Matthew Fowler

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

Articles

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.

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

Treatment with enzalutamide (Xtandi) n combination with androgen deprivation therapy led to a clinically meaningful decrease in the risk of death for patients with non-metastatic castration resistance prostate cancer (nmCRPC).

The risk of death in this patient population was 27% lower than placebo for patients with non-metastatic CRPC, according to a presentation from the 21st Annual Meeting of the Society of Urologic Oncology (SUO).

The PROSPER trial also found consistent adverse events with the previously established safety profile of enzalutamide, and the overall survival (OS) rates were similar across all 3 trials (PROSPER, SPARTAN, and ARAMIS). Metastases-free survival (MFS) benefits were also associated with the improved OS rates.

“All of the results from these trials support that treating patients earlier is better, and we can seriously improve overall survival,” Cora N. Sternberg, MD, FACP, clinical director at the Englander Institute for Precision Medicine, said in her presentation. “These trials have been reflected in the treatment recommendations from the AUA, which gives strong recommendations, and NCCN, category 1 recommendations, to use these novel hormonal agents in the nonmetastatic CRPC setting.”

In regard to MFS, the data found that enzalutamide treatment resulted in a 71% lower risk of radiographic progression or death when compared to placebo (HR, 0.29; 95% CI, 0.24-0.35). More, there was a 22-month increase in MFS from 14.7 months with placebo to 36.6 months with enzalutamide. Median follow-up for the enzalutamide group was 18.5 months while the placebo group saw a median follow-up of 15.1 months.

There was a statistically significant association of enzalutamide and OS, with a 27% reduction in the risk of death for patients in the enzalutamide group compared to placebo. Median survival for the enzalutamide group was 67 months compared to 56.3 months for placebo (HR, 0.73; 95% CI, 0.61-0.89). Median follow-up was approximately 48 months.

The primary end point of the research was MFS, with secondary end points of OS, time to PSA progression, safety, PSA response and quality of life.

“This survival difference was present even though 84% of patients from the placebo group received at least 1 subsequent anti-neoplastic therapy after the study was unblinded,” explained Sternberg. “This includes the 87 patients who received enzalutamide during the open-label extension.”

The PROSPER trial enrolled 1401 men with  nmCRPC defined by bone and CT scans who were randomized to receive either enzalutamide plus androgen deprivation therapy (n = 933) or placebo plus androgen deprivation therapy (n = 468).

As for adverse events, median treatment duration was more than twice as long in the enzalutamide group (33.9 months) than in the placebo group (14.2 months). The incidence of adverse events within the first 3 and 6 months of treatment was higher in the enzalutamide group (65% and 76%, respectively) than in the placebo group (52% and 64%, respectively).

The researchers noted that starting treatment earlier for these patients could improve survival rates and that new standards of care are emerging in the nmCRPC space.

“We know that in studies with enzalutamide, abiraterone, and apalutamide, giving treatment earlier to these patients improves overall survival,” said Sternberg. “For patients who are asymptomatic, we believe that the time to delay and time to metastases, the time to symptoms and time to chemotherapy is also beneficial.”

Sternberg CN. Nonmetastatic CRPC: PROSPER Trial Updates. Presented at: 21st Annual Meeting of the Society of Urologic Oncology; December 3, 2020.

Treatment with enzalutamide in combination with androgen deprivation therapy led to a clinically meaningful decrease in the risk of death for patients with non-metastatic castration resistance prostate cancer.










Lower Risk of Death Observed With Enzalutamide in Patients with nmCRPC

The phase 3 COMBI-I clinical trial of spartalizumab plus dabrafenib and trametinib showed no improvement in investigator-assessed progression-free survival (PFS) in patients with untreated 

 V600-mutant unresectable or metastatic melanoma, missing the primary end point in part 3 of the study.

A presentation during the 2020 European Society of Medical Oncology (ESMO) virtual Congress showed that even though overall survival was not formally tested, a hazard ratio of 0.785 was observed in favor of the spartalizumab plus dabrafenib and trametinib combination, while the median overall survival had not been reached in either arm.

Part 3 of the randomized, Phase 3 COMBI-i study analyzing spartalizumab plus dabrafenib and trametinib for patients with untreated 

 V600-mutant unresectable or metastatic melanoma did not meet its primary endpoint of investigator-assessed progression-free survival (PFS), according to a presentation at the 2020 ESMO Virtual Congress.

Even though overall survival was not formally tested, a hazard ratio of 0.785 was observed in favor of the spartalizumab plus dabrafenib and trametinib combination, while the median overall survival had not been reached in either arm.

“Part 3 of COMBI-i did not meet the primary endpoint, and the triplet of spartalizumab, dabrafenib and trametinib did not significantly improved investigator-assessed progression-free survival compared with the doublet of dabrafenib and trametinib with placebo,” explained study author Paul Nathan, MBBS, PhD, FRCP, of the Mount Vernon Cancer Centre.

Investigator-assessed PFS for the spartalizumab combination was 16.2 months (12.7-23.9 months, 0.820 HR) compared to 12.0 months for the placebo combination (10.2-15.4 months). The objective overall response rate was similar for both arms, with a 68.5% response rate for the spartalizumab combination and a 64.2% response rate for the placebo arm.

As for overall survival, preliminary data saw a hazard ratio of 0.785, but could not be formally tested until the primary endpoint of investigator-assessed PFS is met with statistical significance.

The randomized, double blind, placebo-controlled, phase 3 COMBI-i study enrolled 532 patients with previously untreated 

 V600 mutation-positive unresectable or metastatic melanoma. Patients were randomized into 2 groups for the trial: the spartalizumab with dabrafenib and trametinib arm or the placebo with dabrafenib and trametinib arm.

“We did see differences in the number of dose modifications and discontinuations between pateints receiving treatment on the triplet arm compared to the doublet, reflecting the increased toxicity of this combination,” Nathan said in his ESMO presentation.

Close to 40% (n=106) of patients in the spartalizumab group experienced serious adverse events related to treatment compared with just 20% (53) of patients in the placebo group. Grade 3 or higher adverse events were found in 23.2% (n=62) of patients in the spartalizumab arm versus 11% (n=29) of patients in the placebo arm.

Moreover, adverse events leading to discontinuation of treatment occurred in 31.8% of patients in the spartalizumab group compared to 14.4% of patients receiving the placebo combination.

Specifically, the researchers noted an increase of adverse events for the spartalizumab combination patients including pyrexia (71.5%), diarrhea (34.5%), chills (31.1%), and asparate aminotransferase increase (26.6%) compared to the placebo combination group.

Preclinical activity for the trial suggested the potential for a combination of the anti-PD-1 antibody with dabrafenib and trametinib to enhance antitumor activity compared with dabrafenib and trametinib alone.

“Additional analyses are ongoing and planned to better understand these results,” explained Nathan. “Further overall survival follow-up may well provide additional insights.”

Nathan PD, Dummer R, Long GV, et al. Spartalizumab plus dabrafenib and trametinib (Sparta-DabTram) in patients (pts) with previously untreated BRAF V600–mutant unresectable or metastatic melanoma: results from the randomized part 3 of the Phase III COMBI-i trial. Presented at: 2020 ESMO Virtual Congress; September 19, 2020. Abstract LBA43.

The phase 3 COMBI-I clinical trial of spartalizumab plus dabrafenib and trametinib showed no improvement in investigator-assessed progression-free survival in patients with untreated BRAF V600-mutant unresectable or metastatic melanoma, missing the primary end point in part 3 of the study.

Matthew Fowler | Authors

Articles

HRQoL Maintained With Added Pembrolizumab in Esophageal Cancer

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

Lower Risk of Death Observed With Enzalutamide in Patients with nmCRPC

Spartalizumab Triplet Does Not Improve PFS in Metastatic Melanoma