Health-related quality of life (HRQoL) during an 18-week period proved to be similar over for patients with esophageal cancer treated with either pembrolizumab (Keytruda) or placebo added to chemotherapy, according to data from the phase 3 KEYNOTE-590 trial (NCT03189719) presented during the 2021 Gastrointestinal Cancers Symposium.

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; 

 = 0.9530). 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. Presented at: 2021 Gastrointestinal Cancers Symposium, January 15-17, 2021. Abstract 168.

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

January 16, 2021 - Health-related quality of life during an 18-week period proved to be similar over for patients with esophageal cancer treated with either pembrolizumab or placebo added to chemotherapy.

Addition of Pembrolizumab to Chemo Does Not Negatively Impact QoL in Patients With Esophageal Cancer

Daratumumab (Darzalex) plus lenalidomide, bortezomib, and dexamethasone (D-RVd) followed by daratumumab and lenalidomide (D-R) maintenance showed a statistically significant improvement in response rates and depth of responses when compared to RVd followed bylenalidomide maintenance for patients with transplant-eligible newly diagnosed multiple myeloma, according to data presented at the 2020 American Society of Hematology (ASH) Annual Meeting.

The updated analysis of the GRIFFEN 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.

Daratumumab plus lenalidomide, bortezomib, and dexamethasone followed by daratumumab and lenalidomide maintenance showed a statistically significant improvement in response rates and depth of responses when compared to RVd followed by lenalidomide maintenance for patients with transplant-eligible newly diagnosed multiple myeloma.

Daratumumab Combo Improved Response Rates for Patients with Transplant-Eligible Newly Diagnosed Multiple Myeloma 

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.

Spartalizumab plus dabrafenib did not significantly improve progression-free survival over dabrafenib/trametinib in patients with untreated BRAF V600-mutant unresectable or metastatic melanoma.

Spartalizumab/Dabrafenib Misses PFS End Point in Melanoma

Mirvetuximab soravtansine in combination with bevacizumab (Avastin) to treat patients with platinum-agnostic ovarian cancer demonstrated encouraging overall response rates (ORRs) regardless of platinum status with a favorable tolerability profile, according to a study presented at the 2020 ASCO Virtual Scientific Program.

More, the mirvetuximab soravtansine combination proved to be a good pairing with bevacizumab, as the adverse events (AEs) observed were manageable and consistent with the AE profiles of each agent.

"With a confirmed 64% ORR, the combination of [mirvetuximab soravtansine] with bevacizumab has promising activity in high [folate receptor alpha] recurrent ovarian cancer, regardless of platinum status, and is encouraging with respect to available therapies reported in similar populations," study author Lucy Gilbert, MD, MSc, of McGill University Health Center, said in her presentation.

The ORR for the entire cohort of patients was 47%. More, in a subset analysis of patients with high folate receptor alpha expressing tumors, the ORR for those patients was 64%. Specifically, the platinum-resistant subset and the platinum-sensitive subset recorded an ORR of 59% and 69%, respectively.

Duration of response and progression-free survival data are immature due to the median follow-up of 5.5 months.

Overall, 60 patients were included in the analysis, with a median age of 60 years. Of that group, the primary cancer diagnosis was epithelial ovarian cancer (n = 41), fallopian tube cancer (n = 15), and primary peritoneal (n = 4).

"In this trial, [mirvetuximab soravtansine] was combined with bevacizumab for a broader segment of recurrent ovarian cancer patients, regardless of platinum status," said Gilbert.

The primary objective of this research was to evaluate the safety and tolerability of the mirvetximab soravtansine combination in recurrent epithelial ovarian cancer, primary peritoneal cancer, and fallopian tube cancer.

Of the 60 patients analyzed, 55 out of 60 (92%) demonstrated tumor burden reduction, with a deeper and more durable tumor reduction found in high folate receptor alpha patients.

The most common AEs associated with the combination regimen were diarrhea (68%), blurred vision (63%), fatigue (58%), and nausea (55%), with most adverse events being low grade. Hypertension and myelosuppression were the most common grade 3 or 4 AEs, occurring in 12% and 10% of patients, respectively. Thirteen patients (22%) discontinued treatment with bevacizumab and/or mirvetximab soravtansine due to treatment-related AEs.

"The combination of mirvetximab soravtansine and bevacizumab may benefit an increasing population of recurrent ovarian cancer for whom a non-platinum based regimen would be appropriate," explained Gilbert.

Gilbert L, Oaknin A, Matulonis UA, et al. Mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients (pts) with platinum-agnostic ovarian cancer. Presented at: 2020 ASCO Virtual Scientific Program; May 29, 2020. Abstract 6004.

Mirvetuximab soravtansine in combination with bevacizumab to treat patients with platinum-agnostic ovarian cancer demonstrated encouraging overall response rates regardless of platinum status with a favorable tolerability profile.
 

Mirvetuximab Soravtansine Combination Shows Positive Response, Tolerability in Ovarian Cancer

A phase III study using cediranib and olaparib to treat recurrent platinum-sensitive ovarian cancer did not meet its primary endpoint of progression-free survival but did produce comparable activity to standard of care platinum-based chemotherapy treatment.

While the combination of cediranib and olaparib (Lynparza) did not meet its primary endpoint, data presented at the 2020 ASCO Virtual Scientific Program suggested the combination showed comparable activity to standard of care platinum-based chemotherapy treatment for recurrent platinum-sensitive ovarian cancer.

More, both olaparib alone and the cediranib/olaparib combination demonstrated substantial activity for patients with a germline 

"Three clinical studies have suggested the potential for synergy between anti-angiogenics and PARP inhibitors," lead study author Joyce F. Liu, MD, MPH, of the Dana-Farber Cancer Institute, explained in the study's presentation. "In pre-clinical studies in ovarian cancer cell lines, synergy between cediranib and olaparib has been observed."

For the cediranib/olaparib combination, median progression-free survival (PFS) was 10.4 months (HR, 0.856; 95% CI, 0.66-1.11; 

 = 0.08, 1-tail). For olaparib alone, the median PFS was 8.2 months (HR, 1.20; 95% CI, 0.93-1.54). The standard of care chemotherapy saw a median PFS of 10.3 months.

Median overall survival (OS) for the cediranib/olaparib combination was 30.5 months compared to 31.3 months for standard of care chemotherapy and 29.2 months for olaparib alone. More, overall response rate (ORR) amongst the 3 groups was 71.3%, 69.4%, and 52.4%, respectively, for standard of care chemotherapy, cediranib/olaparib, and olaparib alone.

The primary end point was PFS, with secondary end points including OS, ORR, activity in biomarker-defined populations, safety and adverse event (AE) assessment, and quality of life.

"NRG-GY004 is the first phase III trial to compare an all oral non-platinum regimen to platinum-based chemotherapy in platinum-sensitive ovarian cancer," said Liu.

Overall, 565 patients were enrolled and randomized to 3 groups: standard of care chemotherapy (n = 187), the cediranib/olaparib combination (n = 189), and olaparib alone (n = 189). Of this group of patients, 23.7% had g

 mutation who received the cediranib/olaparib combination had a PFS of 18.0 months (HR, 0.55; 95% CI, 0.73-1.30) and 12.7 months (HR, 0.63; 95% CI, 0.37-1.07) for olaparib alone.

Hematologic AEs were higher among patients treated with standard of care chemotherapy, while non-hematologic AEs were more common amongst patients treated with the cediranib/olaparib combination.

Even though the research did not answer a key question regarding "whether a non-platinum therapy could improve clinical outcomes in platinum-sensitive ovarian cancer," the researchers still recommend further evaluation of this therapy to treat platinum-sensitive ovarian cancer.

"Overall, although NRG-GY004 did not meet its primary endpoint, non-platinum therapies may still offer alternatives in women with recurrent platinum-sensitive ovarian cancer, and GY004 demonstrated that these can be feasibly explored in future studies in this setting," concluded Liu.

Liu JF, Brady MF, Matulonis UA, et al. A phase III study comparing single-agent olaparib or the combination of cediranib and olaparib to standard platinum-based chemotherapy in recurrent platinum-sensitive ovarian cancer (NRG Oncology GY004). Presented at: 2020 ASCO Virtual Scientific Program; May 29, 2020. Abstract 6003.

Cediranib/Olaparib Combo Yields Comparable Results to Chemo in Ovarian Cancer Treatment

Savolitinib showed encouraging efficacy data and an improved safety profile compared with sunitinib (Sutent) as a treatment for patients with 

-driven papillary renal cell carcinoma (RCC), according to results that were presented during the 2020 ASCO Virtual Scientific Program.

“Although patient numbers and follow-up were limited, savolitinib demonstrated encouraging efficacy and an improved safety profile versus sunitinib,” said lead study author Toni K Choueiri, MD, director, Lank Center for Genitourinary Oncology and the Kidney Cancer Center, Dana-Farber Cancer Institute, in his presentation of the data.

Patients taking savolitinib, known as a highly selective 

-tyrosine kinase inhibitor, also experienced fewer grade 3 or 4 adverse events (AEs) while requiring fewer dose modifications than sunitinib, which performed more poorly than the external retrospective data anticipated.

A total of 254 patients were screened for treatment, but only 60 were randomized because the MET-driven alteration was not detected in most of the population (n = 181). Median age for the savolitinib group was 60 years compared to 65 years for the sunitinib group. Overall, 33 patients were randomized to savolitinib and 27 patients to sunitinib.

Median progression-free survival (PFS) for patients in the savolitinib group was 7.0 months (95% CI, 2.8 to not reached) compared to 5.6 months (95% CI, 4.1-6.9) for patients in the sunitinib group (HR, 0.71; 95% CI, 0.37-1.36; 

 = .313). More, overall survival (OS) was not reached for savolitinib and was 13.2 months for sunitinib (HR, 0.51; 95% CI, 0.21-1.17; 

Grade 3 or 4 AEs occurred in 42% of patients in the savolitinib group compared to 81% in the sunitinib group. The most common AEs for the savolitinib group were edema peripheral (33%), alanine aminotransferase increase (24%), aspartate aminotransferase increase (24%), and dyspnea (21%). For sunitinib, the most common AEs were anemia (44%), nausea (33%), and decreased appetite (30%).

The primary endpoint of the research PFS by blinded independent center review. Secondary endpoints were OS, overall response rate by blinded independent center review, safety, and health-related quality of life.

“There’s a subset of papillary RCC that are 

-driven, suggesting perhaps that MET inhibition may be an appropriate targeted treatment approach,” explained Choueiri. “

 has been found to be associated with major chromosome-level alteration in papillary RCC.”

At data cutoff, none of the responding patients in the savolitinib group (n = 9) saw disease progression. However, 1 of the 2 responding patients in the sunitinib group had disease progression. Because of the low response rate, it was not possible to calculate the median duration of response among the population.

Papillary renal cell carcinoma accounts for approximately 15% of all RCC, making it the most common type of non-clear cell RCC.

While no definitive conclusions could be drawn from the data due to a number of factors including a small sample size and early termination, the researchers suggest further studies to examine the viability of savolitinib.

“Early termination of recruitment precludes definitive conclusions from being drawn due to the small dataset,” explained Choueiri. “However, based on the emerging data, further investigation of savolitinib as a treatment option for 

Choueiri TK, Heng DYC, Lee J, et al. SAVOIR: A phase III study of savolitinib versus sunitinib in pts with MET-driven papillary renal cell carcinoma (PRCC). Presented at: 2020 ASCO Virtual Scientific Program; May 29, 2020. Abstract 5002.

Savolitinib showed encouraging efficacy data and an improved safety profile versus sunitinib as a treatment for patients with MET-driven papillary renal cell carcinoma.

Matthew Fowler