Matthew Fowler

In older adult patients undergoing nonmyeloablative allogeneic hematopoietic cell transplantation (HCT), treatment with JSP191 combined with low dose total body irradiation (TBI) and fludarabine appears safe, well-tolerated treatment option capable of clearing minimal residual disease (MRD)–positivity, according to a poster presented during the 2021 Transplantation and Cellular Therapy Meetings.

While the results of this phase 1 trial (NCT04429191) are early, the investigators emphasized that these data are the first to demonstrate that the antiCD117 monoclonal antibody is safe and effective in this disease cohort.

“We are developing a first-in-class monoclonal antibody (mAb), JSP191, which targets and depletes normal and MDS/AML disease-initiating hematopoietic stem cells,” wrote the investigators. “JSP191 acts by inhibiting stem cell factor binding to CD117 present on HSC. We and others showed in pre-clinical models that HSC depletion can be enhanced by combining anti-CD117 mAb with low dose total body radiation.”

The anti-CD117 monoclonal antibody was administered to a total of 6 patients intravenously at a dose of 0.6 mg/kg. Of note, the study population consisted of patients aged 60 years or older with MRD detected via cytogenetics, difference from normal flow cytometry, or next-generation sequencing (NGS).

The dual primary end points of the study are the safety and tolerability of JSP191 combined with low dose total body radiation and fludarabine and of JSP191 pharmacokinetics. The secondary end points include engraftment and donor chimerism, MRD clearance, event-free survival, and overall survival, among others.

The team used serum concentration of JSP191 determined by pharmacokinetics to establish the predicted JSP191 clearance and safety for the administration of fludarabine at 30 mg/m2 per day for 3 days, at days ‑4, -3, and -2 leading up to transplant.

At 28 days following transplant, 5 out of 6 patients showed signs of complete (>95%) donor CD15 myeloid chimerism in the peripheral blood.

To this point, there has been no evidence of significant infusion toxicities or JSP191-related serious adverse events. Also, a reduction or elimination of MRD in all subjects was seen at 28 days following transplant.

The research team explained that blood stem cell transplantation may offer the only curative therapy for many forms of both AML and MDS. Even though the current standard-of-care conditioning regimens administered before blood stem cell transplantation are well tolerated, they remain associated with increased relapse rates due to the prevalence of disease-causing hematopoietic stem cells and inadequate graft versus leukemia effect.

Further accrual for this study continues, while correlative analyses focusing on JPS191’s impact with disease-initiating hematopoietic stem cells are ongoing.

Muffly L, Kwon HS, Chin M, et al. Phase 1 study of JSP191, an anti-CD117 monoclonal antibody, with low dose irradiation and fludarabine in older adults with MRD-positive AML/MDS undergoing allogeneic HCT. Presented at the 2021 Transplantation and Cellular Therapy Meetings, held February 8-12, 2021. Abstract LBA5.

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A phase 1 study is the first to demonstrate that JSP191 is safe and effective in older patients with MRD-positive acute myeloid leukemia or myelodysplastic syndrome who are undergoing nonmyeloablative allogeneic hematopoietic cell transplantation.

JSP191 With Low Dose Irradiation and Chemotherpy Demonstrates Efficacy and Safety in MRD+ AML/MDS

Patients with locally advanced or metastatic PD-L1–positive non–small cell lung cancer (NSCLC) without sensitizing 

 alterations were evaluated on long-term treatment with pembrolizumab (Keytruda) and continued to demonstrate improvement in overall survival (OS), overall response rate (ORR), and time to progression on next-line therapy (PFS-2) compared with chemotherapy, according to follow-up results from the KEYNOTE-042 study (NCT02220894).

According to a presented on the data given as part of the 2020 World Conference on Lung Cancer Singapore (WCLC) Singapore, patients who completed 35 cycles of pembrolizumab treatment saw durable responses, and many patients experienced a continued response after the completion of therapy. A second course pembrolizumab was found to be feasible and was also associated with antitumor activity.

“These findings continue to support first-line pembrolizumab in patients with locally advanced/metastatic PD-L1–positive NSCLC without sensitizing 

 alterations,” explained lead investigator, Byoung Chul Cho, MD, PhD, in a virtual presentation of the data.

Median OS data for patients in the 50% or higher PD-L1 tumor proportion score (TPS) group treated with pembrolizumab was 20.0 months (95% CI, 15.9-24.2) compared with 12.2 months (95% CI, 10.4-14.6) for patients in the chemotherapy group (HR, 0.68; 95% CI, 0.57-0.82). Moreover, the 3-year OS rate was 31.3% (95% CI, 26.1%-36.6%) for the pembrolizumab group and 18.4% (95% C1, 14.2%-23.0%) for the chemotherapy group.

For the 20% or higher PD-L1 TPS group, patients on pembrolizumab experienced a median OS of 18.0 months (95% CI, 15.5-21.5) compared with 13.0 months (95% CI, 11.6-15.3) for patients on chemotherapy (HR, 0.75, 95% CI, 0.64-0.88). The 3-year OS rates were 28.3% (95% CI, 24.1%-32.8%) for the pembrolizumab group and 18.8% (95% CI, 15.1%-22.8%) for the chemotherapy group.

In the 1% or higher PD-L1 TPS cohort, the pembrolizumab group saw a median OS of 16.4 months (95% CI, 14.0-19.6) compared with the chemotherapy group at 12.1 months (95% CI, 11.3-13.3; HR, 0.80; 95% CI, 0.71-0.90). The 3-year OS rates were 25.3% (95% CI, 22.0%-28.7%) and 16.7% (95% CI, 13.8%-19.7%), respectively.

“In the KEYNOTE-042 study, pembrolizumab significantly improved OS versus platinum-based chemotherapy as first-line treatment for locally advanced/metastatic NSCLC without sensitizing 

 alterations with PD-L1 tumor proportion score greater than 1%,” Chu explained.

Median PFS in the TPS 50% or greater group was also measured, with no numerical differences noted (HR, 0.85; 95% CI, 0.71-1.02). However, at 3 years, the rate of PFS was higher in the pembrolizumab arm at 14.5% (95% CI, 10.5%-19.0%) versus 5.3% (95% CI, 3.0%-8.7%) with chemotherapy.

Similarly, median PFS was numerically similar between the pembrolizumab and chemotherapy arms in the other groups stratified by TPS. In those with a TPS of 20% or greater, the 3-year PFS rate was higher at 13.2% (95% CI, 10.0%-16.9%) in the pembrolizumab group compared with 4.7% (95% CI, 2.7%-7.5%) for patients undergoing chemotherapy. In those with a TPS of 1% or greater, the 3-year PFS rate was recorded at 11.0% (95% CI, 8.6%-13.7%) for the pembrolizumab group and 4.1% (95% CI, 2.6%-6.2%) for the chemotherapy group.

Median PFS2 was recorded at 15.0 months (95% CI, 11.6-19.2) in the pembrolizumab group compared with 10.1 (95% CI, 8.9-11.2) in the chemotherapy group in those with a PD-L1 TPS of 50% or more (HR, 0.62; 95% CI, 0.52-0.74). For PD-L1 TPS of 20% or more, median PFS2 was 12.9 months (95% CI, 10.9-15.5) for pembrolizumab versus 10.2 months (95% CI, 9.0-11.3) for chemotherapy (HR, 0.66; 95% CI, 0.57-0.77). Finally, median PFS2 was 11.3 months (95% CI, 10.1-12.9) for the pembrolizumab cohort compared with 9.3 months (95% CI, 8.6-10.2) in the chemotherapy group for PD-L1 TPS of 1% or greater (HR, 0.73; 95% CI, 0.65-0.82).

The group of eligible patients (N = 1274) were randomized 1:1 to receive either 200 mg of pembrolizumab every 3 weeks for up to 35 weeks or platinum-based therapy. The patients randomized to the pembrolizumab group who completed the 35 treatment cycles or had confirmed complete response were eligible to receive a second course of pembrolizumab.

The primary end point of the research was OS in by PD-L1 TPS by groups of 50% or more, 20% or more, and 1% or more. Secondary end points were PFS and ORR in all expression groups and safety in the TPS 1% or greater group.

“In the primary analysis, pembrolizumab significantly improved the primary end point of overall survival in all 3 TPS populations,” said Cho.

Cho BC, Wu YL, Lopes G, et al. KEYNOTE-042 3-Year Survival Update: 1L Pembrolizumab vs Platinum-Based Chemotherapy for PD-L1+ Locally Advanced/Metastatic NSCLC. Presented at: 2020 World Conference on Lung Cancer Singapore. January 27-31, 2021. Abstract FP13.04.

Long-term follow-up results from KEYNOTE-042 show that pembrolizumab continues to improve survival and response outcomes in patients with PD-L1+ locally advanced or metastatic non–small cell lung cancer. 

Pembrolizumab Further Improves Outcomes in PD-L1+ Locally Advanced/Metastatic NSCLC

In patients with esophageal cancer, chemotherapy with or without added pembrolizumab (Keytruda) led to similar health-related quality of life (HRQoL) results over 18 weeks, according to findings from the phase 3 KEYNOTE-590 study (NCT03189719).

Previously reported data presented at the European Society for Medical Oncology 2020 Virtual Congress demonstrated superior overall survival, progression-free survival, and overall response rates and a manageable safety profile with the pembrolizumab plus chemotherapy combination versus placebo plus chemotherapy for the treatment of patients with advanced esophageal cancer.

The update to this trial that was presented at the 2021 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium aimed to determine if the experimental treatment had any adverse effects on HRQoL.

“The addition of pembrolizumab to chemotherapy maintained HRQoL measures relative to baseline and did not worsen HRQoL compared with chemotherapy alone,” explained lead investigator Wasat Mansoor, MBChB, MRCP, PhD, during an oral presentation. “These results support the use of pembrolizumab plus chemotherapy as first-line therapy for locally advanced and metastatic esophageal cancer or Siewert type 1 (esophagogastric junction) adenocarcinoma.”

For global health status/quality of life per the EORTC QLQ-C30 questionnaire, the least square mean (LSM) change from baseline to week 18 found no significant difference between arms (–0.10; 95% CI,–3.40 to –3.20; 

 = .9530). Further, the median time to deterioration for global health status/quality of life was similar between arms (HR, 0.86; 95% CI, 0.66-1.13; 

Investigators did find that, by the QLQ-OES18 pain subscale, an LSM change from baseline to week 18 was better for the pembrolizumab and chemotherapy combination versus chemotherapy alone (–4.78 vs –1.85; [-2.94; 95% CI, –5.86 to –0.02]; 

Even more, there was no significant difference found from baseline to week 18 in LSM change for both reflux (-1.19; 95% CI, –4.49 to –2.10; 

 = 0.4781) or dysphagia (-2.35; 95% CI, –7.78 to –3.07; 

When asked about a concern for the lack of superior quality of life with the pembrolizumab plus chemotherapy combination, Mansoor explained, “We have to remember that these were secondary end points and some of them were exploratory in nature. Invariably, these trials will often show a deterioration in quality of life rather than superiority.”

The research team administered the EORTC QLQ-C30, EORTC QLQ-OES18, and EQ-5D-5L questionnaires electronically at baseline every 3 weeks up to week 24 and then every 9 weeks up to 1 year or the end of treatment. HRQoL was examined for all treated patients who completed the HRQoL assessments (n = 711).

The EORTC QLQ-C30 questionnaire was developed to assess quality of life for patients with cancer, while the EORTC QLQ-OES18 questionnaire is disease specific and was validated to address measures related to esophageal cancers. Lastly, the EQ-5D-5L model includes evaluations of mobility, self-care, usual activity, pain/discomfort, and anxiety/depression plus a visual analogue scale to measure the general state of health.

Time to deterioration in the EORTC QLQ-C30 and EORTC QLQ-OES18 questionnaires was measured as a decline from baseline of greater than or equal to 10. For all assessments, compliance at baseline and at week 18 was greater than or equal to 90%.

The primary end points of the research were overall survival and progression-free survival. Secondary end points included overall response rate and patient-reported outcomes.

Comparable safety profiles were seen with both treatment groups, and no new safety signals were detected. The mean time patients were on each respective therapy was 7.7 months for the pembrolizumab plus chemotherapy combination and 5.8 months for placebo plus chemotherapy.

Mansoor W, Kulkarni AS, Kato K, et al. Health-related quality of life (HRQoL) of pembrolizumab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced esophageal cancer: The phase III KEYNOTE-590 study. 

Kato K, Sun J, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced esophageal cancer: the phase 3 KEYNOTE-590 study. 

. 2020;31(suppl 4):LBA8_PR. doi:10.1016/annonc/annonc325

In patients with esophageal cancer, chemotherapy with or without added pembrolizumab led to similar health-related quality of life results over 18 weeks, according to findings from the phase 3 KEYNOTE-590 study.

HRQoL Maintained With Added Pembrolizumab in Esophageal Cancer

The combination of daratumumab (Darzalex) with lenalidomide, bortezomib, and dexamethasone (D-RVd) followed by maintenance therapy with daratumumab and lenalidomide (D-R) improved response rates and depth of response rates with statistically significance as treatment of patients with transplant-eligible newly diagnosed multiple myeloma compared with RVd followed by lenalidomide maintenance, according to findings presented at the 2020 American Society of Hematology (ASH) Annual Meeting.

The updated analysis of the GRIFFIN study showcased that D-R maintenance therapy improved the depth of response for patients while maintaining remissions.

“As noted, these results support D-RVd as a potential new standard of care for transplant eligible newly diagnosed multiple myeloma patients,” Jonathan L. Kaufman, MD, Winship Cancer Institute, Emory University, said in his presentation of the data.

The researchers found in earlier data cuts that the responses from patients to these treatments deepened over time, with response rates and depths greater for patients in the D-RVd arm at all points in time. At the end of consolidation, the stringent complete response (sCR) rate was 42.4% in the D-RVd arm (n = 104) compared to 32% in the RVd arm alone (n = 103; 

For the data regarding the 12 months of maintenance cutoff, the sCR rate was 63.6% versus 47,4% for the D-RVd arm and RVd alone arm, respectively.

Researchers also examined minimal residual disease (MRD)-negativity after 12 months of maintenance therapy, finding that, in an intent to treat manner, the total MRD-negative rate in the D-RVd arm was 62.5% compared to 27.2% for the RVd alone arm (

 < .0001). Solely examining the MRD evaluable group of patients, the MRD-negativity rate was 78.3% for the D-RVd arm (n = 83) versus 39.4% for the RVd alone arm (n = 71; 

More, durability of MRD-negativity at both 6 and 12 months was significantly higher in the D-RVd arm versus the RVd alone arm. For 6 months, the MRD-negative rate was 37.5% in the D-RVd arm, compared to only 7.8% in the RVd alone arm (

 < .0001). At 12 months, the rates for the D-RVd and RVd alone arms were 28.8% and 2.9%, respectively (

 < .0001). The data showed a significant improvement in the rates of sustained MRD-negativity for the D-RVd arm versus RVd alone.

From an MRD-negativity standpoint, there is not a subgroup of patients that does not benefit from adding DARA to RVd treatment.

“D-RVd is now considered a treatment that is appropriate for (the National Comprehensive Cancer Network). I know that we have made this our standard of care at our center,” explained Kaufman “It is a regimen that is well tolerated, its effective, it doesn’t negatively impact the ability to collect stem cells or patients to engraft after stem cell transplant. The goal of our induction therapy is to induce MRD-negatively and what we see here is that this regimen is very good at reducing MRD-negativity.”

The primary end point of the study was sCR, with secondary end points including MRD-negativity rates and overall response rates (ORR).

The researchers also explained that there is currently no statistical difference between progression-free or overall survival in both arms, with a median follow-up of 27.4 months.

While there was a noticeable increase in rates of neutropenia and upper respiratory infections for the D-RVd group compared to RVd alone, these increased rates did not lead to higher rates of discontinuation for patients. More, similar rates of any grade and grade3/4 infections were observed for D-RVd versus RVd.

Looking ahead, there is an ongoing phase 3 PERSEUS study that is evaluating subcutaneous D-RVd in the transplant-eligible population of patients with newly diagnosed multiple myeloma.

Kaufman JL, Laubach J, Sborov DW, et al. Daratumumab (DARA) Plus Lenalidomide, Bortezomib, and Dexamethasone (RVd) in Patients with Transplant-Eligible Newly Diagnosed Multiple Myeloma (NDMM): Updated Analysis of Griffin after 12 Months of Maintenance Therapy. Presented at: 2020 ASH Annual Meeting and Exposition; December 5-8, 2020; Virtual. Abstract 549.

The combination of daratumumab with lenalidomide, bortezomib, and dexamethasone  followed by maintenance therapy with daratumumab and lenalidomide improved response rates and depth of response rates with statistically significance as treatment of patients with transplant-eligible newly diagnosed multiple myeloma.

Matthew Fowler | Authors

Articles

JSP191 With Low Dose Irradiation and Chemotherpy Demonstrates Efficacy and Safety in MRD+ AML/MDS

Pembrolizumab Further Improves Outcomes in PD-L1+ Locally Advanced/Metastatic NSCLC

HRQoL Maintained With Added Pembrolizumab in Esophageal Cancer

Daratumumab Regimen Shows Promise in Transplant-Eligible Patients With Newly Diagnosed Myeloma