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The combination of elotuzumab, lenalidomide, and dexamethasone showed sustained improvements in progression-free survival (PFS) and overall survival (OS) for patients with relapsed/refractory multiple myeloma, according to a 3-year analysis of the ELOQUENT-2 trial presented at the 2015 Annual Meeting of the American Society of Hematology. (Abstract 28)
In updated data from the phase III study, the additionof elotuzumab reduced the risk of progressionor death by 27%, and overall survival (OS) was improved by 4.1 months versus lenalidomide anddexamethasone alone. Additionally, the minimal incremental toxicity observed with elotuzumab remained consistent.
“Elotuzumab, a novel first-in-class immunostimulatory monoclonal antibody, in combination with enalidomide and examethasone demonstrated a durable and clinically relevant improvement in both progression-free survival and overall response rate,” senior investigator Paul G. Richardson, MD, from the Dana-Farber Cancer Institute, said during a presentation of the data. “I’m very pleased to see that this benefit was sustained. Very importantly, we see a delay in next therapy, which is very relevant.”
On November 30, 2015, the FDA approved elotuzumab in combination with lenalidomide and dexamethasone for patients with multiple myeloma following progression on 1 to 3 prior therapies. This decision was based on a 2-year analysis of the ELOQUENT-2 trial, which showed a 30% improvement in PFS with the addition of elotuzumab compared with lenalidomide/dexamethasone alone.
In the study, 646 patients at a median age of 66 years were randomized in a 1:1 ratio to elotuzumab plus lenalidomide and dexamethasone (n = 321) or lenalidomide and dexamethasone alone (n = 325). Patients had received a median of 2 prior therapiesbefore entering the trial and 35% were refractory to their last therapy.
The dual primary endpoints of the study were PFS and objective response rate (ORR). Key secondary endpoints focused on OS and safety. Additionally, post-hoc analyses were conducted for pain assessment using the Brief Pain Inventory-Short Form (BPI-SF). A sustained improvement in pain was defined as a ≥3-point decline for ≥2 consecutive 28-day treatment cycles.
In the elotuzumab arm, the antibody was administered intravenously at 10 mg/kg once a week for the first 2 cycles followed by biweekly. Dexamethasone was administered intravenously at 8 mg prior to infusion of elotuzumab and orally at 28 mg. In
the control arm and for weeks without elotuzumab, dexamethasone was administered orally at 40 mg. Lenalidomide was administered at 25 mg orally on days 1 to 21 of each cycle for both groups.
Median PFS with elotuzumab was 19.4 versus 14.9 months with lenalidomide and dexamethasone alone. The 3-year PFS rate was 26% with elotuzumab versus 18% with the doublet alone, representing a relative improvement of 44% at 3 years.
The ORR with elotuzumab was 75% compared with 66% in the control arm. The complete response (CR) and very good complete response rate with elotuzumab was 34% versus 29% for lenalidomide and dexamethasone alone. The CR rate was 5% versus 9%, with and without elotuzumab, respectively.
The time to next treatment was 12 months longer with elotuzumab (33 vs 21 months). Overall, 38% fewer patients started subsequent therapy during the follow-up period with elotuzumab, representing a substantial clinical benefit for patients,according to Richardson.
In patients who experienced a response, there was a sustained improvement in BPI-SF scores that favored the elotuzumab arm. An improvement in patient-reported pain was experienced by 74 patients treated with elotuzumab and for 56 patients in the lenalidomide/dexamethasone arm.
At the analysis, 26% of patients continued to receive elotuzumab versus 14% in the control arm. Treatment discontinuation was primarily due to progression in both arms. The most frequently reported grade 3/4 adverse events (AEs) with and without elotuzumab, respectively, were anemia (15% vs 16%) and neutropenia (15% vs 16%).
The most common all-grade nonhematologic AEs with and without elotuzumab, respectively, were fatigue (48% vs 40%), diarrhea (48% vs 37%), pyrexia (38% vs 28%), constipation (36% vs 28%), cough (33% vs 19%), and muscle spasms (30% vs 27%).
Infections of any grade were seen in 83% of patients in the elotuzumab arm compared with 75% with lenalidomide and dexamethasone alone. Once adjusting for treatment exposure, the rates were similar between the two arms. Infusion reactions, which were mostly grade 1/2, occurred in 10% of patients in the elotuzumab arm
“Updated safety and tolerability data are consistent with previous findings, confirming that there is minimal incremental toxicity associated with the addition of elotuzumab to lenalidomide/dexamethasone,” said Richardson.
Treatment with carfilzomib reduced the risk of progression or death by 47% compared with bortezomib for patients with relapsed multiple myeloma, according to findings from the phase III ENDEAVOR trial reported at the 2015 Annual Meeting of the American Society of Hematology (Lancet Oncol. 2016;17(1):27-38).
In the study, the median progression-free survival (PFS) with carfilzomib was 18.7 versus 9.4 months with bortezomib. Median overall survival was 24.3 months in the bortezomib arm but had not yet been reached in the carfilzomib group.
“The randomized, open-label phase III ENDEAVOR study demonstrated that carfilzomib in combination with dexamethasone led to a significant reduction in the risk of progression or death when compared with bortezomib and dexamethasone in patients with relapsed multiple myeloma,” said lead author Meletios A. Dimopoulos, MD, of the School of Medicine at the National and Kapodistrian University of Athens.
“Higher response rates, a greater depth of response, and longer duration of response were also observed with carfilzomib versus bortezomib across cytogenetic subgroups.”
In the phase III study, 929 patients were randomized to receive carfilzomib as a 30-minute infusion along with dexamethasone (n = 464) or bortezomib and dexamethasone (n = 465). The median age of patients enrolled in the trial was 65 years. All but 7% of patients had ECOG performance status of 0 or 1 (about 50% ECOG 0), and about 20% of the patients had high-risk cytogenetics by fluorescence in situ hybridization.
Carfilzomib was administered at a starting dose of 20 mg/m2 on days 1 and 2 of the first cycle. If tolerated, the dose was escalated to 56 mg/m2 on day 8 of the first cycle. After this point, the 56-mg/m2–dose was maintained on days 9, 15, and 16 then throughout subsequent cycles. In the control arm, patients received bortezomib at 1.3 mg/m2. The majority of patients received bortezomib subcutaneously (75%).In a subgroup analysis, those with high-risk cytogenetics had a median PFS of 8.8 months with carfilzomib (n = 97) versus 6.0 months with bortezomib (n = 113). In patients with standard-risk cytogenetics, the median PFS was not evaluable for carfilzomib (n = 284) versus 10.2 months for bortezomib (n = 291).
Those with high-risk cytogenetics who received one prior therapy had a median PFS of 11.1 versus 7.4 months, for carfilzomib and bortezomib, respectively. With more than two prior lines of therapy, median PFS was 7.6 months with carfilzomib versus 5.6 months for bortezomib.
The largest margin of benefit for carfilzomib was seen for patients at standard risk who received just one prior therapy. In this group, the median PFS with carfilzomib was not yet reached compared with 12.1 months with bortezomib.
“Carfilzomib had a favorable benefit–risk profile in patients with high-risk relapsed multiple myeloma, and was superior to bortezomib, regardless of baseline cytogenetic risk status,” explained Dimopoulos.
Across the full population of the study, the objective response rate was 76.9% with carfilzomib versus 62.6% with bortezomib. The complete response rate with carfilzomib was 12.5% versus 6.2% with bortezomib. The rate of very good partial response or better with carfilzomib was 54.3% compared with 28.6% with bortezomib.
Grade 3 adverse events (AEs) occurred more frequently in the carfilzomib arm compared with bortezomib (73% vs 67%). Additionally, serious AEs were more common with carfilzomib (48% vs 36%). However, dose reductions associated with AEs were more frequent with bortezomib versus carfilzomib (48% vs 23%). Treatment discontinuation due to AEs and on-study deaths were comparable between the two arms.
A number of grade ≥3 AEs occurred in a similar proportion of patients in both groups, including anemia, thrombocytopenia, and neutropenia. upper respiratory infection, and pneumonia. However, there was an increase in the incidenceof hypertension and dyspnea with carfilzomib versus bortezomib. The most frequent nonhematologic grade ≥3 AEs were diarrhea, fatigue, dyspnea, pyrexia, constipation, and insomnia.
Peripheral neuropathy occurred in 5% of patients treated with bortezomib and 1.3% of those in the carfilzomib arm. The proportion of patients with grade ≥2 peripheral neuropathy was significantly higher with bortezomib (32% vs 6%).
On January 21, 2016, the FDA approved carfilzomib in combination with dexamethasone or with lenalidomide plus dexamethasone for patients with relapsed/refractory multiple myeloma, following treatment with 1 to 3 lines of therapy. In addition to the combination approvals, this decision also converts carfilzomib’s single-agent accelerated approval in this setting to a full approval. Carfilzomib is now approved as a monotherapy for the treatment of patients with relapsed or refractory multiple myeloma who have received 1 or more lines of therapy.
Beth Fand Incollingo
Ibrutinib reduced the risk of death by 84% versus chlorambucil in treatment-naïve elderly patients with chronic lymphocytic leukemia (CLL) or smalllymphocytic lymphoma (SLL), accordingto results from the phase III RESONATE-2 study presented at the 2015 ASH Annual Meeting. The results also showed a 2-year overall survival (OS) rate of 98% with ibrutinib.1,2
“The ibrutinib data represent some of the most compelling results I’ve seen during my career. These data may change how we clinicians treat patients with CLL or SLL in the frontline setting,” noted lead study investigator Jan Burger, MD, PhD, associate professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. “Theresults showcase the clinical utility of ibrutinib in this setting and the value it may bring as an appropriate treatment option for these patients.”
RESONATE-2 included 269 treatment-naïve patients aged ≥65 years with CLL or SLL. The median age was 73 years. Investigators studied ibrutinib in this population because they thought it “should be highly effective, easy to deliver and safe, and could be a promising treatment for these elderly patients,” one of the study’s authors, Alessandra Tedeschi, MD, of the Azienda Ospedaliera Niguarda Cà Granda in Milan, Italy, said when presenting the data at ASH.
Patients were randomized 1:1 to receive either 420 mg of ibrutinib daily until progression or 0.5 to 0.8 mg/kg of chlorambucil on days 1 and 15 of each 28-day cycle, for a total of 12 cycles. Patients in the chlorambucil arm were allowed to switch over to an extension study that offered ibrutinib if such treatment was indicated, and 43 patients did so.
The median duration of treatment was 17.4 months with ibrutinib and 7.1 months with chlorambucil. At the time of study completion, 87% of patients in the ibrutinib arm remained on therapy.
The study’s primary endpoint was progression-free survival (PFS) as evaluated by an independent review committee (IRC). Overall survival and overall response rate (ORR) were secondary outcome measures.
The IRC found that, compared with chlorambucil, ibrutinib led to an 84% reduction in the risk of progression or death; investigators calculated that risk reduction as 91%. At a median follow-up of 18.4 months, the median PFS was not yet reached with ibrutinib versus 19 months with chlorambucil. The median 18-month PFS rates were 94% and 45%, respectively.
As per IRC review, ORR was 86% with ibrutinib, with 4.4% of those being complete responses, versus 35.3% with chlorambucil, 1.5% of them complete responses.
Investigator-assessed ORR was 90.4%, with 9.6% of those being complete responses, versus 35.3%, with 4.5% of those being complete responses, respectively.
Ibrutinib significantly improved bone marrow function, as reflected by a sustained increase in hemoglobin and platelets. This is important because, in the elderly, bone marrow failure is a common cause of morbidity, Tedeschi said.
A reduction of 50% or more in lymph node burden was observed in 91.2% versus 36.8% of patients (P <.0001) who took ibrutinib and chlorambucil, respectively, and a reduction in spleen enlargement was seen in 75.7% versus 39.1% of patients (P <.0001).
Rates of sustained hematologic improvements were 84% with ibrutinib versus 45% with chlorambucil in patients with baseline anemia (P <.0001), and were, respectively, 77% versus 43% in patients with thrombocytopenia (P = .0054).
Adverse events, most of which were grade 1 and did not result in treatment discontinuation, included diarrhea, fatigue, cough, nausea, peripheral edema, dry eye, arthralgia and vomiting. Neutropenia also occurred in both arms, and was typically more severe than grade 1.
Fatigue, nausea, vomiting and cytopenias were more frequent with chlorambucil, as wereside effects that led to treatment discontinuation. Hypertension was noted more frequently on ibrutinib, but was limited to grades 1 through 3 and managed without dose modification or discontinuation.
Over a median follow-up of approximately 1.5 years, major hemorrhage occurred in 4% of patients with ibrutinib and in 2% with chlorambucil. There were 3 deaths in the ibrutinib arm and 17 in the chlorambucil arm.
1. Tedeschi A, Barr PM, Robak T, et al. Results from the international, randomized phase 3 study of ibrutinib versus chlorambucil in patients 65 years and older with treatment-naïve CLL/SLL (RESONATE-2). Presented at: the 57th Annual Meeting of the American Society of Hematology; Orlando, Florida; December 5-8, 2015.Abstract 495.
2. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia [published online December 6, 2015]. N Engl J Med.
Lauren M. Green
A new study has shown that overall quality of life is similar among patients taking tamoxifen or anastrozole, but patient reports on their hot flashes, night sweats, vaginal dryness, and joint pain can help illuminate which therapy may be right for a particular woman. And, the analysis shows, age matters.
The findings, based on a secondary analysis of the phase III NSABP B-35 trial, mark an important step toward the goal of “personalizing medicine for the whole patient,” remarked Patricia A. Ganz, MD, presenting the findings during a press conference at the San Antonio Breast Cancer Symposium (SABCS).1 The results were also published online December 10 in the Lancet.
NSABP B-35 was a double-blind, placebo-controlled trial that compared the efficacy of 5 years of tamoxifen versus anastrozole in reducing breast cancer recurrence in women treated with lumpectomy and radiation for their HR-positive DCIS. The study enrolled 3104 women, and results reported at the 2015 ASCO Annual Meeting showed that although both agents proved effective on the study’s primary outcome measure of time to any breast cancer event, anastrozole was found to be slightly better than tamoxifenin terms of breast cancer–free interval and most beneficial in women younger than 60 years.2
At SABCS, Ganz, director of the UCLA Jonsson Comprehensive Cancer Center’s Prevention and Control Research program, reported findings on patient-reported outcomes (PROs), a secondary endpoint of NSABP B-35. The findings are based on the responses of 1193 participants to validated measures of PROs used in prior breast cancer prevention trials. In addition to assessing their overall quality of life, women taking tamoxifen (n = 601) or anastrozole (n = 592) were asked to report on specific symptoms, such as hot flashes, vaginal dryness, and muscle and joint pain.
These data were collected over 5 years, with questionnaires issued at baseline and every 6 months thereafter. Data for an additional 12 months have not yet been analyzed, Ganz noted. The women across both treatment arms were divided fairly evenly by age, with slightly more women aged ≥60 years (n = 633); 12% of participants were nonwhite.
On the measure of overall quality of life, investigators found no difference between women in the tamoxifen and anastrozole groups on either their physical or mental component scores using the SF-12 tool over the 5 years of analysis. “There was no change in either physical functioning or mental functioning as women took either of these two drugs,” said Ganz.
Results on specific bothersome symptomsrevealed some difference in PROs for the two medications, however. After 6 months of therapy,the frequency of hot flashes increased with both drugs in both older and younger women, and was “a tad worse” in the tamoxifen group, Ganz reported. Vaginal dryness also went up with both tamoxifen and anastrozole, but more significantly with anastrozole.
“Over 60% of the women entering the trial at baseline had musculoskeletal complaints and joint pain,” Ganz noted. “This is very common in postmenopausal women.” These complaints did rise after 6 months of adjuvant therapy—by 10% in the tamoxifen group and about 20% with anastrozole.
Ganz also discussed severity of symptoms, which she said provides a better picture of women’s experience with both of the drugs. On a 1-5 severity scale, with 5 being the most severe, Ganz stressed that vasomotor and musculoskeletal symptoms remain between 1 and 2 on average after treatment with either of the twotherapies. “We’re talking about modest severity of symptoms. Even though they may be frequent,they’re not that severe.”
Shortly after starting the drugs, a composite of hot flash and night sweat scores did go up (P = .0105), but also iminished over time in both treatment arms, Ganz explained. The musculoskeletal pain composite score (joint pain, muscle aches, and general aches and pains) went up in both treatment groups, but more so with anastrozole (P = .0006), and Ganz said, “[these complaints] do not really subside significantly; they stay up over time.”
Investigators had expected sexual functioning would be worse with anastrozole, but the results did not bear this out. Although sexual functioning was worse than average in both groups, there was no difference in sexual functioning scores between the two arms, a finding which was sustained over the 5 years of the trial (P = .56).
Stratifying results by age may help clinicians to advise their patients on which adjuvant approach may be better for them, Ganz said. For example, “not only are vasomotor symptoms worse in patients treated with tamoxifen, they are significantly greater in younger women [<60 years]…This might be a symptom that would be important to think about in younger women with tamoxifen.”
Although no difference overall was seen between the two therapies with respect to worry over weight (something Ganz noted was a concern among menopausal women generally, and not just breast cancer survivors), “younger women significantly reported greater difficulty with weight gain and being unhappy with their appearance”; however, no difference was reported between the two treatment arms, Ganz said. This trend was also true across both arms with regard to vaginal symptoms in younger women, but these were worse with anastrozole, Ganz noted. Likewise, gynecologic problems (eg, discharge, itching) were worse in younger women in both arms, “but again, very low severity,” Ganz added.
“With this kind of information on patient-reported outcomes…physicians and patients can now make much more personalized decisions about which of these two effective agents they should select,” Ganz concluded.
1. Ganz PA, Cecchini RS, Julian TB, et al. Patient-reported outcome (PRO) results, NRG Oncology/NSABP B-35: a clinical trial of anastrozole vs tamoxifen in postmenopausal patients with DCIS undergoing lumpectomy plus radiotherapy. Presented at: San Antonio Breast Cancer Symposium; December 8-12, 2015; San Antonio, TX.
2. Margolese RG, Cecchini R, Julian TB, et al. Primary results, NRG Oncology/NSABP B-35: a clinical trial of anastrozole versus tamoxifen in postmenopausal patients with DCIS undergoing lumpectomy with radiation. J Clin Oncol. 2015;33 (suppl; abstr LBA500).