ASCO 2017-PEMBROLIZUMAB USE IN SARCOMAS

Pembrolizumab is a potentially viable treatment for a subset of sarcomas, with promising activity in undifferentiated pleomorphic sarcoma (UPS) and liposarcoma in a phase II clinical trial. Melissa A. Burgess, MD, of the University of Pittsburg, presented final results and biomarker analyses from the SARC028 multicenter trial (Abstract 11008) at the Sarcoma Oral Abstract Session on June 2.

Response in UPS correlated with PD-L1 status, and baseline infiltrating cytotoxic T cells also correlated with response, Dr. Burgess said.

SARC028 is a multicenter trial evaluating single-agent pembrolizumab in patients with advanced soft tissue sarcomas (STS) and bone sarcomas. The primary endpoint was objective response rate (ORR) by RECIST 1.1, and secondary objectives included safety and tolerability, progression-free survival (PFS), overall survival (OS), immune-related response rate, and analysis of pretreatment PD-L1 tumor expression and response.

The STS arm included 10 patients in four cohorts: UPS, dedifferentiated liposarcoma, synovial sarcoma, and leiomyosarcoma. The bone sarcoma arm had 40 patients, including 22 with osteosarcoma, 13 with Ewing sarcoma, and five with chondrosarcoma. Most patients in each arm received two or more previous treatments.

Patients received 200 mg of pembrolizumab intravenously every 3 weeks. Biopsies were taken before treatment and while patients were receiving treatment. Tumors were assessed for PD-L1 expression and immune infiltrates using multicolor immunohistochemistry (IHC).

In the overall study, with a median follow-up of 19 months, the projected overall response was 18%, Dr. Burgess said. In the STS arm, one patient had a complete response (CR; 2.5%) and six patients (15%) had a partial response (PR); one patient (10%) with UPS had CR and three had PR (30%). Two patients (20%) with liposarcoma and one (10%) with synovial sarcoma had PR. The median response duration in the STS arm was 33 weeks. Median PFS was 18 weeks, and median OS was 49 weeks.

In the bone sarcoma arm, two patients (5%) experienced PR: one (20%) with chondrosarcoma and one (5%) with osteosarcoma. Nine patients overall had stable disease. The median duration of response was 43 weeks in the bone sarcoma arm. Median PFS was 8 weeks, and median OS was 52 weeks.

Serious adverse events were “infrequent and not unexpected,” Dr. Burgess said. Overall, grade 3 and 4 adverse events were seen in 7% of the STS arm and 12% of the bone sarcoma arm.

In 70 biopsies analyzed for pretreatment PD-L1 expression, three were positive. The PD-L1–positive cases were restricted to UPS; of the two that were evaluable for response, one had CR and one had PR. No post-treatment biopsies were PD-L1–positive. In 28 paired tumor samples, multicolor IHC showed that responders had an increased number of infiltrating cytotoxic T cells at baseline. Further biomarker analysis with a multiplex panel is planned, as are confirmatory trials in UPS and leiomyosarcoma.

Discussant Jean-Yves Blay, MD, PhD, of Centre Léon Bérard, in France, noted that there are multiple levels of complexity in attempting to understand immunotoxicity in sarcoma, and he congratulated the study authors for “looking at biomarkers with a multidimensional approach.” Even though most patients in SARC028 did not experience tumor reduction, he noted, some had significant responses. He said biomarkers in sarcoma must be further investigated “because it could be a link to better guide therapy in the future.”

Commenting on Dr. Burgess’s presentation along with two other abstracts presented in the session, Dr. Blay said, “We can say that immunotherapy works in sarcoma. But it works in immune subsets of molecular subsets of histological subgroups. We must do better. Biomarkers are the key question.” He called for a worldwide collaborative effort by the sarcoma community to undertake basket and umbrella trials exploring combination treatments in subtypes of sarcomas.  

ASCO 2016-IMMUNOTHERAPY FOR SCLC

In the phase I/II CheckMate 032 study, nivolumab (Opdivo) alone and with ipilimumab (Yervoy) demonstrated activity in patients with small cell lung cancer (SCLC) progressing after at least one previous platinum regimen, as reported in The Lancet Oncology by Antonia et al.

Study Details

In the SCLC cohort of the open-label study, 216 patients with limited-stage or extensive-stage disease received nivolumab at 3 mg/kg every 2 weeks(n = 98) or combinations of nivolumab at 1 mg/kg plus ipilimumab at 1 mg/kg (n = 3); nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg (n = 61); and nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg (n = 54) every 3 weeks for four cycles followed by nivolumab at 3 mg/kg every 2 weeks.

Response Rates

Objective response was observed in 10 of 98 patients (10%) receiving nivolumab at 3 mg/kg, 1 of 3 patients (33%) receiving nivolumab at 1 mg/kg plus ipilimumab at 1 mg/kg, 14 of 61 patients (23%) receiving nivolumab at 1 mg/kg plus ipilimumab at3 mg/kg, and 10 of 54 patients (19%) receiving nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg. Median durations of response were not reached in the nivolumab monotherapy group, 7.7 months in the nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg group, and 4.4 months in the nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg group. In total, 16 patients had responses > 6 months.

Toxicity

Grade 3 or 4 treatment-related adverse events occurred in 13% of patients in the nivolumab 3 mg/kg group, 30% of the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg group, and 19% of the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg group, with the most common being increased lipase (0%, 8%, 0%) and diarrhea (0%, 5%, 2%). Treatment was discontinued due to adverse events in 6%, 11%, and 7% of patients. Death due to treatment-related adverse events occurred in two patients in the nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg group and in one patient in the nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg group.

The investigators concluded: “Nivolumab monotherapy and nivolumab plus ipilimumab showed antitumour activity with durable responses and manageable safety profiles in previously treated patients with SCLC. These data suggest a potential new treatment approach for a population of patients with limited treatment options and support the evaluation of nivolumab and nivolumab plus ipilimumab in phase 3 randomised controlled trials in SCLC.”

The study was funded by Bristol-Myers Squibb.

ASCO 2016-NIVOLUMAB-IPILIMUMAB COMBINATION FOR MELANOMA

A combination of the checkpoint inhibitors nivolumab and ipilimumab continues to demonstrate superior clinical activity vs ipilimumab monotherapy in treatment-naive patients with advanced melanoma, according to a study (abstract 9505) presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 3–7 in Chicago.

In the phase III CheckMate 067 trial, the anti–programmed death 1 agent nivolumab plus the anti-CTLA–4 agent ipilimumab significantly improved progression-free survival (PFS) and objective response rate (ORR) vs ipilimumab alone in patients with melanoma. Lead author Jedd Wolchok, MD, PhD, of the Memorial Sloan Kettering Cancer Center in New York, presented updated efficacy and safety results from this study.

The study included 945 treatment-naive patients who received either nivolumab 1 mg/kg every 3 weeks plus ipilimumab 3 mg/kg every 3 weeks for 4 doses (followed by nivolumab 3 mg/kg every 2 weeks); nivolumab 3 mg/kg every 2 weeks plus placebo; or ipilimumab 3 mg/kg every 3 weeks for 4 doses plus placebo, until progression or unacceptable toxicity.

With a minimum follow-up of 18 months and median follow-up of 20.7 months, median PFS continued to be significantly longer for nivolumab plus ipilimumab and nivolumab as compared to ipilimumab. “The reduction in risk of progression or death was 45% for nivolumab and 58% for the combination group. In a descriptive analysis the risk of progression for the combination was reduced by 24% when compared to nivolumab alone,” said Wolchok.

The median PFS was 11.5 months for the combination, 6.9 months for nivolumab, and 2.9 months for ipilimumab.

Median duration of response in nivolumab plus ipilimumab responders has not been reached, and was 22.3 months in the nivolumab group and 14.4 months in ipilimumab responders.

About three-quarters of patients receiving nivolumab in combination or alone have ongoing responses as compared to about half of those on ipilimumab alone.

For the nivolumab plus ipilimumab, nivolumab, and ipilimumab groups, median PFS was 15.5, 5.6, and 4 months in patients with a BRAF mutation and 11.3, 7.1, and 2.8 months in BRAF wild-type patients, respectively.

Median PFS by less than 5% PD-L1 tumor expression was 11.1 months with nivolumab plus ipilimumab, 5.3 months for nivolumab alone, and 2.8 months for ipilimumab. Median PFS rates for patients with more than 5% PD-L1 tumor expression were not reached for the combination, 22 months for nivolumab, and 3.9 months for ipilimumab.

Safety data were consistent with earlier reports, with the frequency and types of drug-related grade 3/4 adverse events being 56.5% with nivolumab plus ipilimumab, 19.8% with nivolumab, and 27% with ipilimumab. There were no new toxicities or safety signals, and no treatment-related deaths with the combination.

In conclusion, Wolchok said: “Nivolumab plus ipilimumab and nivolumab alone improved PFS and ORR vs ipilimumab alone in patients with untreated advanced melanoma. In descriptive analyses, the combination resulted in numerically greater PFS and ORR than nivolumab alone, including in patients with poor prognostic factors. Nivolumab plus ipilimumab resulted in clinically meaningful improvements in ORR regardless of PD-L1 expression. The majority of treatment-related adverse events resolved with immune-modulating medications.”

Results of ongoing survival analyses will further characterize the benefit-risk profile of nivolumab plus ipilimumab and nivolumab alone, he said.

ASCO 2016-NEW TRIPLET THERAPY FOR MYELOMA

Triplet therapy is the initial preferred treatment for myeloma, and various combinations are used around the world. A new combination, with the recently approved oral agent ixazomib (Ninlaro), can now be added to the options. It offers high responses and manageable toxicity at a reasonable cost, say researchers.

Most of the commonly used triplets involve the proteasome inhibitor bortezomib (Velcade), which "is given subcutaneously but is associated with some degree of peripheral neuropathy and frequent hospital visits," said Meletios A. Dimopoulos, MD, from the National and Kapodistrian University of Athens School of Medicine in Greece. He spoke during a Highlights of the Day session here at the American Society of Clinical Oncology (ASCO) 2016 Annual Meeting.

In the United States, the combination of bortezomib, lenalidomide (Revlimid), and dexamethasone (VRd) is often used, whereas in Europe, the combinations of bortezomib, cyclophosphamide, and dexamethasone (CyBorD) and of bortezomib, thalidomide, and dexamethasone (VTD) are often used.

The first oral proteasome inhibitor, ixazomib (Ninlaro), was recently approved for use with lenalidomide and dexamethasone (IRd). This three-agent combination was the first all-oral regimen approved for the treatment of multiple myeloma.

Now another triplet combination — ixazomib, cyclophosphamide, and dexamethasone (ICd) — has shown encouraging clinical results.

The cost of this new regimen compares with others in clinical use, Dr Dimopoulos reported.

ICd costs about $1000 per month and involves one hospital visit, IRd costs about $2000 per month involves one hospital visit, VRd costs about $2000 per month and involves an average of four hospital visits, and CyBorD costs about $1000 per month and involves four hospital visits.

"The take-home message is that ICd is an all oral and effective proteasome-inhibitor-based triple combination," Dr Dimopoulos said. "It is well tolerated, has a reasonable cost, and continuous therapy is feasible and improves quality of response."

New Results With ICd Combination

New results with the ICd combination were reported at the ASCO meeting from a phase 1/2 trial presented by Martha Lacy, MD, from the Mayo Clinic in Rochester, Minnesota, and colleagues.

The study was conducted in 48 newly diagnosed myeloma patients with a median age of 64 years.

Patients received ixazomib 4 mg on days 1, 8, and 15, dexamethasone 40 mg days 1, 8, 15, and 22, and cyclophosphamide 300 or 400 mg/m² on days 1, 8, 15, and 22. Treatment cycles were 28 days. Patients could continue on ixazomib alone after 12 cycles.

Stem cell collection was allowed after four cycles. At 12 months, patients were taken off of the cyclophosphamide and dexamethasone and continued on ixazomib until progression.

The median duration of response was 18.4 months. For patients who remained on study, the depth of response improved over time, Dr Lacy noted.

The overall response rate was 77%, and the overall survival at 12 months was 100%. Progression-free survival at 12 months was 91% for the entire cohort.

A total of 77% of patients experienced grade 3 or higher toxicity, and 71% had grade 3+ hematologic toxicity.

"Only 2% of patients needed a dose reduction of ixazomib," she said. "Importantly, there were no study deaths."

Toxicity, including myelosuppression, was manageable overall, and similar to what has previously been reported with ixazomib. "Neurotoxicity was mild and does not appear to be cumulative," she said.

Well Tolerated, Reasonable Cost

Dr Dimopoulos noted that his own group has been studying the ICd combination. Results from that phase 2 trial were presented last year at the annual meeting of the American Society of Hematology (Abstract 26).

That trial was conducted in an elderly population (median age, 70 years), and the goal was to define a dose of cyclophosphamide in newly diagnosed transplant-ineligible patients.

The results showed promising early response rates in this population, Dr Dimopoulos reported.

The combined complete response and very good partial response was 28% in the group that received cyclophosphamide 300 mg/m² and 21% for those treated with the 400 mg dose. Overall responses were 78% and 65%, respectively, and complete responses were 10% and 9%, respectively.

"Prolonged therapy improved the quality of responses, and lower doses were better tolerated with similar efficacy," said Dr Dimopoulos.

The latest study presented at ASCO included both older and younger patients. Furthermore, he pointed out, patients receiving upfront ixazomib going on to transplant were able to undergo stem cell collection.

Dr Dimopoulos has disclosed no relevant financial relationships. Dr Lacy reports relationship with Celgene.

American Society of Clinical Oncology (ASCO) 2016 Annual Meeting: Abstract 8002. Presented June 3, 2016.

ASCO 2016-CABAZITAXEL AS EFFECTIVE AS DOCETAXEL FOR CRPC

Cabazitaxel at two different doses was no better than docetaxel with regard to overall survival (OS) or progression-free survival (PFS) in men with metastatic castration-resistant prostate cancer (mCRPC), according to results of the phase III FIRSTANA trial. The results were presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 3–7 in Chicago (abstract 5006).

Cabazitaxel is a semisynthetic taxane. “It was initially selected from a wide variety of taxanes to be able to overcome taxane resistance,” said A. Oliver Sartor, MD, of Tulane University in New Orleans, who presented the study. In preclinical studies the drug was particularly active against docetaxel-resistant cells, and it was approved as a second-line option in 2010 based on results of the phase III TROPIC trial.

“Many individuals have been comparing a variety of agents against placebo, mitoxantrone, and other therapies that are not known to prolong survival,” Sartor said. “In this case, two life-prolonging therapies are compared to one another in a phase III trial for the first time.”

The FIRSTANA trial included 1,168 patients randomized to one of three groups: cabazitaxel 20 mg/m2 (389 patients), cabazitaxel 25 mg/m2 (388 patients), or docetaxel (391 patients). All patients also received prednisone. Patients had received no prior chemotherapy and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2; the demographics were well-balanced between groups. Sartor noted that very few patients had received prior enzalutamide or abiraterone.

The OS was no different between the three groups. The median OS in the docetaxel group was 24.3 months, compared with 24.5 months with cabazitaxel 20 mg and 25.2 months with the 25-mg dose. The hazard ratio (HR) for the 20-mg group compared with docetaxel was 1.009 (95% CI, 0.85–1.197; P = .9967). For the 25-mg group compared with docetaxel, the HR was 0.97 (95% CI, 0.819–1.16; P = .7574).

PFS was also very similar, at 5.3 months for docetaxel, 4.4 months for the 20-mg dose, and 5.1 months for the 25-mg dose. The HRs again showed no differences. The tumor response rate with the 25-mg dose was 41.6%, which was significantly better than the 30.9% with docetaxel (P = .0370), but Sartor said that likely doesn’t have much clinical significance.

Almost all patients experienced treatment-emergent adverse events of any grade. There were more serious events in the 25-mg group (47.6%) than in the 20-mg group (34.4%) and in the docetaxel group (32.6%). There were some differences in specific adverse event incidence, such as a higher rate of hematuria with cabazitaxel, and a higher incidence of peripheral sensory neuropathy with docetaxel. Most of the deaths that occurred in the trial were due to disease progression.

ASCO 2016-INTERMITTENT DOCETAXEL THERAPY FOR CRPC

An intermittent docetaxel regimen was non-inferior to continuous docetaxel therapy in patients with metastatic castration-resistant prostate cancer, according to results of a phase III trial presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 3–7 in Chicago (abstract 5005).

The PRINCE study compared a standard docetaxel regimen with a regimen in which the therapy is paused. “The rationale of intermittent therapy and the benefit this might hold for the patient is clearly the treatment holiday,” said Hannes Cash, MD, of Charité University Medicine Berlin in Germany, who presented the study. “With this, [there is] reduced docetaxel exposure for the patient, reduced cumulative toxicities, and possibly delayed resistance to taxanes.” He noted that the study began in 2005, when there was a need to improve docetaxel therapy and some of the newer agents were not yet available.

A total of 187 patients (156 evaluable) were randomized to receive standard continuous docetaxel treatment vs an intermittent regimen involving 12 weeks of treatment followed by a pause until disease progression, when docetaxel was started again. Progression was defined as either serum prostate-specific antigen (PSA) > 4 ng/mL with a 50% increase over baseline level, or radiological or symptomatic progression.

The 1-year survival rate in the continuous therapy group was 75%, compared with 78% in the intermittent group; this met the non-inferiority criteria for the study. As expected, the intermittent patients received a lower cumulative dose of docetaxel (368.16 mg/m2) compared with the continuous patients (444.2 mg/m2), but that difference was not statistically significant (P = .84).

The median overall survival was 18.3 months with continuous docetaxel and 19.3 months with intermittent treatment, for a hazard ratio of 1.14 (95% CI, 0.75–1.72; P= .535); a post-hoc analysis determined that this did not meet the non-inferiority criteria. Differences between the two groups with regard to progression-free survival and time to treatment failure were not significant.

“The lower cumulative dose did not translate into a lower rate of adverse effects,” Cash said. There were no differences between groups with regard to grade 3 or 4 anemia or neutropenia, fatigue, and other events. Cash noted that the study did not end up recruiting its full planned cohort, and thus it remains “speculative” what the outcomes may have been with more patients. He concluded that based on this data, though, this regimen may be offered to metastatic prostate cancer patients.

The discussant for the session, Derek Raghavan, MD, PhD, of the Levine Cancer Institute in Charlotte, North Carolina, said that he thinks “it is reasonable to offer patients a chemo holiday.” He noted that this can reduce costs of therapy without a significant detriment to patients.

ASCO 2016-HORMONE MAINTENACE THERAPY HELPFUL FOR LOW GRADE OVARIAN CANCER

CHICAGO—Hormone maintenance therapy (HMT) is associated with better survival than post-treatment surveillance for women with low-grade serous carcinoma of the ovary or peritoneum, according to a retrospective study presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 3–7 in Chicago (abstract 5502).

“Women with stage II–IV low-grade serous carcinoma who received HMT following primary treatment had significantly better outcome compared to women who underwent surveillance,” reported lead study author David Marc Gershenson, MD, of the University of Texas MD Anderson Cancer Center in Houston.

Low-grade serous carcinoma is a rare subtype representing approximately 10% of serous carcinomas of the ovary or peritoneum. “It may arise de novo or following diagnosis of a serous borderline tumor,” Gershenson noted. Compared with high-grade serous carcinoma, these tumors tend to occur in younger patients, and exhibit aberrations in the MAP kinase pathway, as well as a high frequency of estrogen receptor and progesterone receptor expression.

No prospective clinical trials have been undertaken for frontline treatments, but data from MD Anderson’s Low-Grade Serous Tumor Database suggest that relative to high-grade serous carcinomas, low-grade tumors exhibit chemoresistance in the frontline chemotherapy setting (with more than 40% of patients experiencing persistent disease) and platinum-sensitive or platinum-resistant salvage chemotherapy settings.

“Low-grade serous carcinoma is not as responsive to platinum/taxane chemotherapy as is high-grade serous carcinoma,” Gershenson said.

In order to compare patient outcomes associated with HMT and surveillance following primary cytoreductive surgery and platinum-based chemotherapy in women with pathologically confirmed stage II–IV low-grade serous carcinoma of the ovary or peritoneum, the researchers conducted a retrospective cohort study using the MD Anderson Low-Grade Serous Tumor Database. They identified 240 eligible patients diagnosed between 1981 and 2013; 134 had undergone post-treatment surveillance and 70 had received HMT. Patients whose disease had progressed during primary chemotherapy were not included in the study.

Median progression-free survival (PFS), the primary study endpoint, was 27.3 months for women in the surveillance group (95% CI, 22.7–31.9 months) and 64.9 months in the HMT group (95% CI, 43.5–86.3 months; P < .001). Forty percent (28/70) of HMT patients had not had disease recurrence, compared with 12% (16/134) in the surveillance group.

For overall survival (OS), the difference was not significant (median OS, surveillance group: 98.8 vs 115.7 months; P = .36).

The study was retrospective, covering a long period of time during which there were heterogenous treatments and varying follow-up practice patterns, Gershenson cautioned.

However, in a subset analysis of the 148 women in the cohort who had no evidence of disease following primary chemotherapy, HMT was associated with superior median PFS (81.1 vs 29.9 months; P < .001) and superior OS (191.3 vs 106.8 months; P = .04) compared with surveillance.

In multivariate analysis, HMT was also associated with a reduced risk of relapse (hazard ratio, 0.23 [95% CI, 0.11–0.51]).

Gershenson called the findings “potentially practice-changing,” and called for a prospective clinical trial.

ASCO 2016-CT SURVEILLANCE NOT HELPFUL IN NSCLC

CHICAGO—Routine post-treatment computed tomography (CT) surveillance does not offer better survival rates than clinical symptoms–driven detection of tumor recurrence after treatment for locally advanced non–small-cell lung cancer (NSCLC), according to a single-institution retrospective study presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 3–7 in Chicago (abstract 8515).

The findings suggest that “symptoms-driven evaluation may not adversely affect survival,” said lead study author Joseph Nicholas Bodor, MD, of the University of Maryland Medical Center in Baltimore.

Post-treatment surveillance for tumor recurrence is widely believed to improve patient survival, but the evidence base, including meta-analysis, is “inconclusive,” commented Denise R. Aberle, MD, professor of radiology and bioengineering at the David Geffen School of Medicine at the University of California, Los Angeles, who led a panel discussion on the study.

The study authors retrospectively compared post-treatment outcomes for 167 patients treated for locally advanced (stage IIIA/IIIB) NSCLC during 2000–2015 with chemoradiation with or without surgical resection. A total of 99 patients underwent CT chest surveillance and 68 patients underwent symptoms-based evaluation for recurrence. CT surveillance occurred every 3 months the first year after treatment, every 4 months during the subsequent 2 years, followed by scans every 6 months for a year, and then once annually thereafter.

The CT-surveillance and symptoms-evaluation groups were demographically well-balanced.

Patients undergoing CT surveillance and those receiving symptoms evaluation had different patterns of tumor recurrence, with 56% of surveillance patients vs 29% of symptoms-evaluated patients experiencing local recurrence (P = .001), and 12% vs 38% experiencing metastasis at a single anatomic site, respectively (P = .001).

There was no statistically significant difference in overall survival, but a trend toward better survival among patients with multiple metastases in the surveillance group was noted. That trend did not achieve statistical significance.

During the years included in the study, pemetrexed and targeted therapies were unavailable or were not widely used.

“Recurrence is usually metastatic—in 85% of cases—and therefore less likely to be identified by chest CT,” Aberle noted. “The more common metastases are extrathoracic, and therefore outside the CT region of interest.”

ASCO 2016-NIVOLUMAB BEYOND PROGRESSION FOR RENAL CANCER

In a large randomized study, the immunotherapy drug nivolumab (Opdivo), an anti­­–PD-1 (programmed cell death protein 1) monoclonal antibody, was shown to be a safe and effective therapy for kidney cancer even in patients who continued treatment after their disease progressed. Results of the phase III clinical study conducted by physician-scientists at multiple centers were presented by Escudier et al at the 2016 ASCO Annual Meeting (Abstract 4509).

Study Findings

In this large clinical study (CheckMate 025) conducted in the treatment-refractory setting of metastatic renal cell carcinoma, 406 patients received nivolumab.

Of the patients who had disease progression on nivolumab, 153 continued treatment beyond progression and 145 did not. Patients without progressive disease were excluded from analysis.

Fourteen percent of those who continued treatment experienced a 30% or greater reduction in their tumors. Additionally, patients who continued treatment survived 28.1 months, compared with 15 months for those who did not continue therapy.

“This study demonstrates that patients who continued treatment with nivolumab after their disease progressed may have demonstrated a delayed immune response that ultimately prolonged survival,” said Saby George, MD, FACP, Associate Professor of Oncology in the Department of Medicine at Roswell Park Cancer Institute and senior author of the study. “These findings indicate that the new immunotherapy checkpoint inhibitor drugs merit further study to establish different clinical guidelines with a goal to optimize patient benefit. It is important to translate such findings into clinical practice guidelines in order to have better outcomes.”

ASCO 2016-IMMUNOTHERAPY FOR ANAL CANCER

The immune checkpoint blockade nivolumab (Opdivo, Bristol-Myers Squibb Company) has shown promising results for patients with squamous cell carcinoma of the anal canal (SCCA).

The findings, which were presented at the American Society of Clinical Oncology (ASCO) 2016 Annual Meeting, showed a 24% response rate to nivolumab, including two complete responses.

"Anal cancer refractory to chemotherapy and radiation can respond to PD-1 inhibitory agents — good news to bring home to our clinics," commented Richard Goldberg, MD, physician-in-chief, Ohio State University Comprehensive Cancer Center—James Cancer Hospital and Solove Research Institute, Columbus.

Speaking at a Highlights of the Day session for gastrointestinal (colorectal) cancer, Dr Goldberg noted that although this was a small study, it was "really the first prospective phase 2 trial completed in refractory metastatic SCCA in the United States.

"It showed that single-agent nivolumab was well tolerated and fulfilled the primary endpoint of response," he said. "And it opens the door to the use of immunotherapy in another one of the virally associated cancer, this one with human papilloma virus [HPV]."

He emphasized that these findings may offer a new, badly needed treatment option to this population.

"This abstract provides us with something beyond the NCCN guidelines on metastatic anal cancer, which tell us that 5-FU/cisplatin is recommended for metastatic disease," Dr Goldberg said. "There is basically one validated option for these patients, and at least in my clinic, these patients run out of options long before they run out of the desire for more options."

Although SCCA is a relatively rare disease, its incidence has been increasing by 2% to 3% per year. It is estimated that more than 8000 cases will be diagnosed in the United States this year.

"About 20% of patients present with metastatic SCCA, and there is currently no standard of care for patients with metastatic refractory disease," explained study author Cathy Eng, MD, professor of gastrointestinal medical oncology at the University of Texas MD Anderson Cancer Center in Houston, who presented the findings at the meetinG.

SCCA is primarily driven by HPV, which accounts for approximately 80% to 95% of cases. "The role of HPV in the tumorigenesis of this disease provides rationale for the use of immune checkpoint agents as a novel treatment in a virally driven disease," she said.

"This is the first study to investigate the use of immunotherapy in this patient population," said Dr Eng.

Study Details

The study was conducted through the National Cancer Institute's (NCI's) Experimental Therapeutics Clinical Trials Network (ETCTN), which was created by the NCI to evaluate therapies using a coordinated, collaborative, and inclusive team-based approach to early-phase experimental therapeutic clinical trials.

A total of 39 patients were screened across the ETCTN within a 5-month period; 37 patients were enrolled in the trial and received treatment, and 34 were evaluable for response.

All patients received nivolumab (3 mg/kg) IV every 2 weeks. Optional pretreatment and on-treatment tissue biopsies were performed, and plasma samples were collected for immune biomarkers and HPV/p16 status. Two patients were HIV-positive.

The median number of prior therapies was two (range, one to eight). PD-L1 expression was not required for participation in the study.

Of the 34 patients who were eligible for evaluation, two patients (5.4%) achieved a complete response, seven (18.9%) had a partial response, 17 (45.9%) had stable disease, and eight (21.6%) had progressive disease.

The overall response rate in the intent-to-treat group was 24.3% (n = 9). In the evaluable group, the overall response rate was 26.5% (n = 9).

Progression-free survival was 3.9 months, which Dr Eng explained was "not surprising, given that our data have shown a progression-free survival of about 5 months in treatment-naive patients with cytotoxic chemotherapy."

Dr Eng pointed out a few individual cases. One patient with dermal and liver metastases and lymph node involvement had undergone two previous lines of therapy. "She just came off treatment after 23 doses and has been on study for 11 months," she said. "Her dermal metastases completely resolved with treatment."

At baseline, CD8, PD1, and PDLI expression was increased in responders as compared with nonresponders, she added.

There were very few grade 3 toxicities, which included fatigue, anemia, rash, and hyperthyroidism. There was one incidence of pneumonitis.

The study was funded by MD Anderson's HPV Moon Shots Program, the HPV Anal Cancer Foundation, the E. B. Anal Cancer Fund, and a philanthropic donation. Dr Eng and several coauthors report relationships with industry, as noted in the abstract. Dr Goldberg has relationships with Baxter, Biothera, Forty Seven, Immunocare Therapies, Immunovative Therapies, Kanghong Pharma, Lilly, Merck, Momenta Pharmaceuticals, Novo Nordisk, Pfizer, Sirtex Medical, Taiho Pharmaceutical, Targovax, Bayer (Inst), Bristol-Myers Squibb (Inst), Immunomedics (Inst), Sanofi (Inst), Amgen, and Merck KGaA.

American Society of Clinical Oncology (ASCO) 2016 Annual Meeting: Abstract 3503. Presented June 6, 2016.

ASOC 2016-IMMUNOTHERAPY IN MELANOMA PATIENTS WITH AUTOIMMUNE DISEASES

CHICAGO — Clinical trials that led to the approval of new therapies often have strict exclusion criterion, and so yield no data on how the drugs fare in patients with preexisting conditions. For that, data from the real-world setting are needed, and the latest to come in for the anti-PD-1 immunotherapies are data to show that they are safe and effective even in patients with preexisting autoimmune diseases.

Researchers reporting a retrospective study at the American Society of Clinical Oncology (ASCO) 2016 Annual Meeting say that the new data are reassuring and that preexisting autoimmune diseases should not preclude treatment with immunotherapy with the PD-1 inhibitors pembrolizumab (Keytruda, Merck & CO) and nivolumab (Opdivo, Bristol-Myers Squibb).

"In the real world, one frequently encounters patients with autoimmune disease who develop melanoma. In fact, these patients have the highest risk for developing cancers," presenter Alexander Menzies, MD, PhD, from the Melanoma Institute Australia, University of Sydney, told Medscape Medical News. "Our study shows that current immunotherapies are safe and work in many of these patients," he added.

Dr Menzies also suggested that the results of their study could be applied to other cancers, such as lung and renal cell, which can now be treated with immunotherapy.

Two melanoma experts not involved in the study welcomed the new findings.

"This is an important study and addresses important issues physicians face in clinical practice: how to treat patients who are typically excluded from clinical trials," Michael A. Postow, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City, told Medscape Medical News.

"An extension of this study is reevaluating eligibility and exclusion criteria for clinical trials," Dr Postow said. "Clinical trials are highly restrictive, and many patients do not have access to them. Determining the efficacy and safety of agents in high-risk patients in prospective studies informs clinical practice," he added.

"We can indeed treat patients with PD-1 blockade when they have low-grade or even moderate-grade autoimmunity, as well as those who had high-grade ipilimumab-related toxicity," Jeffrey S. Weber, MD, PhD, deputy director of the Laura and Isaac Perlmutter Cancer Center at New York University's Langone Medical Center, told Medscape Medical News. He indicated that in his own practice, he has seen similar patients, and he considers immunotherapy with nivolumab or pembrolizumab an option.

"A study such as this one expands the population of patients who can receive immunotherapy with PD-1 inhibitors," he noted.

Baseline Characteristics

For the study, Dr Menzies and colleagues retrospectively identified 119 patients with advanced melanoma who had been treated with anti-PD-1 immunotherapy and who either had preexisting autoimmune diseases (n = 52) and/or had experienced major immune-related adverse events (irAEs) when they received prior immunotherapy with ipilimumab (Yervoy, Bristol-Myers Squibb).

The 52 patients with preexisting autoimmune disease had advanced disease: 85% had M1c disease, 35% had brain metastases, 48% had elevated lactate dehydrogenase (LDH), and 56% had an Eastern Cooperative Oncology Group performance status of 1 or more. "With these baseline characteristics, these patients are poor candidates for clinical trials," Dr Menzies said.

Disease was not active in 71% of patients, and 62% were not receiving treatment for their autoimmune disease, whereas 17% were being treated with steroids. The autoimmune diseases cover a wide spectrum: rheumatologic (52%), dermatologic (15%), gastrointestinal (12%), neurologic (10%), endocrine (8%), and respiratory (4%).

The other 67 patients who had prior ipilimumab toxicities also had advanced disease: 87% had M1c disease, 27% had brain metastases, 40% had elevated lactate dehydrogenase, and 63% had an Eastern Cooperative Oncology Group performance status of 1 or more. The toxicity was grade 3 in 76% of these patients, and grade 4 in 10%. Major irAEs experienced included colitis (42%) and endocrine-related (11%) and dermatologic-related (4%) events. Others included rheumatologic, ocular, hepatitic, neurologic, and hematologic events.

These irAEs were managed with oral steroids (46%), intravenous steroids (24%), and infliximab (22%). In all but one of these patients, the irAEs resolved before starting pembrolizumab or nivolumab.

Most of the patients received pembrolizumab (109 of 119), and the remaining 10 patients received nivolumab. Median follow-up was 4.6 months, with 72% of the patients having 3 or more months of follow-up.

Results in Patients With Preexisting Autoimmune Disease

Among the 56 patients with preexisting autoimmune diseases, 38% (20 patients) experienced flares after a median of 38 days. Flares were most commonly seen in patients with rheumatologic conditions, occurred most commonly with active disease, and tended to occur more in patients receiving immunosuppressants at the start of PD-1 inhibitor therapy, Dr Menzies indicated.

Immunosuppression with steroids was administered in 21% of patients, and steroid-sparing agents were administered in 12% of patients. In patients experiencing flares, PD-1 dosing was continued in 10 (20%) of 58 patients, was interrupted in 8 (15%) of 58 patients, and was permanently discontinued in 2 patients; irAEs were reported in 15 (29%) of 52 patients and were symptomatically managed in 8 patients (15%).

Overall response rate (ORR; complete or partial) was reported in 17 of 52 patients (33%), median progression-free survival was 6.2 months, and duration of response and overall survival were not reached at time of reporting. ORR was similar in patients who experienced flares (35%) compared with those who were flare free (31%).

"Patients with preexisting autoimmune diseases can be successfully treated with PD-1 inhibitors. The response is as good as that seen in other patients. Even when the autoimmune disease flares, it can be managed," Dr Menzies said.

Commenting on the study, Dr Postow agreed. "This study has absolute relevance to clinical practice," he said. It shows that patients with preexisting autoimmune diseases can benefit from therapy with PD-1 inhibitors. Although about 40% of patients experienced flares, most exacerbations were low grade in nature and were treatable with immunosuppressive agents, he noted. "The efficacy seen in the study approximates to the efficacy we see in clinical trials," Dr Postow said. "PD-1 inhibitors should not be withheld from these patients who stand to benefit from immunotherapy," he noted.

Results in Patients With Prior irAEs

Among the 67 patients who had developed irAEs to prior ipilimumab, these events recurred in two patients (3%): colitis and arthritis. Other irAEs related to PD-1 inhibitors were reported in 23 (34%) of 67 patients: grade 1/2, 13%; grade 3, 18% (colitis, hepatitis, arthritis, myasthenia, pneumonitis, diabetic ketoacidosis); and grade 4, 3% (pneumonitis, hepatitis).

Clinically, irAEs were managed symptomatically (in 9% patients), with oral steroids (15%) and intravenous steroids (6%), among others. Of the 23 patients experiencing irAEs with PD-1 inhibitors, nine patients continued therapy, six patients had an interruption of treatment, and eight patients permanently discontinued the treatment. ORR was reported in 27 (40%) of 67 patients; median progression-free survival was 7.2 months, and duration of response and median overall survival were not reached.

ASCO 2016-A NOVEL ANTIBODY FOR GASTRIC CANCER

CHICAGO — A novel antibody added to standard chemotherapy extends survival in patients with advanced gastric cancer, according to findings from the phase 2 randomized FAST study.

The first-in-class agent, IMAB362 (Ganymed Pharmaceuticals AG), targets claudin-18 splice variant 2 (CLDN18.2), a tight junction protein that is expressed by a number of cancers, including gastric and gastroesophageal junction adenocarcinoma.

Median overall survival was significantly longer in patients who received IMAB362 than in those who did not (13.2 vs 8.4 months). For patients with the highest levels of CLDN18.2, median overall survival was even longer (16.7 vs 9.0 months).

The study was presented here at the American Society of Clinical Oncology (ASCO) 2016 Annual Meeting.

"As claudin 18.2 is abundant in gastric tumors, we estimate that half of all patients with advanced gastric cancer may be candidates for this new treatment," said lead study author Salah-Eddin Al-Batran, MD, a medical oncologist and director of the Institute of Clinical Cancer Research at Nordwest Hospital in Frankfurt, Germany.

"IMAB362 significantly improved overall survival and progression-free survival," said Dr Al-Batran. "IMAB362 plus epirubicin, oxaliplatin, and capecitabine is feasible and was well tolerated."

Results from this study provide a "strong rationale for a confirmatory phase 3 trial," he noted.

Use in Other Cancers?

IMAB362 is a chimeric monoclonal antibody that mediates specific killing of CLDN18.2-positive cancer cells by activating immune effector mechanisms. It has already demonstrated single-agent activity, safety, and tolerability in patients with pretreated gastric cancer

CLDN18.2 is found in a variety of tumors. It is broadly expressed in about 70% to 90% of biliary duct, pancreatic, gastric, and mucinous ovarian cancers, and in about 10% of non-small-cell lung cancers.

It is not expressed in any healthy tissue expect for stomach mucosa, Dr Al-Batran explained.

"Claudin 18.2 is expressed in approximately 50% of cancers, suggesting that this treatment could apply to many patients," said ASCO spokesperson Smitha Krishnamurthi, MD, from University Hospitals in Cleveland.

Improvement in All End Points

The FAST trial involved 161 patients with advanced or recurrent gastric or gastroesophageal junction cancer with CLDN18.2 expression of at least 2+ in at least 40% tumor cells and an ECOG performance status of 0 or 1. None of the patients were eligible for trastuzumab.

All patients received first-line epirubicin 50 mg/m² and oxaliplatin 130 mg/m² on day 1, and capecitabine 625 mg/m² twice daily on days 1 to 21. In addition, 77 patients were randomized to received a loading dose of IMAB362 800 mg/m², then IMAB362 600 mg/m² on day 1. The other 84 patients served as the control group.

The study also involved an exploratory group of 85 patients who received the same first-line chemotherapy regimen plus high-dose IMAB362 (1000 mg/m²). Those results were not presented.

Median progression-free survival was worse in the control group than in the IMAB362 group (4.8 vs 7.9 months; hazard ratio [HR], 0.47; P = .0001). The same was true for median overall survival (8.4 vs 13.2 months; HR, 0.51; P = .0001).

In the subset of patients with very high CLDN18.2 expression (intensity of at least 2+ in at least 70% tumor cells), efficacy was more pronounced. Median progression-free survival was worse for the 59 patients in the control group than for the 57 in the IMAB62 group (5.6 vs 7.2 months; HR, 0.36; P = .005). Again, the same was true for median overall survival (9.0 vs 16.7 months; HR, 0.45; P < .0005).

Objective response rates also favored IMAB62 plus chemotherapy over chemotherapy alone (25% vs 39%).

Complete responses were achieved by more patients in the IMAB62 group than in the control group (3 vs 8), as were partial responses (18 vs 22).

Adverse effects were mostly manageable, said Dr Al-Batran, and the addition of IMAB362 did not significantly increase grade 3/4 events.

The most common IMAB362-related adverse events were vomiting, neutropenia, and anemia. Grade 3/4 neutropenia was higher in the IMAB362 group than in the control group (32.5% vs 21.4%), as were grade 1/2 vomiting (55.8% vs 34.5%) and grade 3/4 vomiting (10.4% vs 3.6%).

Tinkering Needed

This study shows promising improvement in survival with minimal increases in toxicity, said Peter Enzinger, MD, from the Dana-Farber Cancer Institute in Boston.

However, even though the initial FAST results are promising, additional data and some "tinkering" are needed before moving on to phase 3, he explained.

The inclusion criteria for a phase 3 study are also an issue. "And why not include an arm of negative patients to confirm that the mechanism of action is related," Dr Enzinger said.

In addition, because epirubicin is highly emetogenic, whether it is the "the best partner" for IMAB362 needs to be assessed, because nausea and vomiting appear to be the primary toxicity. "Why not FOLFOX or FOLFIRI?" he asked.

Overall, the study showed good survival and low toxicity, but there are some considerations to make before moving to phase 3, Dr Enzinger concluded.

This study received funding from Ganymed Pharmaceuticals AG. Dr Al-Batran reports financial relationships with Merck, Roche, Celgene, Lilly, Nordic Bioscience, Novartis, Vifor Pharma, Medac, and Hospira. Some of his coauthors report relationships with industry, as detailed in the abstract. Dr Krishnamurthi reports receiving research funding from Nektar and Taiho Pharmaceutical. Dr Enzinger reports relationships with Amgen, Pfizer, Merck, Sirtex Medical, and Five Prime Therapeutics.

American Society of Clinical Oncology (ASCO) 2016 Annual Meeting: Abstract LBA 4001. Presented June 6, 2016.

ASCO 2016-IMMUNOTHERAPY FOR MESOTHELIOMA

CHICAGO—The novel anti-PD-L1 agent avelumab showed some promising clinical activity and was generally well tolerated in a phase I trial of patients with unresectable, previously treated mesothelioma. Results of the trial were presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, held June 3–7 in Chicago.

“Approximately 3,000 new cases of malignant mesothelioma are diagnosed each year in the United States,” said Raffit Hassan, MD, of the National Cancer Institute in Bethesda, Maryland, who presented the study. The current standard treatment of pemetrexed and cisplatin yields a median overall survival of 12.1 months, and there is no US Food and Drug Administration (FDA)-approved therapy for patients progressing after first-line chemotherapy.

Avelumab is a fully human anti-PD-L1 IgG1 antibody; it is under investigation in multiple malignancies. PD-L1 is expressed on the surface of mesothelioma cells, providing a rationale for avelumab’s use in this malignancy. In the new JAVELIN study, more than 1,600 patients have been treated with the drug across a variety of malignancies; in this analysis, 53 patients with unresectable pleural or peritoneal mesothelioma were included. All patients had progressed after a platinum/pemetrexed-containing regimen; they were unselected for PD-L1 expression.

The median treatment duration was 12 weeks, and the median age of patients was 66 years. Most patients (73.6%) had an ECOG performance status of 1, and the median number of prior treatments was 1.5.

The unconfirmed objective response rate (ORR) was 9.4%, with five partial responses (four confirmed); response was ongoing in four of five of those patients, and the median duration of response was not reached. Twenty-five patients had stable disease (47.2%), and the disease control rate was 56.6%. The median progression-free survival (PFS) was 17.1 weeks; at 24 weeks, the PFS rate was 38.4%.

Of 39 evaluable patients, 14 (35.9%) were found to be PD-L1–positive based on a staining cut-off of ≥ 5% of positive cells. The ORR was 14.3% in those patients, compared with 8% in PD-L1–negative patients. The median PFS was 17.1 weeks in PD-L1–positive patients, and 7.4 weeks in the PD-L1–negative patients. That advantage was not evident in terms of PFS rate at 24 weeks, however, at 39.2% in PD-L1–positive patients and 40.7% in PD-L1–negative patients.

Treatment-related adverse events (AEs) occurred in 41 patients (77.4%). The most common AEs included infusion-related reaction (37.7% of patients), fatigue (15.1%), chills (15.1%), and pyrexia (11.3%); all of those were grade 1 or 2 AEs. There were grade 3 or higher AEs in four patients (7.5%); these included colitis, decreased lymphocytes, and increased GGT or CPK. The study had no treatment-related deaths.

“Ongoing follow-up will further characterize durability of the clinical benefit,” Hassan said. “This dataset is the largest study to date of patients with mesothelioma treated with an anti–PD-1 or anti–PD-L1 antibody.”

ASCO 2016-IMMUNOTHERAPY FOR CERVICAL CANCER

CHICAGO—Pembrolizumab is well-tolerated and shows promising antitumor activity and early survival rates among patients with PD-L1–positive cervical squamous cell cancer, according to preliminary results from the phase Ib KEYNOTE-028 trial, presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 3–7 (abstract 5515).

“Pembrolizumab had durable antitumor activity in patients with PD-L1–positive advanced cervical cancer,” said lead study author Jean-Sébastien Frenel, MD, of the Institut de Cancérologie in Saint-Herblain, France. “Responses lasted for a median of 26 weeks with some extending to 1 year.”

Median progression-free survival was 2 months, and the 6-month and 12-month progression-free survival rates were 21% and 8%, respectively. Overall survival was promising, Dr. Frenel reported. The median overall survival was 9 months (range, 4–12 months). The 6-month overall survival rate was 67%, and the 12-month overall survival rate was 33%.

Combination therapy with chemotherapy and bevacizumab is an approved first-line treatment for advanced cervical cancer, but additional effective treatment options for advanced cervical cancer are urgently needed, particularly for patients whose cancer progresses on first-line therapy. “Many patients are platinum-resistant,” Frenel noted.

Twenty-four patients with metastatic or unresectable, PD-L1–positive cervical cancer that had failed (or who were unable to receive) standard chemotherapy were administered pembrolizumab (10 mg/kg intravenously, every 2 weeks). Response was assessed every 8 weeks for the first 6 months, and then every 12 weeks. Patients with complete or partial responses, or stable disease, were treated for 24 months or until progression or intolerable toxicity. Patients who experienced disease progression or who did not tolerate toxicity discontinued pembrolizumab.

No patients experienced complete responses upon investigator review using RECIST v1.1 criteria. Four of 23 evaluable patients experienced partial responses, three had stable disease and 16 had disease progression.

The safety profile was in line with previous reports for pembrolizumab in other cancer types. Two patients discontinued treatment following grade 3 treatment-related adverse events. No patient deaths or grade 4 treatment-related adverse events were reported.

The clinical benefit and safety of pembrolizumab in advanced cervical cancer will undergo additional study in the currently enrolling phase II KEYNOTE-158 trial (NCT02628067).

ASCO 2016-A NOVEL TREATMENT FOR AML

CHICAGO—CPX-351, a liposomal formulation of cytarabine and daunorubicin encapsulated at a 5:1 molar ratio, significantly improved event-free survival, overall survival, and response compared with a traditional dose of cytarabine/daunorubicin in older patients with high-risk secondary acute myeloid leukemia (AML), according to the results of a study presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 3–7 (abstract 7000).

“CPX-351 demonstrated superior efficacy compared to 7+3”—cytarabine 100 mg/m2/day for 7 days with daunorubicin 60 mg/m2 on days 1, 2, and 3—“in all key efficacy parameters,” said study presenter Jeffrey E. Lancet, MD, of H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida. “We feel that CPX-351 should be considered standard first-line treatment of older patient with high-risk AML.”

AML is a disease of older people and survival is significantly worse in older patients. A previous phase II trial in this patient population showed an almost doubling of overall survival from 6.1 months with the 7+3 regimen compared with 12.1 months with CPX-351.

In this open-label, phase III trial, 309 patients with secondary AML were randomly assigned to induction therapy with CPX-351 or the 7+3 regimen of cytarabine/daunorubicin. All patients were aged 60 to 75 and had a history of prior cytotoxic treatment, antecedent myelodysplastic syndrome or chronic myelomonocytic leukemia, or AML with WHO-defined myelodysplastic syndrome–related cytogenetic abnormalities.

After a minimum follow-up of 13.7 months, results showed that treatment with CPX-351 resulted in a 31% reduction in the risk for death compared with the 7+3 regimen (hazard ratio [HR], 0.69; P = .005). The median overall survival was 9.56 months with CPX-351 compared with 5.95 months with the 7+3 regimen of cytarabine/daunorubicin. Patients treated with CPX-351 also had a 26% improved event-free survival compared with the 7+3 regimen (HR, 0.74; P = .021). In addition, patients assigned CPX-351 also a had significantly improved rate of response (47.7% vs 33.3%; P = .016).

Looking at patients who ultimately underwent transplant, Lancet and colleagues conducted a landmark survival analysis at the time of transplant. Median survival was not yet reached in patients assigned CPX-351 compared with 10.25 months in patients assigned 7+3 (HR, 0.46; P = .0046).

“Even though the numbers are small, there appears to be a major difference in outcome favoring CPX compared with 7+3 in patients who actually went through transplant, and please keep in mind that the majority of patients that went to transplant did so during complete remission,” Lancet said.

Richard A. Larsen, MD, of the University of Chicago, was the discussant of this abstract. He said that “these data will be sufficient for FDA approval and after approval, this agent should be considered for frontline use in this subset of AML patients.”