The addition of pembrolizumab (Keytruda) to belantamab mafodotin (Blenrep) resulted in a higher overall response rate (ORR) in patients with relapsed/refractory multiple myeloma than what has been observed with the antibody-drug conjugate (ADC) alone, according to results from the phase 1/2 DREAMM-4 trial (NCT03848845).

At a median follow-up of 14.7 months, the combination elicited an ORR of 47% (95% CI, 29.8%-64.9%) among 34 patients who were enrolled to parts 1 and 2 of the trial. Of those who responded to treatment, 12% had a complete response, 18% had a partial response, and 18% had a very good partial response (VGPR). Twenty-nine percent (95% CI, 15.1%-47.5%) of patients had a VGPR or better.

When belantamab mafodotin was evaluated as a monotherapy in patients with heavily pretreated relapsed/refractory multiple myeloma, as a part of the DREAMM-2 study (NCT03525678), the ORR achieved with the ADC was 32% (97.5% CI, 21.7%-43.6%).

Additional data from DREAMM-4 showed that the median time to response with the combination in parts 1 and 2 was 0.7 months (95% CI, 0.7-1.4), and the median duration of response (DOR) was 8.0 months (95% CI, 2.1–not reached [NR]). Investigators noted that the upper 95% confidence interval for DOR was NR in either part of the trial. Moreover, the median progression-free survival (PFS) with the doublet was 3.4 months (95% CI, 1.4-5.6).

“The result of this study helped reinforce the body of research supporting belantamab mafodotin use in patients with myeloma,” Attaya Suvannasankha, MD, lead study author, associate professor of clinical medicine at Indiana University School of Medicine, and a staff physician at Richard L. Roudebush VA Medical Center, said in a poster presentation of the data during the 2022 ASCO Annual Meeting. “Future studies will pursue other combination therapy options to enhance the efficacy and safety profile [of the ADC].”

FDA granted an accelerated approval to belantamab mafodotin

, the BCMA-targeted ADC, for use in adult patients with relapsed or refractory multiple myeloma who have received 4 previous therapies, including an immunomodulatory drug (IMiD), a proteasome inhibitor (PI), and an anti-CD38 antibody.

 The agent has a multimodal mechanism that eliminates myeloma cells via direct cytotoxicity and a systemic antitumor immune response, that investigators hypothesized could be augmented by an immune checkpoint inhibitor.

In DREAMM-4, eligible patients had received at least 3 prior lines of therapy including an anti-CD38 monoclonal antibody, a PI, and an IMiD. Patients were also required to have an ECOG performance status of 0 or 1 and have undergone stem cell transplantation, if eligible. Patients who received a monoclonal antibody within 30 days of enrollment; received prior therapy with an agent targeting PD-1, PD-L1, or PD-L2; or received treatment with a coinhibitory T-cell receptor–directed agent were excluded.

The primary end point for part 1 of the trial was number of patients with dose-limiting toxicities and percentage of those with adverse effects (AEs), and the primary end point of part 2 was investigator-assessed ORR. Secondary end points in part 1 included ORR and pharmacokinetics (PK); in part 2, secondary end points included clinical benefit rate, DOR, time to response, time to best response, PFS, time to progression, overall survival, AEs, and PK

Study participants received belantamab mafodotin at 2.5 mg/kg in combination with pembrolizumab at 200 mg.

The median patient age in parts 1 and 2 of the trial was 61.0 years (range, 40-81). Forty-four percent of patients were female and 82% were White. Twenty-nine percent of patients had high-risk cytogenetic abnormalities, 26% had extramedullary disease, and 41% were triple-class refractory. The median number of prior therapies received was 5 (range, 3-13).

The data cutoff for the primary analysis of all treated patients was October 17, 2021. Of the 24 patients included in the analysis, 6 were from part 1 and 28 were from part 2 of the research.

Ninety-seven percent of patients in both parts of the trial experienced any-grade AEs, and the rate of grade 3 or higher AEs was 74%. Similarly, 97% of patients experienced any-grade treatment-related AEs; 65% of these cases were grade 3 or higher in severity. The most common toxicities reported with the regimen were keratopathy (76%), blurred vision (38%), and thrombocytopenia (35%).

Nine patients experienced serious AEs; 4 patients had at least 1 serious AE related to study treatment. The most common serious AEs included pneumonia (15%), infusion-related reaction (9%), infection (6%), and urinary tract infection (6%). Infusion-related reactions and pneumonia were determined to be related to treatment, as well as 1 case of serious platelet count decrease.

Notably, no deaths that occurred on the study were attributed to AEs.

Thirty-two percent of patients experienced AEs that required dose reductions, and 65% required dose interruptions. The most common toxicities that resulted in dose interruptions were keratopathy (44%) and thrombocytopenia (12%).

Suvannasankha A, Bahlis NJ, Trudel S, et al. Safety and clinical activity of belantamab mafodotin with pembrolizumab in patients with relapsed/refractory multiple myeloma (RRMM): DREAMM-4 study. 

 2022;40,(suppl 16):8018. doi:10.1200/JCO.2022.40.16_suppl.8018

Lonial S, Lee HC, Badros A, et al. Longer term outcomes with single-agent belantamab mafodotin in patients with relapsed or refractory multiple myeloma: 13-month follow-up from the pivotal DREAMM-2 study. 

. 2021;127(22):4198-4212. doi:10.1002/cncr.33809

FDA granted accelerated approval to belantamab mafodotin-blmf for multiple myeloma. News release. FDA. August 5, 2020. Accessed July 14, 2022. 

Articles

The addition of pembrolizumab to belantamab mafodotin resulted in a higher overall response rate in patients with relapsed/refractory multiple myeloma than what has been observed with the antibody-drug conjugate alone, according to results from the phase 1/2 DREAMM-4 trial. 

Belantamab Mafodotin/Pembrolizumab Combo Elicits Favorable ORR in Heavily Pretreated Multiple Myeloma

Eltanexor (KPT-8602) has been granted a fast track designation from the FDA for use as a single agent in the treatment of patients with relapsed or refractory, intermediate-, high-, or very high–risk myelodysplastic syndromes (MDS).

 The European Commission (EC) also decided to designate the agent as an orphan medicinal product for use in this disease in the European Union.

The investigational SINE compound binds with and inhibits the nuclear export protein XP01; this leads to tumor suppression protein accumulation in the cell nucleus. This process serves to reinitiate and strengthen the tumor suppressor function and has been hypothesized to lead to selective induction of apoptosis in cancer cells, largely sparing normal cells.

The efficacy, safety, and tolerability of the agent is currently under investigation in patients with relapsed or refractory cancers, including MDS, as part of a phase 1/2 trial (KCP-8602-801; NCT02649790).

“These recent designations from the FDA and EC reinforce eltanexor’s potential to improve clinical outcomes for patients with relapsed/refractory MDS,” Richard Paulson, president and chief executive officer of Karyopharm Therapeutics, Inc., stated in a press release. “We are dedicated to advancing our ongoing clinical trials and remain committed to bringing eltanexor to these patients and their families as a new treatment option.”

Eltanexor has been shown to result in a lower percentage of loss of body weight and improved food consumption vs selinexor (Xpovio) in animal models. Based on these preclinical data, investigators have hypothesized that more frequent dosing is possible with the agent than with selinexor; this allows for a longer period of drug exposure.

Additional findings from an investigator-sponsored, phase 1 trial demonstrated that single-agent eltanexor produced an overall response rate (ORR) of 53% in patients with MDS that was refractory to hypomethylating agents (HMAs). In these patients, the agent also resulted in an overall survival (OS) of 9.9 months; this favorably compares with the 4- to 6-month survival that has historically been observed in this population.

Initial data from the cohort of patients with HMA-refractory MDS included in the phase 1 portion of the ongoing, open-label, phase 1/2 trial have been reported. To participate, patients were required to have high-risk or intermediate-2 disease per the International Prognostic Scoring System (IPSS), and myeloblasts ranging from 5% to 19%.

 They also needed to be at least 18 years of age and have adequate hepatic and renal function.

If patients underwent a major surgical procedure within 4 weeks prior to day 1 of cycle 1, had impaired cardiac function or significant cardiac disease, known symptomatic brain metastases, select prior malignancies, or uncontrolled active severe systemic infection requiring parenteral antibiotics, antivirals, or antifungals within 1 week of treatment, they were excluded.

Data from a subgroup analysis presented during the 2021 ASCO Annual Meeting focused on 15 evaluable patients.

 The drug was evaluated at 10 mg in 5 patients and 20 mg in 15 patients; the agent was administered daily for the duration of 5 days each week of a 28-day cycle.

In the 15 evaluable patients, the median age was 76 years (range, 62-89); the majority of patients (93%) had IPSS high- or intermediate-2–risk disease, and the median number of prior treatments received was 2 (range, 1-4).

In the 20 total patients, 35% experienced a marrow complete response (mCR) and 25% achieved stable disease. Moreover, the disease control rate was 60% in these patients. In the 15 patients evaluable for efficacy, the mCR was 47% with the agent, and 33% achieved stable disease. All patients who received eltanexor at 10 mg derived clinical benefit; 60% had a mCR and 40% had stable disease. Among those who received the agent at 20 mg, the mCR was 40% and 30% had stable disease with treatment.

Additional findings showed that a total of 4 patients experienced hematologic improvement (HI) and became transfusion independent for at least 8 weeks; this included 2 patients with trilineage HI.

The median OS was found to be significantly longer in the 7 patients who experienced a mCR with the agent compared with those who did not, at 11.86 months and 8.67 months, respectively (HR, 0.27; 

= .05). Those who achieved a mCR with eltanexor also experienced a longer OS than those who experienced progressive disease (n = 3); the median OS in the latter population was 3.15 months (HR, 0.23; 

The 12 patients who achieved disease control with eltanexor were found to also experience a numerically longer OS compared with those who experienced disease progression; the median OS in these groups was 9.86 months vs 3.15 months, respectively (HR, 0.38; 

= .09). Moreover, those with HI had a median OS of 10.58 months with the agent.

Previously, in January 2022, the FDA granted an 

 for use as a potential therapeutic option in patients with MDS.

Karyopharm granted regulatory designations for eltanexor for the treatment of myelodysplastic syndromes. News release. Karyopharm Therapeutics, Inc. July 20, 2022. Accessed July 21, 2022. 

Study of the safety, tolerability and efficacy of KPT-8602 in participants with relapsed/refractory cancer indications. ClinicalTrials.gov. Updated December 30, 2021. Accessed July 21, 2022. 

https://clinicaltrials.gov/ct2/show/NCT02649790

Lee S, Mohan S, Knupp J, et al. Updated overall survival of eltanexor for the treatment of patients with hypomethylating agent refractory myelodysplastic syndrome. 

. 2021;39(suppl 15):e19037. doi:10.1200/JCO.2021.39.15_suppl.e19037

Karyopharm receives orphan drug designation from FDA for eltanexor for the treatment of myelodysplastic syndromes. News release. Karyopharm Therapeutics, Inc.; January 24, 2022. Accessed July 21, 2022. 

Eltanexor has been granted a fast track designation from the FDA and an orphan medicinal product designation from the European Commission for use as a potential therapeutic option in patients with myelodysplastic syndromes.

Eltanexor Gets FDA Fast Track Status and Orphan Medicinal Product Designation in Europe for MDS 

The FDA has granted an orphan drug designation to PBI-200 for the treatment of patients with 

fusion–positive solid tumors, including primary and metastatic brain tumors.

PBI-200, which is an oral, highly potent and selective inhibitor of TRK kinase, was designed by Pyramid Biosciences to overcome a wide range of on-target resistance mutations that have been observed with first-generation TRK inhibitors.

 gene fusions are found in a broad range of cancers. Orphan designation for drugs in development such as PBI-200 are important to ensure continued innovation to address unmet needs for these patients, including primary and metastatic brain tumors,” Brian Lestini, MD, PhD, chief executive officer of Pyramid Biosciences, stated in a press release.

Preclinical studies in intracranial xenograft models showed that PBI-200 delivered higher efficacy and a manageable safety profile when compared with other TRK inhibitors. In a subcutaneous xenograft model of MK-12 colorectal cancer, results showed that PBI-200 induced tumor stasis when given at intraperitoneal doses of 15 mg/kg or 30 mg/kg.

 At the 15-mg/kg dose, the agent resulted in 93% tumor growth inhibition compared with 100% when given at the 30-mg/kg dose. In the mouse model, PBI-200 was also found to have superior brain penetration when administered intraperitoneally or orally compared with prior TRK inhibitors.

PBI-200 will undergo further evaluation in the phase 1/2 PBI-200-101 trial (NCT04901806) in patients with 

 fusion–positive advanced or metastatic tumors, including primary and metastatic central nervous system tumors. The trial is comprised of a dose-escalation phase and multicohort expansion at the recommended phase 2 dose (RP2D).

In phase 1 of the trial, patients will be required to have EWSR1 WT1–positive desmoplastic small round cell tumors (DSRCTs).

 fusion–positive solid tumors other than primary brain tumors are required to have received prior treatment with a TRK inhibitor, unless the patient did not have access to treatment with a TRK inhibitor. Patients with 

-amplified solid tumors, primary brain tumors, or EWSR1 WT1–positive DSRCTs may have received prior treatment with a TRK inhibitor, although it is not required.

Key exclusion criteria include having received treatment with cytotoxic chemotherapy, a biologic agent, an investigational agent, or radiation therapy within 3 weeks of the first dose of PBI-200; or having received treatment with small molecule kinase inhibitors or hormonal agents within 14 days and 5 half-lives prior to the first dose of PBI-200.

Notably, patients with either primary brain tumors or brain metastasis must have completed brain radiation 12 weeks prior to the trial’s baseline brain MRI, which will be performed 4 weeks before the first dose of PBI-200.

The primary end points of the phase 1 portion of the trial include examining adverse effects and establishing the RP2D of the investigative agent. Secondary end points include area under the plasma drug concentration time curve after 1 dose and 28 doses, overall response rate (ORR), duration of response, and progression-free survival.

In phase 2 of the trial, ORR will serve as the primary end point in each cohort examined.

“We are extremely pleased that the orphan designation was granted, and we look forward to continued enrollment in our global phase 1/2 clinical trial of PBI-200,” Jordan Leef, chief operating officer and co-founder of Pyramid Biosciences co-founder, added in a press release.

Pyramid Biosciences receives orphan drug designation for PBI-200 from FDA. News release. Pyramid Biosciences. July 6, 2022. Accessed July 7, 2022. 

Regina A, Elagoz A, Albert V, et al. PBI-200: A novel, brain penetrant, next generation pan-TRK kinase inhibitor. 

. 2019;79(suppl 13):2198. doi:10.1158/1538-7445.AM2019-2198

Study of PBI-200 in subjects with NTRK-fusion-positive solid tumors. ClinicalTrials.gov. Updated July 7, 2022. Accessed July 7, 2022. 

https://clinicaltrials.gov/ct2/show/NCT04901806

The FDA has granted an orphan drug designation to PBI-200 for the treatment of patients with NTRK fusion–positive solid tumors, including primary and metastatic brain tumors.

Pipeline Report: July 2022

Articles

Belantamab Mafodotin/Pembrolizumab Combo Elicits Favorable ORR in Heavily Pretreated Multiple Myeloma

Eltanexor Gets FDA Fast Track Status and Orphan Medicinal Product Designation in Europe for MDS