AEs were observed in 50% (n = 161) of patients after a median time of 98 days (range, 9-506). Second-level dose reductions of cabozantinib to 20 mg every 2 days were observed in 8.1% of patients (n = 26) after a median time of 173 days (range, 65-613).

Because of AEs, 7.5% of patients (n = 24) discontinued cabozantinib, 6.6% of patients (n = 21) discontinued nivolumab, and 5.6% of patients (n = 18) discontinued both agents.

With a database lock date of March 30, 2020, investigators sought to understand the relationship between cabozantinib exposure, and the efficacy and safety outcomes observed in the CheckMate 9ER trial utilizing time-to-event Cox proportional hazard ER models.

The models evaluated specified end points, including PFS, dose modifications (holds or reductions), and select AEs, such as grade 1 or greater PPE, grade 3 or greater diarrhea, grade 3 or greater hypertension, grade 3 or greater fatigue/asthenia, and grade 3 or greater alanine aminotransferase (ALT)/aspartate aminotransferase (AST) increase.

“Cabozantinib exposure was defined as the overall average concentration from time zero to time of event or censoring [CAVG0T] for each end point and estimated by population pharmacokinetic modeling,” Shah and co-authors wrote.

As of the database lock date, survival data were immature, so the relationship between OS and cabozantinib exposure was not assessed.

Regarding end points, the number of patients at risk receiving 1 or more doses of cabozantinib were 311 for PFS, 318 for dose modification, 320 each for PPE, diarrhea, hypertension, and fatigue/asthenia, and 317 for ALT/AST elevation. Of these, the number of patients with 1 or more measurable cabozantinib concentration was 303 for PFS, 306 for dose modification, 308 each for PPE, diarrhea, hypertension, and fatigue/asthenia, and 307 for ALT/AST elevation.

Regarding the number of events by end point, the number of patients receiving at least 1 dose of cabozantinib was 144 for PFS, 285 for dose modification, 128 for PPE, 22 for diarrhea, 44 for hypertension, 24 for fatigue/asthenia, and 35 for ALT/AST elevation. Of these, patients with at least 1 measurable cabozantinib concentration included 139 for PFS, 279 for dose modification, 128 for PPE, 21 for diarrhea, 44 for hypertension, 23 for fatigue/asthenia, and 34 for ALT/AST elevation.

In evaluable populations, patients were a median age of 62 years (range, 29-90), with a median body weight of 80.3 kg (range, 36.0-159.3), and the majority of patients (77%) were male with high Karnofsky Performance Statuses (≥90, 79%) and low lactase dehydrogenase (≤1.5 x upper limit of normal, 94%). The median nivolumab clearance was 0.009 L/h (range, 16.0-53.4).

The target lesions were a median of 69 mm (range, 10-330). Most patients did not have prior radiotherapy (86%) but underwent prior nephrectomy (69%).

Most patients (65%) were randomized to treatment in the CheckMate 9ER trial less than 1 year from initial diagnosis.

The majority of patients (74%) had a baseline PD-L1 status of less than 1% or an indeterminate status and International Metastatic RCC Database Consortium (IMDC) scores of 1 or 2 (58%).

In the PFS analysis population (n = 303), more favorable IMDC scores were observed in patients in higher exposure quartiles. However, baseline characteristics were generally similar otherwise.

Further results revealed that cabozantinib exhibited higher interpatient variability in apparent clearance (n = 306; median 1.93 L/h; range, 0.64-10.3) and average exposure (n = 303; median 564.6 ng/mL; range, 29.3-1995).

With regard to PFS, the median exposure in quartile 4 was 848.1 ng/mL (HR relative to CAVG0T, 1.00; 95% CI, 1.00-1.00). Comparatively, the median exposure was 302.3 ng/mL (HR, 0.99; 95% CI, 0.71-1.40) in quartile 1, 485 ng/mL (HR, 1.00; 95% CI, 0.79-1.25) in quartile 2, and 641.2 ng/mL (HR, 1.00; 95% CI, 0.88-1.14) in quartile 3. Overall, this suggested that PFS was not different between cabozantinib exposure quartiles.

Regarding the development of grade 1 or greater PPE, the median exposure in quartile 4 was 872.1 ng/mL (HR relative to CAVG0T, 1.00; 95% CI, 1.00-1.00). Comparatively, the median exposure was 318.9 ng/mL (HR, 0.51; 95% CI, 0.37-0.70) in quartile 1, 512.5 ng/mL (HR, 0.65; 95% CI, 0.53-0.80) in quartile 2, and 658.6 ng/mL (HR, 0.77; 95% CI, 0.68-0.87) in quartile 3.

Regarding the development of grade 3 or higher diarrhea, the median exposure in quartile 4 was 825.1 ng/mL (HR relative to CAVG0T, 1.00; 95% CI, 1.00-1.00). Comparatively, the median exposure was 312.2 ng/mL (HR, 0.38; 95% CI, 0.19-0.75) in quartile 1, 471.2 ng/mL (HR, 0.51; 95% CI, 0.32-0.82) in quartile 2, and 606.9 ng/mL (HR, 0.66; 95% CI, 0.49-0.88) in quartile 3.

“The risk of developing PPE or diarrhea was greater at higher cabozantinib exposure quartiles; there was not association for hypertension, fatigue/asthenia, or AST/ALT elevation,” wrote Shah and co-authors.

Regarding dose modifications, the median exposure was 2.96 L/h in clearance quartile 4 (HR relative to CL/F, 1.00; 95% CI, 1.00-1.00). Comparatively, the median exposure was 1.32 L/h (HR, 1.20; 95% CI, 0.91-1.57) in quartile 1, 1.74 L/h (HR, 1.13; 95% CI, 0.94-1.35) in quartile 2, and 2.19 L/h (HR, 1.07; 95% CI, 0.97-1.18) in quartile 3.

“The risk of cabozantinib dose modification increased with decreasing cabozantinib clearance but was not significantly different between cabozantinib clearance quartiles,” Shah and co-authors wrote.

Additionally, cabozantinib exposure was not found to be a statistically significant predictor of PFS, and the rate of progression or death was not significantly associated with daily cabozantinib exposure (20 mg vs 40 mg). CAVG0T was 386 ng/mL at the 20 mg daily dose vs 772 ng/mL at the 40 mg daily dose (HR, 1.00; 95% CI, 0.78-1.27).

Increased cabozantinib exposure was significantly associated with an increased risk of PPE (HR, 0.63; 95% CI, 0.50-0.78) and diarrhea (HR, 0.48; 95% CI, 0.29-0.80), but no significant exposure-response relationships were identified for hypertension, fatigue/asthenia, or ALT/AST elevation.

Although not statistically significant, higher cabozantinib clearance was associated with a lower rate of cabozantinib dose modification (2.2 L/h vs 1.2 L/h; HR, 0.87; 95% CI, 0.71-1.07; 3.2 L/h vs 1.2 L/h; HR, 0.80; 95% CI, 0.57-1.12).

A multivariable analysis with backward elimination showed that certain baseline patient characteristics, including sex, nivolumab clearance, and baseline albumin, were significant covariates. Patients with higher baseline nivolumab clearance or lower baseline albumin levels were predicted to have higher rates of disease progression or death.

Shah AY, Motzer RJ, Apolo AB, et al. Cabozantinib exposure-response analysis for the phase 3 CheckMate 9ER trial of nivolumab plus cabozantinib versus sunitinib in first-line advanced renal cell carcinoma. 

 2021;39(suppl 15):4561. doi:10.1200/JCO.2021.39.15_suppl.4561

While cabozantinib exposure was not a predictor of progression-free survival, it was related to high rate of palmar-plantar plantar erythrodysesthesia  and diarrhea in patients with advanced renal cell carcinoma who are given frontline cabozantinib plus nivolumab. 

Cabozantinib Associated With Higher Rates of Certain AEs in Advanced Kidney Cancer

Men with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer (mCRPC) who are being treated with radium-223 (Xofigo) plus enzalutamide (Xtandi) can reduce their risk of fractures with the use of bone-protecting agents (BPAs), according to findings presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.1

“This safety analysis confirms the importance to give a bone-protecting agent when treating patients with CRPC and bone metastases,” Silke Gillessen, MD, Oncology Institute of Southern Switzerland, said during a presentation of the safety analysis.

In the randomized phase 3 EORTC-1333-GUCG/Peace-3 trial (NCT02194842), investigators randomized patients 1:1 to receive either enzalutamide at 160 mg daily plus radium-223 at 55 kBq/kg every 4 weeks for 6 cycles, or enzalutamide alone.

The study population included patients with bone-predominant mCRPC (≥2 bone metastases); asymptomatic or mildly asymptomatic disease; a WHO performance score of 0 or 1; no prior treatment with cyp17 inhibitors, enzalutamide, other radionucleotides, or hemibody radiotherapy; and no known brain or visceral metastases.

Radiographic progression-free survival served as the primary end point.

Following results of fractures occurring in the ERA223 trial (NCT02043678),2 the investigators of the EORTC-1333-GUCG/PEACE-3 trial decided to send out an urgent safety letter. “In this, it was made mandatory to use a bone-protecting agent in all patients for at least 6 weeks before starting radium-223. In April 2018, an IDMC analysis was done, and the recommendation was to continue the trial, but to use a bone-protecting agent in all patients from both arms,” explained Gillessen. “The IDMC is regularly monitoring the trial, and after the review in December last year, recommended to present the updated numbers regarding bone fractures to the scientific community.”

In her presentation at the 2021 ASCO Annual Meeting, Gillessen offered updated results of the safety analysis from the trial, highlighting the impact of BPAs on fracture rates.

As of the April 2021 cut-off, of the 267 patients randomized to both treatment arms, 74 in each were given BPAs.

Before administering the safety letter, 45.2% of patients had not received a BPA, compared with just 3% who had not after the letter was sent out.

The cumulative incidence of fractures at 1 year was 37.1% (95% CI, 21.3%-53.0%) in the combination arm and 15.6% (95% CI, 5.6%-30.3%) in the enzalutamide alone arm. In men who received a BPA, the 1-year incidence of fractures was reduced to 2.7% (95% CI, 0.5%-8.5%) and 2.6% (95% CI, 0.5%-8.3%), respectively.

At 18 months, the cumulative incidence was 45.9% (95% CI, 28.6%-61.6%) in the combination arm and 21.9% (95% CI, 9.5%-37.5%) in the enzalutamide alone arm, without a BPA. With a BPA, the incidence was 4.3% (95% CI, 1.1%-10.9%) and 2.6% (95% CI, 0.5%-8.3%), respectively.

“According to our study, we will continue and want to motivate all investigators to include [bone-protecting agents in the treatment of] patients. And hopefully, we can still report efficacy results as well. Importantly, the IDMC will also continue to closely monitor the study,” Gillessen said.

Radium-223 is an alpha-emitting radiopharmaceutical that has demonstrated an overall survival benefit in men with mCRPC, with the hypothesis that combining it with a novel androgen receptor (AR) pathway inhibitor could improve clinical outcomes.

In the randomized, double-blind, placebo-controlled ERA223 trial, investigators evaluated the use of concurrent treatment with abiraterone acetate (Zytiga; 1000 mg once daily) plus prednisone (5 mg twice daily) or prednisolone (5 mg twice daily) and radium-223 (55 kBq/kg) in 806 patients with mCRPC.2 Symptomatic skeletal event-free survival served as the primary end point.

BPAs were only permitted in the trial if a patient was receiving them at baseline. Initiation of such agents during the study was prohibited to prevent confounding effects. Therefore, only 60% of patients had not received a BPA at study entry.

In a posthoc analysis of the trial, BPAs significantly reduced the rate of fractures in both treatment arms.

“To better understand the nature of these fractures, an independent review of the fracture events was performed. Interestingly, the maturity of fractures in both groups occurred at sites with no detectable metastasis and were considered osteoporotic or traumatic,” Gillessen explained.

“Treatment with [androgen-deprivation therapy (ADT)] can induce bone loss. And we know that bone-protecting agents can be used in this bone loss and also in osteoporotic fractures in men treated with ADT,” Gillessen said. “Bone protecting agents can also delay the time to a first skeletal-related event [SRE] in men with castration-resistant prostate cancer and bone metastasis.”

Skeletal complications may be common in patients with advanced prostate cancer and result in 2 distinct mechanisms, she added: frailty, or osteoporotic fractures are reported in 11% of patients and SREs occur in up to 40% of those treated with ADT and an AR pathway inhibitor.

“To prevent these SREs, many guidelines recommend using bone-protecting agents for patients with castration-resistant prostate cancer and bone metastasis. Combining gamma radiation and hormonal manipulation is a well validated treatment strategy in prostate cancer,” Gillessen said.

1. Gillessen S, Choudhury A, Rodriguez-Vida A, et al. Decreased fracture rate by mandating bone protecting agents in the EORTC 1333/PEACEIII trial combining Ra223 with enzalutamide versus enzalutamide alone: An updated safety analysis. 

. 2021;39:(suppl 15; abstr 5002). doi: 10.1200/JCO.2021.39.15_suppl.5002.

2. Smith M, Parker C, Saad F, et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. 

Men with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer who are being treated with radium-223 (Xofigo) plus enzalutamide (Xtandi) can reduce their risk of fractures with the use of bone-protecting agents.

Bone-Protecting Agents Reduce Fracture Risk During Prostate Cancer Treatment

The FDA has granted a priority review to the new drug application (NDA) seeking approval of plinabulin plus granulocyte colony-stimulating factor (G-CSF) for the prevention of chemotherapy-induced neutropenia (CIN).

The NDA includes findings from the phase 3 PROTECTIVE-2 trial (Study 106; NCT03294577), along with 5 supportive trials that enrolled over 1200 patients. Notably, PROTECTIVE-2 demonstrated that the combination of plinabulin and pegfilgrastim (Neulasta) was 53% more effective in reducing the incidence of CIN compared with pegfilgrastim alone in patients who were receiving chemotherapy.

The plinabulin regimen resulted in less neutropenia than pegfilgrastim alone, at 21.6% and 46.4%, respectively (

 = .0001) in patients with breast cancer who were receiving a chemotherapy regimen that included docetaxel, doxorubicin, and cyclophosphamide (TAC). The addition of plinabulin improved the rate of prevention of grade 4 neutropenia in cycle 1 vs pegfilgrastim alone, going from 13.6% to 31.5% (

 = .0015), meeting the primary end point of the trial.

The doublet also reduced the risk of febrile neutropenia by 41% compared with pegfilgrastim alone. Moreover, those in the investigative arm experienced a 50% reduction in the mean duration of profound neutropenia vs those in the control arm, at 0.3 days and 0.6 days, respectively (

“We are pleased that the FDA has accepted with priority review our NDA filing for plinabulin, which is one of the key milestones for this product in 2021. We look forward to continue to work closely with the FDA through the review process,” Lan Huang, PhD, co-founder, chief executive officer, and chairwoman of BeyondSpring Inc., stated in a press release.

In the double-blind, active-controlled, international phase 3 trial, 221 patients were randomized to receive TAC (day 1 dose) in a 21-day treatment cycle in combination with 40 mg of plinabulin (day 1 dose) and 6 mg of pegfilgrastim (day 2 dose; n = 11) or a single dose of pegfilgrastim at 6 mg (day 2 dose; n = 110).

Previously, the addition of plinabulin to pegfilgrastim was found to improve the duration of severe neutropenia (DSN) cycle 1 on days 1 through 8 (absolute neutrophil count [ANC] <0.5 x 109 cells/L; 

 = .0002), and duration of profound neutropenia cycle 1 (ANC <0.1 x 109 cells/L; 

Full data also indicated that key secondary end points were also met, including DSN cycle 1, days 1 to 8; DSN cycle 1, and mean ANC nadir cycle 1. A lower frequency of grade 4 adverse effects was also reported with plinabulin regimen compared with pegfilgrastim alone, at 58.6% and 80.0%, respectively.

In the phase 2 portion of the trial, the doublet reduced CIN compared with single-agent pegfilgrastim in those given TAC chemotherapy.4 Specifically, plinabulin/pegfilgrastim resulted in a 50% rate of grade 3 neutropenia vs 81% with pegfilgrastim alone (

 <.05). Moreover, the plinabulin regimen also led to lower rates of grade 4 neutropenia than pegfilgrastim alone, at 38% vs 57%, respectively.

Patients who were given the plinabulin combination also reported less bone pain than those who were given pegfilgrastim by itself. Six percent of patients in the investigative arm vs 95% of those in the control arm experienced bone pain for day 1 or longer (

 <.001). Additionally, 0% and 33% of those in the investigative and control arms, respectively, reported bone pain that persisted for 4 days or longer (

“Chemotherapy is a very important therapy regimen for [patients with] cancer, even more so with its approval in combination with checkpoint inhibitors. With COVID-19, the National Comprehensive Cancer Network panel had updated the guidelines to potentially double the patient population included in CIN prevention,” Huang added. “If approved, plinabulin and G-CSF combination would be an important new and improved option to prevent CIN for approximately 467,500 [patients with] cancer in the United States annually.”

BeyondSpring announces US FDA acceptance and priority review of new drug application for plinabulin and G-CSF combination for the prevention of chemotherapy-induced neutropenia (CIN). News release. BeyondSpring Inc. June 1, 2021. Accessed June 1, 2021. 

Blayney DW, Huang L, Mohanlal R. Superior and clinically meaningful protection against profound neutropenia with the plinabulin/pegfilgrastim (Plin/Peg) combination versus peg in breast cancer patients receiving TAC chemotherapy: phase 3 results from Protective-2 (BPI-2358-106). Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Abstract PS13-53-01.

BeyondSpring announces positive topline results from its PROTECTIVE-2 phase 3 registrational trial of plinabulin in combination with pegfilgrastim for prevention of chemotherapy-induced neutropenia. News release. BeyondSpring Therapeutics. November 16, 2020. Accessed June 1, 2021. 

BeyondSpring announces positive topline interim results from PROTECTIVE-2 (Study 106) phase 3 trial evaluating superiority of plinabulin in combination with Neulasta for chemotherapy-induced neutropenia prevention. News release. BeyondSpring Pharmaceuticals. June 15, 2020. Accessed June 1, 2021. 

FDA Grants Priority Review to Plinabulin Plus G-CSF for CIN Prevention

The FDA has granted a priority review to the new drug application seeking approval of plinabulin plus granulocyte colony-stimulating factor for the prevention of chemotherapy-induced neutropenia.

Chemo-Induces Neutropenia Prevention Regimen Gets FDA Priority Review

Certain factors such as being younger in age, having more comorbidities and having had a higher number of prior cancer treatments all contribute to higher levels of sleep disturbance in patients with gastrointestinal (GI) cancers, according to Yufen Lin MSN, RN, of the Duke University School of Nursing.

At this year’s Oncology Nursing Society’s Annual Congress, Lin explained that chemotherapy is a common primary treatment for various GI cancers, and sleep disturbance is a frequent and distressing symptom that patients experience as a result of treatment. These disturbances often lead to a decrease in patients’ functional status, treatment responses and quality of life (QOL).

Previous studies have focused on various aspects of sleep disturbance and its impact on patients with cancer, including risk factors, but few have looked at sleep characteristics or combined all of this information into one study.

“Most studies have focused on patients with breast cancer, lung cancer and prostate cancer. Less is known about sleep disturbance in patients with GI cancer,” Lin said in her presentation.

Therefore, Lin and her team took a “person-centered approach” to identify the subsets of patients with GI cancers with distinct sleep disturbance profiles and evaluate the differences among these subgroups in demographic, clinical, and sleep characteristics, co-occurring symptoms, as well as QOL outcomes.

To do so, 405 participants were asked to complete questionnaires 6 times over 2 cycles of chemotherapy. Levels of sleep disturbance were evaluated using the General Sleep Disturbance Scale (GSDS). This was also the first study to use latent profile analysis (LPA) to identify subgroups of patients with GI cancers with distinct sleep disturbance profiles.

In this analysis, researchers evaluated the differences in demographic, clinical, and sleep characteristics, co-occurring symptoms, and QOL outcomes among the subgroups, using parametric and non-parametric analyses.

In total, 3 different sleep disturbance classes were identified across the six assessments: Low (35.8%), High (48.6%), and Very High (15.6%). When compared to patients in the Low class, those in the High and Very High classes were significantly younger, had more comorbidities, had a higher number of prior cancer treatments, were less likely to be married or partnered, and were less likely to exercise on a regular basis.

Compared to the Low class, patients in the Very High sleep disturbance class were less likely to be employed and had a diagnosis of back pain, while patients in the Very High class were more likely to report having childcare responsibilities.

Among all 3 sleep disturbance classes, significant differences that gradually increased in each group were found for comorbidity burden, occurrence of depression, and the GSDS subscale and total scores. Additionally, patients in the Very High class reported higher levels of anxiety, depressive symptoms, morning and evening fatigue, and pain, and lower levels of attentional function and QOL scores at enrollment.

According to Lin, these findings provide new insights into the risk factors and co-occurring symptoms that could lead to higher levels of sleep disturbance in patients with GI cancers, which can, in turn, help health care providers identify and address these problems before they start.

“Clinicians can use common and distinct factors to identify high-risk patients with sleep disturbance, and also initiate appropriate sleep hygiene education and referrals,” Lin said.

Additionally, these findings highlighted the need for further research into the underlying mechanisms that contribute to the development of sleep disturbance, and could prompt providers to develop personalized symptom management interventions to reduce symptom burden and improve QOL.

Yufen L., Bailey D., Docherty S. Distinct Sleep Disturbance Profiles in Patients with Gastrointestinal Cancers Receiving Chemotherapy. Presented at: Oncology Nursing Society 46th Annual Congress; April 20, 22, 27, and 29, 2021. Late-Breaking Abstract #5.

Factors such as being younger in age, having more comorbidities, and more prior cancer treatments all contribute to higher levels of sleep disturbance in patients with gastrointestinal cancers.

Factors Correspond With Higher Levels of Sleep Disturbance in Patients with GI Cancers

The optimal treatment of patients with early-stage and locally advanced non–small cell lung cancer (NSCLC) in 2021 consists of multidisciplinary management, 

 gene testing, and consolidation treatment with durvalumab (Imfinzi) in addition to clear pathways that enable the successful delivery of such care to all patients, explained Jacob Sands, MD.

“We’ve discussed all these best ways to treat patients based upon the data that we have, and one element of this in the real world that then becomes a challenge is the logistics,” said Sands. “One of the things within our health care system and within our hospital systems to start really recognizing more and doing a better job of is how to help make [high level care] feasible for everybody.”

®, Sands, a physician at Dana-Farber Cancer Institute, and an instructor in medicine at Harvard Medical School, discussed current approaches to the treatment of patients with early-stage and locally advanced NSCLC.

®: How would you define the multidisciplinary treatment of patients with early-stage NSCLC?

: In early-stage disease, treatment can involve a few different things. Often patients end up with surgically resectable disease, so there’s surgery, and then there’s the postoperative pathology that we look at, which really defines what we do after surgery. That pathology gives us a lot more information. If the size [of the tumor] is greater than 4 cm, particularly if there are lymph nodes involved, we are talking about adjuvant chemotherapy in the case of NSCLC. In the case of small cell lung cancer, we really give adjuvant chemotherapy to anybody.

What is your optimal approach to molecular testing?

In early-stage disease, when we’re talking about something that has been resected and there’s no evidence of disease, those individuals often end up getting adjuvant chemotherapy. If [the tumor is] greater than 4 cm, if there’s any lymph node involvement, that becomes a stage in which adjuvant chemotherapy is important.

As far as genomic testing, we have the recent ADAURA publication that showed a substantial improvement in [disease-]free survival. The overall survival data are going to [require] more [time to mature], but [the results] led to [the] approval [of osimertinib in the adjuvant setting]. Now [the results of] 

 testing, in particular, on the pathology of these patients [is important]. 

As far as doing genomic testing for other potential targets, the data are really compelling [in the metastatic setting] and given how osimertinib [Tagrisso] works for patients with 

 mutations, what about alectinib [Alecensa] for patients with 

 fusions, or some of these other really effective targeted therapies that we use as a standard of care in stage IV disease? Should we be using those agents in earlier-stage disease as well? Those [questions] have led to a number of other trials that are ongoing and now getting started.

Would you say that, if not for standard practice, but for clinical trials, that next-generation sequencing should be ordered rather than a single-gene panel for

Right now, we really don’t have a number of different approved therapies. In the earlier-stage setting, we just have osimertinib right now as an approved adjuvant therapy. It is really important for those patients to also be offered chemotherapy, assuming that they qualify for it. In the ADAURA publication, I was a little surprised by the number of people that actually didn’t get chemotherapy, so it’s important to highlight that these patients should get offered adjuvant chemotherapy, and then, if appropriate, osimertinib.

We don’t really have other approved therapies, so testing for 

 alone right now as far as what you’re clinically going to do is meaningful. Other agents we don’t really have a defined role for, but consideration of enrollment to these various other trials, I would really encourage. In that sense, getting genomic testing to drive enrollment to some of these other studies is really compelling.

What is the role of postoperative radiation in treatment?

For patients who get surgical resection and have N2 mediastinal node involvement, there is really kind of a question now about radiation. There was a recent trial that was negative for inclusion of postoperative radiation. That being said, there are still patients where I would expect postoperative radiation to provide some potential benefits. This is really a population that requires interaction with radiation oncologists and discussion about each individual case, and whether you think that someone is going to really benefit from radiation in that setting.

What are your thoughts on immunotherapy entering the early-stage treatment paradigm?

We have seen great results with immunotherapy in metastatic disease. We have seen also really impressive results after chemoradiation. Now the question is: In resectable disease, do these checkpoint inhibitors have a potential role to play? There are multiple studies that are being done or have enrolled [to that end]. These are studies that enroll after chemotherapy, but a study that is currently open within the ALCHEMIST portfolio is a study called ACCIO. This is a study I’m running, and I would love for people to enroll and to be aware of this. It’s a 3-arm study [that is enrolling patients] after surgical resection, an R0 resection, who are 

 negative, wild-type. Patients need PD-L1 testing for stratification, but all-comers with any level of PD-L1 can enroll, and all [patients with] NSCLC can enroll, [be it] squamous [or] nonsquamous [histology].

The [treatment arms will consist of] standard chemotherapy, followed by observation standard of care vs chemotherapy, followed by pembrolizumab [Keytruda] in a sequential arm, and then the third arm consists of concurrent chemotherapy plus pembrolizumab. Both the sequential and the concurrent arm [will administer] the same duration [of pembrolizumab], which is 1 year, just [at] different starting [points]. This trial is currently open throughout the country, and we certainly welcome enrollment.

Shifting to the stage III setting, what are some of the best practices for ensuring that patients receive durvalumab after concurrent chemoradiation?

The PACIFIC data have really showed pretty impressive and durable results in patients who get chemotherapy plus radiation with curative intent. Specifically, concurrent chemoradiation followed by durvalumab. I was a little skeptical at first [based on] the initial data that were reported. There was separation of curves, the progression-free survival was statistically significant, [but] at the time, I thought maybe some of the people who were in the control arm later on at recurrence [would] end up getting immunotherapy and [the curves] might even out.

[However,] we’ve really seen impressive separation of the curves that has persisted, and the longer these data mature, the more impressive [the data look] to me. In the control arm of the study, there was a pretty good number of patients who at recurrence did end up getting immunotherapy, so we really have a fair comparator arm, which is an important thing to look into.

Not in all of the immunotherapy trials did the control arm later on get immunotherapy in the appropriate setting, but [those in the PACIFIC trial] did, so this is a very fair comparison that had a good standard-of-care control arm. The responses have really been impressive as the data mature. For everybody that gets concurrent chemoradiation for stage III unresectable disease, I then put them on durvalumab for 1 year. We can use [every-4-week] dosing, which is a little better than the initial [every-2-week] week dosing and is easier for patients.

Also, in PACIFIC, those who got durvalumab earlier seemed to do better. That being said, I suspect that those [were] patients who tolerated their prior treatment and had better prognosis. Specifically, individuals who got chemoradiation and recovered immediately and didn’t really have any problems who were then able to start durvalumab earlier. I don’t necessarily take that [to mean that] people have to immediately start durvalumab earlier.

That being said, I want to start it about 4 weeks after, get that scan, making sure that there’s no new disease, and then start durvalumab. However, if somebody is really struggling to recover, for whatever reason, I don’t really stress pushing back or not immediately starting durvalumab after that. That’s probably still okay [to do].

On durvalumab there are people that then end up with adverse effects [AEs] from the treatment. Thankfully, most people getting these checkpoint inhibitors generally do really well, so AEs are somewhat limited. But I certainly have patients that have had AEs, and pneumonitis is always the tough one. Someone with pneumonitis [should be] started on steroids and make sure that they recover. I have patients restart [durvalumab] if it wasn’t a really severe pneumonitis. If [the pneumonitis] recovers well—when I start prednisone, once we complete the taper, and if they’re doing well off of steroids—I do restart durvalumab. In some cases, that’s worked out. In other cases, I’ve had patients who had pneumonitis again, so I haven’t been able to get everybody through 1 year of therapy. We do as much as we can. If patients are having really significant AEs, then we stop at that time.

In the trial, we did see that not everybody was able to complete the full year [of durvalumab], but those who were able to complete the full year had really impressive outcomes. If you’re more than a year out from finishing the chemoradiation, your prognosis is better in that setting as well, so I would expect those numbers to look better, but the results are actually really impressive. I try to get as much of [durvalumab] in as I can over the course of that year. If we have to start a little bit later than I want to start the therapy, that’s fine. I don’t stress about that. If there are AEs that really don’t allow for further treatment, then we stop at that time. However, getting durvalumab is very meaningful [for those patients].

What are some important resources regarding the management of immune-related adverse effects?

I really benefit from being at a center with so many specialists. I’m able to draw in specialists who really focus on some of these specific AEs. When AEs come up on some of these checkpoint inhibitors, whether it be durvalumab after chemoradiation, or any of the others in any setting, there are guidelines on how to manage them, which is important. Thankfully, most people really tolerate the therapy well, but when there are AEs, we really need to make sure that we’re managing them appropriately. Checking the guidelines on how to do that [is important]. There are publications on this, there are the National Comprehensive Cancer Network guidelines on how to manage these AEs, and it’s important to look at those.

For patients who do complete the full year of durvalumab, is there ever a situation where you would continue it?

As far as whether or not to continue treatment after 1 year, I really wouldn’t. A percentage of these patients are cured of their disease. The trouble is, we can’t define and identify prospectively who’s cured and who’s not. That is an area of important research. We know that a percentage of patients are, and the data that we have doesn’t really support doing any treatment beyond 1 year, so I would stop the treatment at 1 year and then monitor patients closely at that time going forward.

Does PD-L1 status affect whether you recommend durvalumab to patients who do not progress on concurrent chemoradiation?

As far as giving durvalumab after concurrent chemoradiation, PD-L1 expression really isn’t something that drives my decision making. If I have somebody who never smoked where I have a high suspicion of them having an 

An expert gives an overview of recent advancements in the lung cancer space.

Adverse Event Management