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

Data from the prospective COVIDSurg-Cancer study (NCT04384926) demonstrated that patients with urological cancer who were infected with COVID-19 were more likely to develop respiratory complications and to be at an increased risk of dying following elective surgery for their disease, compared to patients with urological cancer who had not contracted the virus. 

The study results, which were presented during the 36th Annual European Association of Urology (EAU) Congress, demonstrated that those with SARS-CoV-2 positivity were significantly more likely to experience postoperative respiratory complications such as adult respiratory distress syndrome (n = 3; 21.4%; P < .01), pneumonia (n = 4; 28.6%; P < .01), oxygen therapy (n = 10; 71.4%; P < .01), and pulmonary embolism (n = 1; 7.1%; P < .01) within 30 days of their operation.


Moreover, 2 of 412 patients (0.5%) who did not have the virus died within 30 days following their surgical procedure vs 3 of 14 patients (21.4%) with COVID-19 (P <.01). The rates of postoperative Clavien-Dindo Grade III+ complications were 1.7% (n = 2/119), 7.6% (n = 4/53), and 3.3% (n = 2/61) for nephrectomy, cystectomy, and prostatectomy, respectively.


In the international, multicenter, prospective, observational study, investigators set out to examine the impact of the COVID-19 pandemic on the 30-day outcomes of patients with urological cancers such as kidney cancer, bladder cancer, and prostate cancer, who had undergone elective cancer surgery.


To be included, patients must have been planned for curative cancer surgery and underwent the procedure during the pandemic or they had their procedure delayed or cancelled during the pandemic.


Patients needed to be at least 18 years of age and have a confirmed diagnosis of an included cancer type. They could not have surgery planned with non-curative intent. Moreover, patients could not have planned neoadjuvant therapy without a set date for surgery, nor could they be awaiting restaging.


The primary outcome measure for the trial was mortality within 30 days, and key secondary outcomes comprised COVID-19 infections, respiratory complications, and postoperative complications within 30 days.


Prospective data from 436 consecutive patients with urological cancer were collected from several centers between March 11, 2020, and April 19, 2020. Of those patients, 39.7% had kidney and upper tract urothelial cancer (UTUC; n = 173), 28.9% had bladder cancer (n = 126), and 31.4% had prostate cancer (n = 137).


Of the 173 patients with kidney cancer and UTUC, 172 underwent elective cancer surgery. The majority, or 98.8% (n = 170) of these patients were alive at 30 days after the procedure, but 2 patients died. One of the patients who died (50.0%) were positive for COVID-19.


Among the 126 patients with bladder cancer, 120 underwent surgery; 115 patients were alive at 30 days and 3 had died at that time point. Two of the 3 patients (66.6%) who died had COVID-19. Of the 137 patients with prostate cancer, all patients received elective cancer surgery and no patients died at 30 days.


“To continue elective cancer surgery throughout future waves of the pandemic, it would be sensible to take precautions to minimize the risk of patients developing COVID-19 perioperatively,” lead study author Chuanyu Gao, of the British Urology Researchers in Surgical Training, and colleagues, concluded.


1.	Gao C. Characteristics and 30-day outcomes for urological cancer patients operated on during the COVID-19 pandemic. Presented at: 36th Annual European Association of Urology (EAU) Congress; July 9-12, 2021; virtual. Abstract P0186. https://bit.ly/2TNz6l3
2.	Outcomes of elective cancer surgery during the COVID-19 pandemic crisis (CovidSurg-Can). ClinicalTrials.gov. Updated May 12, 2020. Accessed July 10, 2021. https://clinicaltrials.gov/ct2/show/NCT04384926
This article was originally published on OncLive as “Patients With Urological Cancer and COVID-19 Undergoing Elective Surgery at Higher Risk for Mortality”


This article was originally published on OncLive as 

“Patients With Urological Cancer and COVID-19 Undergoing Elective Surgery at Higher Risk for Mortality”

A diagnosis of COVID-19 was associated with an increased risk of respiratory problems and mortality in patients with urological cancer undergoing elective procedures for their disease. 

 COVID-19 Heightens Mortality Risk in Patients with Urological Cancer Undergoing Elective Procedures

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

Preliminary evidence from an ongoing phase 1/2a trial (NCT04263090)1 has shown that treatment with the novel combination of rigosertib and nivolumab (Opdivo) may be associated with potential anticancer activity in patients with advanced metastatic KRAS-mutated non-small cell lung cancer (NSCLC).

The maximum-tolerated dose (MTD) for the doublet has not yet been reached in the 3 cohorts that are being assessed in the dose-escalation phase of the trial. Notably, participants enrolled to the trial have previously received multiple lines of therapy and have progressed on various combinations of immune checkpoint inhibitors.

Investigators continue to enroll patients to the expansion phase of the trial, to examine the highest dose of oral rigosertib defined in the current protocol. Based on positive preliminary data, a protocol amendment is being prepared that will permit the assessment of increased rigosertib doses in combination with the full dose of nivolumab, as recommended in the product label.

“The preliminary results from the phase 1/2a trial are very encouraging and demonstrate the potential of rigosertib to address a critical unmet medical need by overcoming checkpoint inhibitor resistance in 

-mutated lung adenocarcinoma,” Mark S. Gelder, MD, chief medical officer of Onconova, stated in a press release. “The observation of preliminary evidence of efficacy in combination with acceptable safety of the doublet in this extremely challenging patient population provides a promising signal.”

The open-label phase 1/2a study enrolled patients aged 18 years or older who had a histologically or cytologically confirmed diagnosis of stage IV metastatic lung adenocarcinoma and progressed on or were intolerant of standard-of-care frontline treatment with PD-1 monotherapy or in combination with platinum-doublet chemotherapy.2

Patients also needed to have measurable disease per RECIST v1.1 criteria and investigator assessment, a life expectancy of at least 3 months, an ECOG performance status of 0 to 2, and acceptable organ function. They could not be receiving any other investigational drugs or have tumors that harbored an 

 translocation. Patients also could not have untreated central nervous system metastases or carcinomatosis meningitis.

The trial is comprised of 2 phases: the dose-escalation phase 1 portion and the dose-expansion phase 2a portion. Study participants are given oral rigosertib twice daily on days 1 through 21 and intravenous nivolumab at a fixed dose of 240 mg on days 1 and 15 of 28-day treatment cycles. Rigosertib is currently under examination at the following 3 dose levels: 280 mg twice daily, 560 mg in the morning and 280 mg in the evening, and 560 mg twice daily.

The primary end points of the trial are to establish the MTD, and the overall response rate achieved with the regimen. Key secondary end points include progression-free survival and overall survival.

Previously, rigosertib was examined as a single agent and in combination with immune checkpoint blockade in immunocompetent mouse models with 

Results showed that rigosertib was well tolerated when given at a dose of 300 mg/kg in mice. The agent resulted in approximately 50% inhibition of tumor growth as a single agent and approximately 70% when given in combination with a PD-1 agent and a CTLA-4 agent.

Tumor growth inhibition induced by rigosertib was found to be dependent on CD40 upregulation in melanoma cells followed by immunogenic cell death; this led to enriched dendritic cells and activated T cells in the tumor microenvironment. Moreover, tumor suppression initiated by the drug was partially reversed by either knockdown of CD40 expression in melanoma cells or depletion of CD8+ cytotoxic T cells.

Moreover, treatment with dabrafenib (Tafinlar) and trametinib (Mekinist) or with rigosertib increased the number of CD40+ SOX10+ melanoma cells in the tumors of patients with melanoma, as well as in patient-derived xenografts. A high expression level of CD40 was found to correlate with beneficial T-cell responses and improved survival in a TCGA dataset of patients with melanoma.

“The phase 1 study supports the preclinical observation in melanoma of the up-regulation of crucial cell surface molecules by rigosertib which may synergize with immune checkpoint blockade, as was recently published in 

, and strongly supports the continued clinical development of rigosertib/checkpoint inhibitor combination therapy,” Gelder added.

Preliminary data with the combination will be shared at the 3rd Annual RAS Targeted Drug Development Summit that is being held in September 2021. As the data mature, they will be presented at a future medical meeting.

“We are very pleased both with the safety and preliminary efficacy signal we have seen from the 

-mutated NSCLC trial to date, considering the multiple lines of therapy many of these patients have previously failed, including checkpoint inhibitors in various combinations,” Steven M. Fruchtman, MD, president, and chief executive officer of Onconova, added in the release. “We are supportive of the plan to expand dose-escalation of rigosertib to determine the optimal recommended phase 2 dose of the combination; and are eagerly anticipating results of important correlative science that is part of the trial.”

Onconova Therapeutics provides an update on the phase 1/2a trial of rigosertib-nivolumab combination in KRAS+ non-small cell lung cancer. News release. Onconova Therapeutics, Inc. June 28, 2021. Accessed July 6, 2021. https://bit.ly/2SSjJav

Rigosertib plus nivolumab for KRAS+ NSCLC patients who progressed on first-line treatment. ClinicalTrials.gov. Updated July 1, 2021. Accessed July 6, 2021. https://clinicaltrials.gov/ct2/show/NCT04263090

Yan C, Saleh N, Yang J, et al. Novel induction of CD40 expression by tumor cells with RAS/RAF/PI3K pathway inhibition augments response to checkpoint blockade. 

. 2021;20(1):85. doi:10.1186/s12943-021-01366-y

“Rigosertib/Nivolumab Combo Shows Early Potential in KRAS-Mutated NSCLC”

The preliminary results of an early-phase study of rigosertib combined with nivolumab for the treatment of advanced metastatic KRAS-mutated non-small cell lung cancer are scheduled to be presented at an upcoming medical conference. 

Early Study Results Show Novel Combo Therapy May Be Effective in Lung Cancer Subtype

Adult patients with multiple myeloma who have received at least 1 prior line of therapy, including lenalidomide (Revlimid) and a proteasome inhibitor, are now able to be treated with daratumumab plus hyaluronidase-fihj (Darzalex Faspro) plus pomalidomide and dexamethasone (Pd) following an FDA approval.

The regulatory decision was supported by data from the phase 3 APOLLO trial (NCT01960348), which showed that the combination regimen resulted in a significant reduction in the risk of progression or death compared with Pd alone in this patient population.

The median progression-free survival in the investigative arm was 12.4 months vs 6.9 months in the control arm (HR, 0.63; 95% CI, 0.47-0.85; 

= .0018); this translated to a 37% reduction. Moreover, the overall response rate proved to be higher with the addition of daratumumab plus hyaluronidase-fihj to Pd vs Pd alone, at 69% vs 46%, respectively. Complete response rates in the investigative and control arms were 25% vs 4%, respectively, and partial response rates were 51% vs 20%, respectively.

“Clinical studies including APOLLO have continued to show the ability of daratumumab-based combination treatment regimens to significantly reduce the risk of progression in patients with multiple myeloma,” Meletios A. Dimopoulos, MD, professor and chairman of the 2 Department of Clinical Therapeutics at the National and Kapodistrian University of Athens School of Medicine, Athens, Greece, and principal investigator, stated in a press release. “With this approval, we are now able to combine pomalidomide and dexamethasone with a daratumumab subcutaneous option that can be administered in minutes rather than the hours needed for intravenous administration.”

Janssen announces US FDA approval of DARZALEX 

 (daratumumab and hyaluronidase-fihj) in combination with pomalidomide and dexamethasone for patients with multiple myeloma after first or subsequent relapse. News release. The Janssen Pharmaceutical Companies of Johnson & Johnson. July 12, 2021. Accessed July 12, 2021. https://bit.ly/3k7AOIu

Dimopoulos MA, Terpos E, Boccadoro M, et al. Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma (APOLLO): an open-label, randomised, phase 3 trial. 

. 2021;22(6):801-812. doi:10.1016/S1470-2045(21)00128-5

“FDA Approves Subcutaneous Daratumumab Plus Pd for Multiple Myeloma at First or Subsequent Relapse”

The FDA approval of daratumumab plus hyaluronidase-fihj (Darzalex Faspro) plus pomalidomide and dexamethasone (Pd) was supported by data from the APOLLO trial.

FDA Approves Subcutaneous Daratumumab Combo Regimen for Second-Line Multiple Myeloma

Adult patients with locally advanced or metastatic urothelial cancer who are ineligible for cisplatin-containing chemotherapy and have received 1 or more prior lines of therapy will now be able to be treated with enfortumab vedotin-ejfv (Padcev), following FDA approval. 

The conversion from the accelerated approval to a regular approval was supported by 2 supplemental biologics license applications that included data from the phase 3 EV-301 trial (NCT03474107).

Results from the trial indicated that at the time of the prespecified interim analysis, the median overall survival (OS) in those who received the ADC was 12.9 months (95% CI, 10.6-15.2) vs 9.0 months (95% CI, 8.1-10.7) with chemotherapy (HR, 0.70; 95% CI, 0.56-0.89; 

= .001); this translated to a 3.9-month benefit with enfortumab vedotin in patients with locally advanced or metastatic urothelial cancer who received prior treatment with a platinum-based chemotherapy and a PD-1 inhibitor.

“With [enfortumab vedotin], for the first time, physicians can treat advanced urothelial cancer following treatment with a platinum-containing therapy and immunotherapy using an FDA-approved therapy that has demonstrated an OS benefit compared with chemotherapy," Andrew Krivoshik, MD, PhD, senior vice president and Oncology Therapeutic Area Head at Astellas Pharma Inc., stated in a press release.

The open-label, multicenter phase 3 EV-301 trial was required to confirm the clinical benefit that supported the accelerated approval. A total of 608 patients with locally advanced or metastatic urothelial cancer who had previously received a PD-1 or PD-L1 inhibitor and platinum-based chemotherapy were enrolled to the trial.

Participants were randomized 1:1 to receive the antibody-drug conjugate (ADC) at a dose of 1.24 mg/kg on days 1, 8, and 15 of a 28-day treatment cycle (n = 301) or investigator's choice of single-agent chemotherapy in the form of docetaxel, paclitaxel, or vinflunine (n = 307).

The primary end point of the trial was OS, and important secondary end points comprised investigator-assessed progression-free survival and overall response rate (ORR) per RECIST v1.1 criteria.

Additional findings from the trial showed that the median PFS was 5.6 months (95% CI, 5.3-5.8) in the investigative arm and 3.7 months (95% CI, 3.5-3.9) in the control arm (HR, 0.62; 95% CI, 0.51-0.75; 

<.0001). Additionally, enfortumab vedotin elicited an ORR of 40.6% (95% CI, 34.9%-46.5%) in this population vs 17.9% (95% CI, 13.7%-22.8%) with chemotherapy (

Previously, in December 2019, the regulatory agency 

granted an accelerated approval to enfortumab vedotin

 for use in adult patients with locally advanced or metastatic urothelial cancer who have received a prior PD-1/L1 inhibitor and a platinum-containing chemotherapy either before or after surgery, or in a locally advanced or metastatic urothelial cancer setting.

The decision had been supported by data from the phase 2 EV-201 trial (NCT03219333), which examined the efficacy of the agent in a total of 125 patients with locally advanced or metastatic urothelial cancer who previously received a PD-1 or PD-L1 inhibitor and were not candidates for cisplatin-containing chemotherapy.

For this trial, the primary end point was confirmed ORR per blinded independent central review. The secondary efficacy end point was duration of response (DOR).

Results indicated that the ADC induced an ORR of 44% (95% CI, 35.1%-53.2%) in patients with locally advanced or metastatic urothelial cancer; this included a 12% complete response rate and a 32% partial response rate. The estimated median DOR with the agent was 7.6 months (95% CI, 6.3–not estimable [NE]).

Among 89 patients who comprised cohort 2 of the trial, the confirmed ORR was 51% (95% CI, 39.8%-61.3%); this included a CR rate of 22%. The median DOR in this population was 13.8 months (95% CI, 6.4–NE).

Regarding safety, the most frequent toxicities, including laboratory abnormalities, comprised rash, increased aspartate aminotransferase, increased glucose, increased creatinine, fatigue, peripheral neuropathy, decreased lymphocytes, alopecia, decreased appetite, decreased hemoglobin, and diarrhea.

Additional common adverse reactions include decreased sodium, nausea, pruritus, decreased phosphate, dysgeusia, increased alanine aminotransferase, anemia, decreased albumin, decreased neutrophils, increased urate, increased lipase, decreased platelets, reduced weight, and dry skin.

US FDA grants approval and expands indication for PADCEV (enfortumab vedotin-ejfv) for patients with locally advanced or metastatic urothelial cancer. News release. Seagen Inc. and Astellas Pharma Inc. July 9, 2021. Accessed July 9, 2021. https://bit.ly/3r7jzJ2

FDA grants regular approval to enfortumab vedotin-ejfv for locally advanced or metastatic urothelial cancer. News release. FDA. July 9, 2021. Accessed July 9, 2021. https://bit.ly/3xxXlSC

FDA grants accelerated approval to enfortumab vedotin-ejfv for metastatic urothelial cancer. News release. FDA. December 18, 2019. Accessed July 9, 2021. https://bit.ly/3htZCJ5

“FDA Grants Regular Approval to Enfortumab Vedotin, Expands Indication for Locally Advanced or Metastatic Urothelial Cancer”

“For the first time, physicians can treat advanced urothelial cancer following treatment with a platinum-containing therapy and immunotherapy using an FDA-approved therapy that has demonstrated an OS benefit compared with chemotherapy.”

FDA Approves Enfortumab Vedotin for Treatment of Locally Advanced or Metastatic Urothelial Cancer

Rusfertide (PTG-300) has proven to be effective in reversing iron deficiency, improving disease-related symptoms, and erasing the need for therapeutic phlebotomy, making it a quality option for patients with polycythemia vera (PV).

“The rate of phlebotomies was very high in this heavily phlebotomy-dependent patient population prior to initiation of therapy. As soon as patients initiated treatment with rusfertide, the rate of phlebotomy decreased dramatically [

<.0001],” said Marina Kremyanskaya, MD, PhD, lead study author and assistant professor of medicine, hematology, and oncology at Mount Sinai Hospital, in a presentation on the data. “Most of the patients who required phlebotomy during this period were in the dose-saturation phase of the trial and needed a higher dose.”

Moreover, hematocrit and red blood cell count in patients with PV continued to be well controlled throughout the study, according to Kremyanskaya. No significant change in platelets or white blood cell count was observed. Notably, at the beginning of the study, all patients had very low ferritin. As the study continued, ferritin levels steadily increased, demonstrative of improvement in iron deficiency with the study drug.

PV is characterized by the increased production of red blood cells and a higher risk of thrombosis; this population is treated with periodic phlebotomy with or without cytoreductive therapy. These patients are known spend significant time with hematocrit levels of greater than 45%, thereby potentially increasing their risk of thrombosis.

Often, patients with polycythemia vera have iron deficiency at the time of diagnosis and receiving several phlebotomies can worsen this condition. As such, symptomatic iron deficiency signifies a key challenge faced with this disease.

However, investigators have postulated that iron deficiency and expanded erythropoiesis in PV can result in hepcidin suppression and that this suppression could serve to strengthen iron availability for erythropoiesis in this patient population. To this end, the phase 2 PTG-300-04 trial was launched to evaluate the hepcidin mimetic rusfertide in phlebotomy-dependent patients with PV.

“In the setting of polycythemia vera, hepcidin is low. Therefore, ferroportin is open, thus allowing iron to freely flow into the plasma, making it available…in the bone marrow and resulting in uncontrolled erythropoiesis and high hematocrit,” Kremyanskaya explained. “In the presence of rusfertide, ferroportin is closed, and therefore, iron is not available to freely flow into the plasma; this limits the amount of iron that is available for erythropoiesis and results in hematocrit control.”

In June 2021, the FDA granted a breakthrough therapy designation to rusfertide for the treatment of patients with PV for the reduction of erythrocytosis in those patients who do not require further treatment for thrombocytosis and/or leukocytosis.

 The decision is supported by data from the ongoing phase 2 trial that was presented at the ongoing congress.

The phase 2 study enrolled patients with PV as per 2016 World Health Organization criteria and at least 3 phlebotomies with or without concurrent cytoreductive therapy in the 6 months prior to the trial. Rusfertide was subcutaneously administered at doses of 10 mg to 80 mg on a weekly basis in addition to previous standard therapy.

The primary end point of the trial was the proportion of patients in the randomized withdrawal period whose hematocrit is maintained without the need for phlebotomy.

The trial is comprised of 3 parts. In the dose-finding phase of the trial, patients were started on a low dose of rusfertide, which was titrated every 4 weeks to control the hematocrit at less than 45%. Once the effective dose of the agent was determined, patients remained on the dose until 28 weeks.

Then, they entered the blinded withdrawal phase of the trial where they were randomized to continue on their last effective dose or to receive placebo. If the patient required a therapeutic phlebotomy at any point in this phase of the trial, they were withdrawn and entered into the open-label extension phase of the research. Here, they were restarted on their last effective dose of rusfertide.

At the time of the presentation, 63 patients with PV had been dosed with rusfertide, duration of exposure ranged from 2 to 81 weeks, and the median exposure to treatment was 15 weeks.

The median age of study participants was 56 years (range, 27-76), 72.6% were male, 48.4% were in the low-risk category, and 14.5% of patients had prior thrombotic events. Additionally, 55% of patients had a diagnosis of PV for 3 years or less.

Just under half, or 46.8%, of patients received phlebotomy only and the remainder received phlebotomy with another cytoreductive agent such as hydroxyurea (29%), interferon (14.5%), and ruxolitinib (Jakafi; 4.8%). In the 6 months before the trial, 46.8% of patients had received 4 to 5 phlebotomies. Sixty-eight percent of patients had an allele burden of less than 60%.

Investigators also examined symptom scores, as demonstrated by the MPN Symptom Assessment Form Total Symptom Score. Results revealed a decrease in total symptom score at week 28 of treatment vs baseline. “This was mostly contributed to by the symptoms of fatigue and problems with concentration, with some contribution from pruritus,” Kremyanskaya said. “These data are still preliminary, as the number of patients with available data at week 28 is still relatively small.”

When looking at the patient global impression of change, 71% of patients experienced an improvement at 9 weeks of treatment, with most patients reporting to have been much improved and very much improved.

Regarding safety, rusfertide was found to be very well tolerated, according to Kremyanskaya. The majority of treatment-related adverse effects (AEs) were grade 1 or 2 in severity. Two grade 3 AEs were reported, but were not determined to be associated with the drug; 1 patient experienced vomiting and the other experienced distal popliteal artery aneurysm and both continued the drug. No grade 4 toxicities were reported.

The most common toxicities were injection site reactions and were linked with 28.1% of injections. All of these reactions were transient and none of the patients discontinued because of these effects. Notably, no serious AEs related to rusfertide were reported, and only 1 patient discontinued treatment because of toxicity, which was thrombocytosis. No anti-drug-antibody response was observed in any patient.

“These results provide additional evidence that rusfertide may have a clinical benefit for patients with polycythemia vera,” Ronald Hoffman, MD, the Albert A. and Vera G. List Professor of Medicine and director of the Myeloproliferative Disorders Research Program at Mount Sinai, stated in a press release on the data.

 “The need for a new non-cytoreductive therapeutic option in polycythemia vera is urgent. I look forward to the next steps in rusfertide’s development for this disease, as it may alleviate the burden of phlebotomy for patients who cannot control their hematocrit levels through currently existing treatment options and need an alternative therapeutic approach.”

Kremyanskaya M, Ginzburg Y, Kuykendall A, et al. PTG-300 eliminates the need for therapeutic phlebotomy and reverses iron deficiency in both low and high-risk polycythemia vera patients. Presented at: European Hematology Association 2021 Virtual Congress; June 9-17, 2021; virtual. Abstract S200.

Marchioli R, Finazzi G, Specchia G, et al. Cardiovascular events and intensity of treatment in polycythemia vera. 

. 2013;368(1):22-33. doi:10.1056/NEJMoa1208500

Protagonist Therapeutics receives FDA breakthrough therapy designation for rusfertide in polycythemia vera. News release. Protagonist Therapeutics. June 3, 2021. Accessed June 12, 2021. 

Protagonist Therapeutics announces updated phase 2 data supporting long-term efficacy of rusfertide in polycythemia vera. News release. Protagonist Therapeutics. June 11, 2021. Accessed June 11, 2021. 

This article weas originally published on OncLive as 

“Rusfertide Eliminates Need for Phlebotomy, Reverses Iron Deficiency in Polycythemia Vera”

Symptomatic iron deficiency, a key challenge in facing polycythemia vera, might be effectively treated with rusfertide.

Rusfertide Helps Combat Iron Deficiency and Improve Symptoms in Patients with Polycythemia Vera

Patients with renal cell carcinoma (RCC) who underwent a nephrectomy or underwent a nephrectomy with resection of metastatic lesions demonstrated superior disease-free survival (DFS) when using adjuvant single agent pembrolizumab (Keytruda) as an adjuvant treatment.

Additionally, the toxicity profile of pembrolizumab proved to be consistent with what had previously been reported with the agent.

The trial will continue to examine the overall survival (OS) benefit achieved with the immunotherapy, as an important secondary end point. Data from the trial will be shared at an upcoming medical conference, according to Merck; the findings will also be presented to regulatory authorities.

“Since its first approval in RCC nearly 2 years ago, [pembrolizumab] has become an important first-line treatment option in combination with axitinib [Inlyta] for patients with advanced RCC,” Roy Baynes, MD, PhD, senior vice president, head of global clinical development, and chief medical officer at Merck Research Laboratories, stated in a press release. “These new data are the result of our research to evaluate the role of [pembrolizumab] in helping patients with earlier stages of disease and are the first positive results for an anti–PD-1 therapy in the adjuvant treatment of patients with RCC.”

In the double-blind phase 3 trial, investigators examined single-agent pembrolizumab in the adjuvant treatment of patients with RCC who had intermediate-high risk, high-risk, or M1 no evidence of disease with a clear cell component who had undergone nephrectomy.

To be eligible for enrollment, patients had to have an ECOG performance status of 0 to 1 and acceptable organ function.

Patients could not have previously received systemic therapy for advanced disease. If they had undergone major surgery other than nephrectomy within 12 weeks before randomization, received previous radiotherapy, had pre-existing brain or bone metastatic lesions, or had residual thrombus following nephrectomy in the vena renalis or vena cava, they were excluded.

A total of 950 patients were enrolled to the trial. Participants were randomized to receive either intravenous pembrolizumab at 200 mg on day 1 of each 3-week cycle for up to 17 treatment cycles or placebo on day 1 of each 3-week cycle for up to 17 cycles.

The primary end point of the trial was DFS, with key secondary end points of OS and safety.

In the United States, Europe, and Japan, the 

PD-1 inhibitor has been approved for use in combination with axitinib

 in the frontline treatment of patients with advanced RCC based on data from the phase 3 KEYNOTE-426 trial (NCT02853331). Here, the combination was found to result in a significantly better overall response rate, PFS, and OS vs sunitinib (Sutent) in patients with advanced disease.

 Specifically, the doublet reduced the risk of death by 47% vs sunitinib (HR, 0.53; 95% CI, 0.38-0.74; 

<.0001); the regimen also reduced the risk of progression of disease or death by 31% vs sunitinib (HR, 0.69; 95% CI, 0.57-0.84; 

Merck’s KEYTRUDA (pembrolizumab) demonstrated superior disease-free survival (DFS) compared with placebo as adjuvant therapy in patients with renal cell carcinoma (RCC) following surgery. News release. Merck. April 8, 2021. Accessed April 8, 2021. 

Safety and efficacy study of pembrolizumab (MK-3475) as monotherapy in the adjuvant treatment of renal cell carcinoma post nephrectomy (MK-3475-564/KEYNOTE-564). ClinicalTrials.gov. Updated May 28, 2020. Accessed April 8, 2021. 

https://clinicaltrials.gov/ct2/show/NCT03142334

FDA approves Merck’s KEYTRUDA (pembrolizumab) in combination with Inlyta (axitinib) as first-line treatment for patients with advanced renal cell carcinoma (RCC). News release. Merck. April 22, 2019. Accessed April 8, 2021. 

This article was originally published on OncLive as “

Adjuvant Pembrolizumab Demonstrates Superior DFS Over Placebo in Post-Nephrectomy RCC.”

Phase 3 KEYNOTE-564 trials demonstrated that single-agent pembrolizumab resulted in improved DFS in comparison to placebo group. 

Post-Nephrectomy Patients with RCC Show Improved DFS with Adjuvant Pembrolizumab 

Patients with recurrent or metastatic nasopharyngeal carcinoma reported superior progression-free survival (PFS) with addition of immunotherapy agent toripalimab to gemcitabine plus cisplatin (GP) compared to patients undergoing chemotherapy alone.

The toripalimab regimen resulted in a median PFS of 11.7 months (95% CI, 11.0–not evaluable [NE]) via blinded independent review committee (BIRC) per RECIST v1.1 criteria vs 8.0 months (95% CI, 7.0-9.5) with chemotherapy alone (stratified HR, 0.52; 95% CI, 0.36-0.74; 

= .0003) in this population, according to data presented during a press briefing ahead of the 

 Additionally, the median overall survival (OS) was NE in both arms (stratified HR, 0.603; 95% CI, 0.364-0.997; 

“From this first international trial, we can see that the addition of toripalimab to GP as a first-line treatment for nasopharyngeal carcinoma showed better PFS and OS than GP alone. The combination was safe, and no new safety signals were found,” Rui-Hua Xu, MD, PhD, of Sun Yat-Sen University Cancer Center, China, said in a virtual presentation on the data. “These results support the use of the toripalimab combination as a new standard of care in the first-line treatment of patients with recurrent or metastatic [disease].”

Nasopharyngeal carcinoma is endemic in Southern China and Southeast Asia, according to Xu, who explained that the incidence of this cancer is 1.2 per 100,000 globally, while it is 3.0 per 100,000 in China. Moreover, patients with recurrent or metastatic disease have limited therapeutic options available to them, and the current standard-of-care frontline treatment worldwide for this population is GP.

The anti–PD-1 monoclonal antibody toripalimab was designed to block PD-1 interactions with its ligands PD-L1 and PD-L2 and strengthen receptor endocytosis function.2 The tumor checkpoint proteins PD-L1 and PD-L2 recognize the PD-1 receptor on T cells and deplete their antitumor activity. It is hypothesized that blocking PD-1 interactions with the proteins will result in a recharged immune system, boosting its ability to attack and eliminate cancer cells.

In February 2021, toripalimab was granted a conditional approval by the National Medical Products Administration of China for the treatment of patients with recurrent or metastatic nasopharyngeal carcinoma in whom at least 2 prior lines of systemic treatment has failed.3

The regulatory decision was supported by data from the phase 2 POLARIS-02 trial (NCT02915432), where the agent elicited an objective response rate (ORR) of 20.5% (95% CI, 15.0%-27.0%), a median duration of response (DOR) of 12.8 months (95% CI, 9.4-NE), a median PFS of 1.9 months (95% CI, 1.8-3.5), and a median OS of 17.4 months (95% CI, 11.7-22.9) in the intent-to-treat population.4

In the global, double-blind, placebo-controlled phase 3 JUPITER-02 trial, investigators sought to examine toripalimab in combination with GP vs GP with placebo in the frontline treatment of patients with recurrent or metastatic nasopharyngeal carcinoma.

To be eligible for enrollment, patients needed to be between 18 and 75 years of age and have primary or metastatic nasopharyngeal carcinoma or recurrent disease following curative-intent treatment. Patients also needed to be treatment naïve for recurrent or metastatic disease, have an ECOG performance status of 0 or 1, and have measurable disease per RECIST v1.1 criteria.

A total of 289 participants from mainland China, Taiwan, and Singapore were randomized 1:1 to receive toripalimab at 240 mg plus GP every 3 weeks for 6 treatment cycles followed by toripalimab maintenance at 240 mg every 3 weeks, (n = 146) or GP plus placebo every 3 weeks for 6 cycles followed by placebo maintenance every 3 weeks (n = 143).

Patients were stratified based on disease (recurrent vs primary metastatic) and ECOG performance status (0 vs 1). Treatment was continued until disease progression, unacceptable toxicity, withdrawal of consent, investigator decision, or a maximum of 2 years.

The primary end point of the trial was PFS per BIRC and RECIST v1.1 criteria, while secondary end points include PFS per investigator assessment, ORR, DOR, disease control rate, and OS, as well as 1- and 2-year PFS and OS rates.

Additional data from the trial showed that the 1-year PFS rates in the investigative and control arms were 49.4% (95% CI, 36.4%-61.1%) and 27.9% (95% CI, 18.0%-38.8%), respectively.

The OS data were not mature at the interim analysis, according to Xu. “Nine months after the interim analysis we observed a 40% reduction in risk of death in the toripalimab arm vs the placebo arm,” Xu said.

The 1-year OS rate achieved with the toripalimab regimen was 91.6% (95% CI, 85.6%-95.1%) vs 87.1% (95% CI, 80.4%-91.7%) with chemotherapy alone; the 2-year OS rates were 77.8% (95% CI, 68.0%-85.0%) and 63.3% (95% CI, 49.8%-74.1%), respectively.

Regarding safety, a similar incidence of any-grade adverse effects (AEs; 100% in both), grade 3 or higher toxicities (89.0% vs 89.5%), infusion reactions (any-grade, 4.1% vs 4.2%), and fatal AEs (2.7% vs 2.8%) was observed between the investigative and control arms, respectively. The most frequently reported grade 3 or higher AEs included leukopenia (61.6% vs 58.0%), neutropenia (57.5% vs 63.6%), and anemia (47.3% vs 39.9%).

“The most common AEs were hematologic toxicity, which were mainly attributed to the GP chemotherapy regimen,” Xu noted. “The incidence of immune-related AEs, such as hypothyroidism, were higher in the toripalimab arm; this was expected [with immunotherapy] and [proved to be] manageable.”

All-grade immune-related AEs were reported in 39.7% of patients who received the toripalimab regimen vs 18.9% of those who received chemotherapy alone; grade 3 or higher immune-related toxicities were experienced by 7.5% and 0.7% of patients, respectively.5

Data from the phase 3 JUPITER-02 trial (NCT03581786) suggests that frontline toripalimab plus gemcitabine/cisplatin improves progression-free survival (PFS).

Kristi Rosa