More treatment does not necessarily offer more benefit for patients—at least when it comes to multiple myeloma.

According to the results of the phase III StaMINA trial evaluating posttransplant therapy in multiple myeloma, a second a round of chemotherapy or stem cell transplant does not improve progression-free survival (PFS) or overall survival (OS) compared with the current standard course of treatment alone.

The addition of lenalidomide/bortezomib/dexamethasone (RVD) consolidation or a second autologous hematopoietic stem cell transplant (ASCT) was not superior to a single ASCT, followed by lenalidomide maintenance, in the upfront treatment of multiple myeloma.

“When compared with the current standard course of treatment alone, these data suggest that additions to standard multiple myeloma therapy to do not improve benefit for patients,” said Edward A. Stadtmauer, MD, section chief of Hematologic Malignancies at the Abramson Cancer Center, University of Pennsylvania. “Based on these results, I believe that it would be reasonable to compare any new treatments to the standard therapy of melphalan followed by a single ASCT followed by lenalidomide maintenance.”

As Stadtmauer reported at the 2016 ASH Annual Meeting, despite remarkable advances in multiple myeloma therapy over the past decade, many patients will ultimately see their disease progress. Although lenalidomide maintenance after ASCT has improved PFS and OS, the role of additional interventions after ASCT, such as tandem ASCT or triple therapy consolidation, remains to be determined.

“There’s always room for improvement,” said Stadtmauer. “New therapies and interventions need to be actively investigated to see how much they further benefit the early treatment of patients with myeloma.”

From June 2010 to November 2013, researchers from 54 centers enrolled 758 transplant-eligible patients with symptomatic multiple myeloma. The patients, who were all within 2 to 12 months of initial therapy and without prior progression, were randomly assigned to receive either standard care (melphalan 200mg/m

 ASCT), standard care plus additional chemotherapy (4 cycles of RVD consolidation), or standard care plus a second round of ASCT. All arms included lenalidomide maintenance (at maximum tolerated dose up to 15 mg orally daily until progression) with dose modifications for toxicities.

Randomization was stratified by disease risk factors and center, and all patients were reviewed centrally for eligibility, response and progression. Of those enrolled, 24% were classified as high risk.

The primary objective was to compare 38-month PFS of the 3 treatment arms. PFS events included progression, nonprotocol anti-myeloma therapy, or death.

With almost all patients nearing the end of follow-up, the study’s Data and Safety Monitoring Board released the results Stadtmauer reported at ASH which showed no difference among the 3 groups in terms of the study’s primary endpoint.

At a median follow-up of 38 months, PFS was not significantly improved by these interventions: PFS rates were 52% in the single-transplant arm, 57% in the consolidation arm and 56% in the tandem transplant arm (

Outcomes were also similar with respect to OS, said Stadtmauer. At 38 months, the corresponding probabilities of OS were 82.0%, 85.7%, and 83.4%, respectively.

In high-risk patients, PFS was between 40% and 48% at 38 months, with no difference in OS. Regarding the survival rate, Stadtmauer said it was “impressive that about 77% to 79% of high-risk patients are alive at 38 months.”

Finally, second malignancies emerged in 39 of the 758 patients (5.1%), including 15 in the consolidation arm, 14 in the tandem transplant arm, and 10 in the single-transplant arm. The most frequently reported secondary malignancies were leukemia in the tandem transplant and consolidation arms and solid tumors in the single ASCT arm.

“In the era of thalidomide analogs and proteasome inhibitors used in the initial therapy for myeloma and the use of prolonged maintenance therapy with lenalidomide, posttransplant consolidation with cycles of RVD or a second transplant do not produce incremental PFS benefit,” Stadtmauer concluded.

The researchers will continue to track long-term trends and outcomes of patients in a follow-up study.

Stadtmauer EA, Pasquini MC, Blackwell B et al. Comparison of autologous hematopoietic cell transplant (autoHCT), bortezomib, lenalidomide and dexamethasone (RVD) consolidation with lenalidomide maintenance (ACM), tandem autoHCT with lenalidomide maintenance (TAM), and autoHCT with lenalidomide maintenance (AM) for upfront treatment of patients with multiple myeloma (MM): Primary results from the randomized phase III trial of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0702 — StaMINA Trial). Presented at: American Society of Hematology 58th Annual Meeting; December 3-6, 2016; San Diego, CA. Abstract LBA-1.

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According to the results of the phase III StaMINA trial evaluating posttransplant therapy in multiple myeloma, a second a round of chemotherapy or stem cell transplant does not improve progression-free survival or overall survival compared with the current standard course of treatment alone.

Multiple Myeloma Transplant Trial Shows No Extra Benefit with Additions to Standard Therapy

An FDA-approved blood cancer drug has demonstrated encouraging findings, including an overall response rate (ORR) of 67%, in treatment of patients with chronic graft-versus-host-disease (cGVHD) that was not resolved by corticosteroids.

In a multicenter study presented as a late-breaker at the 2016 ASH Annual Meeting, ibrutinib (Imbruvica) showed clinically meaningful and durable responses in patients who failed at least 1 prior treatment for cGVHD. In addition, the majority of responders were able to reduce steroid doses to an acceptable minimal level.

Of the 42 participants who experienced GVHD, 67% responded to ibrutinib, and 71% had sustained improvements over a 5-month period. According to the researchers, the results are encouraging for a subset of patients with limited treatment options beyond corticosteroids.

Lead author of the study, David Miklos, MD, PhD, called the findings “remarkable” and said that ibrutinib appears to exceed the therapeutic benefits of other agents.

"This is a very high response rate," said Miklos, associate professor of Blood and Marrow Transplantation at the Stanford University Medical Center. “Clinicians will find these data support the use of ibrutinib in patients with steroid-refractory chronic GHVD, who currently suffer a range of symptoms that can be chronic and debilitating.”

cGVHD is a serious complication of allogeneic stem cell transplantation (ASCT), in which the transplanted stem cells attack the patient’s body, causing symptoms such as rashes, mouth ulcers, dry eyes, gastrointestinal problems, shortness of breath, and decreased mobility in the joints and limbs. Although immune-suppressing corticosteroid meditations are the standard treatment for cGVHD, they do not benefit all patients, Miklos explained.

Ibrutinib is a first-in-class, once-daily Bruton’s tyrosine kinase inhibitor that is used in the post-allogeneic setting for the treatment of chronic lymphocytic leukemia. Preclinical laboratory studies suggested that ibrutinib might also inhibit immune cells involved in cGVHD.

Supported by earlier results of this phase II study presented at ASH, ibrutinib was granted a breakthrough therapy designation by the FDA for cGVHD after failure of 1 or more lines of systemic therapy.

For the multicenter, open-label, phase II study, researchers enrolled 42 patients with steroid dependent/refractory cGVHD following ASCT.

Patients had failed 3 or fewer prior therapies for cGVHD and had either more than 25% body surface area involving an erythematous rash or a National Institutes of Health (NIH) mouth score greater than 4.

Ibrutinib was administered daily at 420 mg until cGVHD progression or unacceptable toxicities. The primary endpoint was cGVHD response based on the 2005 NIH consensus response criteria.

Results showed that 21% of responders had a complete response and 19% had a partial response. Seventy-one percent of the 28 responders had a sustained cGVHD response of at least 5 months.

Furthermore, cGVHD response was observed across multiple organs: 56% (20/25) of patients with 2 or more involved organs at baseline responded in at least 2 organs, and 42% of patients with 3 or more involved organs at baseline responded in at least 3 organs.

“These responses seen across all organs and multiple organs suggest that ibrutinib is actually targeting the underlying process of cGVHD and not simply masking the symptoms of cGVHD,” said Miklos.

Patients also had meaningful improvement in their cGVHD symptoms as assessed by Lee Symptom Score improvements of greater than 7 points. Consistent with this improvement, clinician-assessed and patient-reported reductions in overall cGVHD severities were reported throughout the study, as well.

In addition, patients on ibrutinib experienced reductions in corticosteroid doses. Overall, 26 patients achieved corticosteroid doses less than .15 mg/kg daily while on ibrutinib and 5 responders were able to discontinue all corticosteroid treatment.

An analysis of biomarker changes also support the beneficial effect of ibrutinib on cGVHD-related immune cell subsets.

Regarding safety, 45% of participants experienced serious adverse events (AEs) such as pneumonia, septic shock, or severe fever. Additional AEs include fatigue, diarrhea, muscle spasms, nausea, and bruising.

As Miklos reported, however, these side effects are consistent with those previously reported for ibrutinib and those observed in patients with cGVHD on concomitant corticosteroids.

Overall, he added, ibrutinib represents a promising potential new therapy for GVHD.

“By targeting allogeneic B cells and TH2 lymphocytes, ibrutinib is targeting a pathogenic mechanism that we believe causes GVHD, while leaving protective and antitumor cytotoxic T cells intact,” said Miklos. “This is a targeted therapy that does not just bluntly suppress the immune system; it leaves patients better able to fight their cancer as well as viral infections.”

Miklos and colleagues are recruiting participants for additional trials that will further investigate the use of ibrutinib in preventing or treating GVHD and compare it with other agents.

Miklos D, Cutler CS, Arora M, et al. Multicenter open-label phase 2 study of ibrutinib in chronic graft versus host disease (cGVHD) after failure of corticosteroids. Presented at: 2016 ASH Annual Meeting; December 3-6, 2016; San Diego, California. Abstract LBA3.

An FDA-approved blood cancer drug has demonstrated encouraging findings, including an overall response rate of 67%, in treatment of patients with chronic graft-versus-host-disease that was not resolved by corticosteroids.

Ibrutinib Shows Promise in Treating GVHD After Stem Cell Transplant

Treatment with anthracyclines was proven to be beneficial for patients with high-risk, HER2-negative, early-stage breast cancer, according to a joint analysis of the “ABC” trials presented at the 2016 ASCO Annual Meeting

The analysis, which included more than 4000 patients, demonstrated that docetaxel plus cyclophosphamide (TC) was significantly inferior to various taxane-plus-anthracycline-based (TaxAC) chemotherapy regimens.

“Statistical noninferiority of the non-anthracycline regimen could not be demonstrated,” said lead investigator Joanne Lorraine Blum, MD, PhD, medical oncologist with Texas Oncology at the Baylor-Sammons Cancer Center in Dallas. “In terms of the study’s primary endpoint, invasive disease-free survival, TC x 6 was significantly inferior to TaxAC.”

National Surgical Adjuvant Breast and Bowel Project (NSABP) and US Oncology Research (USOR) collaborated with separate sponsors on 3 sequential clinical trials that randomized women with resected high-risk, early-stage breast cancer to receive TC or one of several standard TaxAC regimens. The researchers prospectively agreed to combine the efficacy data in an analysis that was prespecified in the third protocol (NSABP B-49). These are collectively referred to as the “ABC Trials.”

Researchers analyzed 4156 of the 4242 patients randomized in the ABC Trials. Patients with node-positive or high-risk node-negative breast cancer participated in the trials, which were designed to test non-inferiority of TC to TaxAC with respect to invasive disease-free survival (iDFS). A hazard ratio (HR) from a stratified Cox model of 1.18 or more was pre-defined as inferior. HRs above 1 favor TaxAC.

The TaxAC options included AC every 2 or 3 weeks followed by paclitaxel every week or every 2 weeks; all were compared to TC every 3 weeks for 6 cycles. Patients were stratified for parent trial, positives nodes (0, 1-3, 4-9, 10+), and hormonal status (negative, positive). Follow-up ranged from 2.2 years to 6.3 years in the separate studies.

Data cutoff for the interim analysis was October 31, 2015. The observed HR on the initial 334 events was 1.202, which exceeded the pre-specified threshold for futility (>1.18) and triggered consideration for early reporting.

The 4-year iDFS was 88.2% in the TC arm versus 90.7% for patients on TaxAC. At approximately 95% in both groups, researchers observed no difference in overall survival, Blum reported.

Exploratory subgroup analyses suggested that TaxAC provided minimal, if any, benefit in ER-positive/node-negative cohorts; a small benefit in ER-positive/1-3 positive nodes and ER-negative/node-negative cohorts; and a large benefit in ER-positive/≥4 positive nodes and ER-negative/node-positive cohorts.

There were more first iDFS events, both distant and local or regional, in the TC arm (n = 220) versus TaxAC arm (n = 179). However, said Blum, acute leukemia occurred as a first event in 5 of 2050 patients assigned to TaxAC versus none in the TC arm.

“Additional follow-up and correlative studies to identify biomarkers of anthracycline benefit will be crucial for fully determining the utility of anthracyclines across the heterogeneous patient population,” Dr. Blum concluded.

Despite the small percentage of first events, leukemia risk associated with TaxAC remains low, she added, and subset analyses should be interpreted with caution.

“As of today, anthracycline and taxane-based adjuvant regimens are an appropriate choice for node-positive or high-risk, node-negative breast cancers. While not perfect, it’s highly encouraging to see how well this entire study population performed,” Traina concluded.

Prior to the findings from the ABC trial, the role for anthracyclines in patients with HER2-negative breast cancer had been hotly debated, according to Blum. Although subsets of early anthracycline trials suggested that only patients with HER2-positive tumors derived benefit from anthracyclines, these subset analyses were never conclusive.

Recent trials have shown that when taxanes are added to anthracyclines breast cancer mortality is reduced by more than a third compared with no chemotherapy. However, these benefits must be considered in the context of risk, said Blum, as anthracyclines are associated with a slight, but real, risk of cardiotoxicity and acute leukemia.

In addition, the sequential development of anthracyclines followed by taxanes has made evaluation of de-escalation of TaxAC regimens by removing anthracyclines challenging.

“The pivotal study of TC x 4 versus AC x 4 demonstrated overall survival superiority for TC,” said Blum. “This established TC as an effective non-anthracyclines regimen appropriate for comparing with TaxAC regimens.”

Blue JL, Flynn PJ, Yothers G, et al. Interim joint analysis of the ABC (anthracyclines in early breast cancer) phase III trials (USOR 06-090, NSABP B-46I/USOR 07132, NSABP B-49 [NRG Oncology]) comparing docetaxel + cyclophosphamide (TC) v anthracycline/taxane-based chemotherapy regimens (TaxAC) in women with high-risk, HER2-negative breast cancer. 

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Tiffany A. Traina, MD, Clinical Director of the Breast Medicine Service at Memorial Sloan Kettering and Assistant Professor of Medicine at Weill Cornell Medicine, said, “The overall trial results demonstrate that not only is TC not non-inferior to TaxAC in DFS, but TC x 6 is significantly inferior to the anthracycline and taxane-containing regimens in terms of DFS.”

Treatment with anthracyclines was proven to be beneficial for patients with high-risk, HER2-negative, early-stage breast cancer, according to a joint analysis of the Anthracyclines in Early Breast Cancer (ABC) trials.

Study Supports Use of Anthracyclines for Early, HER2-Negative Breast Cancer

Phase III results of the KRISTINE trial demonstrated that patients with HER2-positive early breast cancer had a significantly higher pathological complete response (pCR) rate when they received the neoadjuvant regimen of docetaxel, carboplatin, and trastuzumab plus pertuzumab (TCH+P) versus trastuzumab emtansine (T-DM1) plus pertuzumab (T-DM1+P).

While the TCH+P regimen was also associated with a higher rate of breast conserving surgery, researchers reported that T-DM1+P had a notably better safety profile and that health-related quality of life and physical functioning were maintained longer.

“Neoadjuvant TCH+P achieved a superior pCR rate compared with T-DM1+P and was associated with a higher breast-conserving-surgery rate,” said Sara A. Hurvitz, MD, General Internal Medicine, Hematology & Oncology, UCLA Medical Center. “However, neoadjuvant T-DM1+P had a more favorable safety profile, with lower incidence of grade 3 or greater adverse events, serious adverse events, and adverse events leading to treatment discontinuation.”

T-DM1 and pertuzumab bind to different HER2 domains and have marked antitumor activity in HER2-positive breast cancer. KRISTINE, results of which were presented at the 2016 ASCO Annual Meeting, shows the first phase III data for a neoadjuvant regimen that omits standard chemotherapy for HER2-positive breast cancer.

From June 2014 to June 2015, researchers at 68 centers in 10 countries enrolled 444 patients with centrally confirmed HER2-positive breast cancer greater than 2 cm in size. Patients were randomly assigned to receive T-DM1+P or the TCH+P regimen. Both regimens were given every 3 weeks for 6 cycles. At the end of the first cycle, patients underwent a core needle biopsy of the tumor for biomarker endpoints.

After 6 cycles, patients received standard of care surgery, and after surgery, they went on to receive 12 more doses of HER2-directed therapy according to the arm they were in. Patients in the T-DM1+P arm who had significant residual disease at the time of the surgery were encouraged to receive standard chemotherapy before receiving a maintenance therapy regimen.

Baseline characteristics were well distributed to 2 treatment arms by age, world region, estrogen receptor (ER)/progesterone receptor (PR) status, and stage.

The pCR rate in the breast and lymph nodes was 56% in the TCH+P arm and 44% in the T-DM1+P arm. This 11% difference was statistically significant, said Hurvitz, favoring the TCH+P arm.

In patients with ER- and PR-negative breast cancer, TCH+P yielded a pCR of 73% in breast and lymph nodes compared with 54% in the T-DM1+P arm.

In hormone receptor (HR)—positive breast cancer, the pCR was 44% in the TCH+P arm and 35% in the T-DM1+P arm, also favoring TCH+P. Over 60% of patients had HR-positive breast cancer, Hurvitz noted.

A preplanned, subgroup analysis showed that the benefits seen with TCH+P tended to favor all subgroups (age, world region, clinical stage at diagnosis and HR status). In addition, more women in the TCH+P underwent breast-conserving surgery (52.6% vs 41.7%, P = .0228).

In contrast, neoadjuvant T-DM1+P was associated with longer maintenance of patient-reported health-related quality of life and physical functioning, said Hurvitz. Neoadjuvant T-DM1+P also had a more favorable safety profile with a lower rate of grade 3/4 adverse events (AEs) (13% vs. 64%), serious AEs (5% vs. 29%), and AEs leading to treatment discontinuation (3% vs. 9%).

Cardiac event rates were unusual and were similar in the 2 treatment arms. Grade 3/4 AEs occurring in at least 3% of patients in either treatment arm included febrile neutropenia, neutropenia, diarrhea, and cytopenias, all of which were more common in the traditional chemotherapy arm compared with the T-DM1+P regimen.

Biomarker data and longer-term follow-up will be reported at a later date, said Hurvitz. In addition, there are several studies evaluating the use of T-DM1 in the early stage setting, including the KATHERINE and KAITLIN trials.

Hurvitz SA, Martin M, Symmans WF, et al. Pathologic complete response (pCR) rates after neoadjuvant trastuzumab emtansine (T-DM1 [K]) + pertuzumab (P) vs docetaxel + carboplatin + trastuzumab + P (TCHP) treatment in patients with HER2-positive (HER2+) early breast cancer (EBC) (KRISTINE). 

Phase III results of the KRISTINE trial demonstrated that patients with HER2-positive early breast cancer had a significantly higher pathological complete response rate when they received the neoadjuvant regimen of docetaxel, carboplatin, and trastuzumab plus pertuzumab versus trastuzumab emtansine plus pertuzumab.

TCH+P Still Standard Choice for Patients With HER2+ Breast Cancer

An analysis of patients with advanced hepatocellular carcinoma (HCC) and elevated α-fetoprotein (AFP) who received second-line ramucirumab (Cyramza) showed a significant improvement in overall survival (OS), according to data from the randomized phase III REACH study presented at the 2015 Gastrointestinal (GI) Cancers Symposium.

“Clinically meaningful improvement in overall survival was observed in populations with a baseline AFP greater than 400 ng/mL,” said lead author Andrew Zhu, MD, director of Liver Cancer Research at Massachusetts General Hospital.

Initiated in 2010, the double-blind phase III REACH study enrolled 565 patients across 27 countries. Patients with advanced HCC were randomized to receive best supportive care plus either the VEGFR-2 inhibitor ramucirumab or placebo following first-line treatment with sorafenib (Nexavar).

“After first-line sorafenib, no treatment has demonstrated a survival benefit in the second-line setting,” said Zhu.

In June 2014, Eli Lilly and Company, the manufacturer of ramucirumab, announced that REACH had missed its primary endpoint of a statistically significant improvement in OS.

The safety data for REACH were consistent with previous studies of single-agent ramucirumab, according to the company’s press release. The most common grade ≥3 adverse events occurring at a higher rate in the ramucirumab arm compared with the control arm were hypertension and fatigue.

In posthoc analysis of the trial results, it was observed that ramucirumab treatment led to a greater reduction in the risk of death in patients with progressively higher baseline AFP values (≥400 ng/mL). Thus, additional analyses were conducted to evaluate the relationship between baseline AFP and ramucirumab treatment.

The analyses found that with ramucirumab, the median OS for patients with a baseline AFP >400 ng/mL was 7.8 months, compared with 4.2 months for the placebo group (HR = 0.674; 95% CI, 0.51-0.90; 

 = .0059). In contrast, for patients with a baseline AFP <400 ng/mL, OS was 10.1 months with the treatment compared with 11.8 months for those receiving placebo.

“The forest plot of overall survival by subgroup in patients with baseline AFP above 400 clearly and numerically shows a favorable outcome with ramucirumab for overall survival in all subgroups tested,” Zhu noted.

“The overall survival decreases in both [ramucirumab and placebo] arms as increasing AFP thresholds were applied because these patients represent worse prognosis. However, the difference between these arms was generally in the range of 3 to 3.5 months,” he added.

When asked by a member of the audience at the GI symposium to explain the underlying biology of this phenomenon—why patients with higher AFP levels responded to ramucirumab treatment&mdash;Zhu was uncertain, but stressed the importance of finding an answer.

“This is a critical question we are actively pursuing,” he said. “We think there may be an underlying link with increased endiogenesis, but whether this is driven by VEGF or VEGFR-2, the literature is not clear. There is mounting evidence suggesting the high AFP group is really a unique subgroup of patients with a unique genetic signature,” he hypothesized, “but this is a critical question.”

Zhu noted that further investigation of the relationship between baseline AFP level and angiogenesis inhibition was ongoing to better understand ramucirumab’s mechanism of action in HCC.

“The additional AFP threshold was posthoc analysis,” he concluded. “There are no clear data yet. Patients will probably benefit between the normal and upper-limit, too, but additional study is necessary.”  

Ramucirumab has approved indications as a single-agent and in combination with paclitaxel to treat patients with advanced gastric or gastroesophageal junction adenocarcinoma. It is also approved in combination with docetaxel for the treatment of patients with metastatic non—small cell lung cancer.

In data from the phase III RAISE trial reported at the GI symposium, second-line ramucirumab combined with standard FOLFIRI extended survival by 1.6 months versus FOLFIRI alone in patients with metastatic colorectal cancer.

	Zhu AX, Ryoo B-Y, Yen C-J, et al. Ramucirumab (RAM) as second-line treatment in patients (pts) with advanced hepatocellular carcinoma (HCC): analysis of patients with elevated α-fetoprotein (AFP) from the randomized phase III REACH study. Presented at: 2015 Gastrointestinal Cancers Symposium; January 15-17, 2015; San Francisco, CA. Abstract 232.

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An analysis of patients with advanced hepatocellular carcinoma and elevated Î±-fetoprotein who received second-line ramucirumab showed a significant improvement in overall survival.


Chase Doyle

Articles

Multiple Myeloma Transplant Trial Shows No Extra Benefit with Additions to Standard Therapy

Ibrutinib Shows Promise in Treating GVHD After Stem Cell Transplant

Study Supports Use of Anthracyclines for Early, HER2-Negative Breast Cancer

TCH+P Still Standard Choice for Patients With HER2+ Breast Cancer

Ramucirumab Improves Survival in HCC Subgroup