The OBR Blog

June 04, 2019 - 05:06 pm comments0 Comments

As the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting comes to an end, one of today’s final sessions included follow-up data from a phase 1b study of acalabrutinib and obinutuzumab in chronic lymphocytic leukemia (CLL), endpoint analyses of the phase 3 CLL-14 trial, and results of the phase 2 ORIENT-4 trial in NK/T cell lymphoma.

High and durable response rates with acalabrutinib plus obinutuzumab in CLL (Abstract 7500)

This open-label, phase 1b/2 trial (NCT02296918) evaluated acalabrutinib plus obinutuzumab in patients with treatment-naïve (n=19) or relapsed, refractory (n=26) CLL.

Primary endpoints were overall response rate (ORR) and safety. Minimal residual disease negativity (MRD–) was assessed at a sensitivity of 10-4. Common grade 3 and 4 adverse events (AE) included decreased neutrophil count (24%), syncope (11%), decreased platelet count, increased weight, and cellulitis (9% each). There were 2 (4%) grade 3 bleeding events and one (2%) grade 3 atrial fibrillation event.

With a median follow-up of about 3.5 years ORR was 95%, with 31.6% complete responses (CR) in the treatment-naïve patients and 92% with 7.7% CR in the relapsed, refractory patients. Neither median duration of response nor median progression-free survival (PFS) were reached in either group. MRD– in the bone marrow at day 1 of cycle 12 occurred in 26% of treatment-naïve patients and in 15% of those with relapsed refractory CLL.

Acalabrutinib plus obinutuzumab was well tolerated with no new safety signals and resulted in high response rates that were durable and deepened over time.

Fixed-duration venetoclax plus obinutuzumab induced MRD-negativity in previously treated CLL (Abstract 7502)

CLL-14, a phase 3, open-label trial (NCT02242942) compared fixed-duration venetoclax plus obinutuzumab to chloramabucil plus obinutuzumab in previously untreated patients with CLL and comorbidities typical of the CLL population, defined as a cumulative illness rating score (CIRS) >6 or an estimated creatinine clearance <70 mL/min. Patients were randomly assigned to 12 cycles of chlorambucil (n=216) or venetoclax (n=216) in combination with obinutuzumab for the first 6 cycles.

Progression-free survival (PFS) was the primary endpoint. MRD– in peripheral blood or bone marrow 3 months after end of treatment was a secondary endpoint. MRD– was analyzed every three months by an allele-specific polymerase chain reaction assay (ASO-PCR, cut-off 10-4) or by next generation sequencing (NGS, cut-offs 10-4, 10-5, 10-6).

At a median follow-up of 28 months, PFS was significantly longer in the venetoclax arm (88%) vs the chlorambucil arm (64%; HR 0.35; 95% CI 0.23-0.53; P<.0001). There was no difference in overall survival (OS) between arms.

MRD– by ASO-PCR was significantly higher in the venetoclax arm vs chlorambucil in both blood (76% vs 35%; P<.0001) and bone marrow (57% vs 17%; P<.0001) 3 months after treatment end. More patients in the venetoclax arm had MRD– in both blood and bone marrow (75% vs 49% in the chlorambucil arm), and a landmark analysis showed that MRD- in the blood was associated with longer PFS.

Higher, earlier, and more durable MRD– rates occurred in the venetoclax group; 81% had MRD negativity at 12 months after treatment end vs 27% in the chlorambucil arm (HR for MRD conversion 0.19; 95% CI 0.12-0.30; median time off treatment 18 months). MRD– by NGS was also higher in the venetoclax arm than in the chlorambucil arm (78% vs 34% at <10-4).

AE were similar between group; neutropenia was notable, and febrile neutropenia was low.

Fixed duration venetoclax plus obinutuzumab resulted in prolonged PFS associated with deep, high, and durable MRD– and low conversion to MRD positivity at one 1-year post-treatment in this patient population.

Sintilimab shows promise for relapsed, refractory extranodal NK/T cell lymphoma (Abstract 7504)

Sintilimab, an anti-PD-1 monoclonal antibody, was approved in China in 2018 to treat relapsed, refractory classical Hodgkin lymphoma. ORIENT-4, a single-arm, phase 2 trial (NCT03228836), evaluated the efficacy and safety of single agent sintilimab in relapsed, refractory extranodal NK/T cell lymphoma, which has a dismal prognosis after relapse, is more common in Asia than in North America and Europe, and has high levels of PD-L1 expression.

Patients (n=28) received sintilimab after failure of prior L-asparaginase and a median of 3 prior therapies. ORR was 67.9% with 7.1% CR, and disease control rate was 85.1%. The 1-year overall survival (OS) was 82.1%; median OS was not reached at a follow-up of 15.4 months, and 19 patients continue on study.

Grade 3 decreased lymphocyte count occurred in 2 patients; there were no grade 4 or 5 AE and no anti-drug antibodies. QoL significantly improved from baseline throughout the study.

Sintilimab was associated with early disease progression by PET in 5 patients who went on to experience CR (n=1) or partial response; this possible pseudoprogression requires further study.

By Lynne Lederman, PhD

June 03, 2019 - 09:06 pm comments0 Comments

Late-breaking studies featured today at this morning’s press briefing as the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting continues included the phase 3 OSLO-COMET trial, the phase 2 EV-201 trial, and a study suggesting clinical trial participation of patients with lung cancer could be increased by revising eligibility criteria.

Laparoscopic and open resection equally effective for colorectal liver metastases (LBA3516)

Results of the first study to compare laparoscopic versus open resection for colorectal cancer liver metastases were presented. This Norwegian study randomly assigned 280 patients to either minimally invasive laparoscopic surgery (n=133) or open surgery (n=147) using liver parenchyma-sparing techniques.

Laparoscopic surgery was cost-effective and was associated with improved health-related quality of life, fewer post-operative complications (19% vs 31%), and shorter hospital stays (2 vs 4 days), compared with open surgery.

At a median follow-up of 45 months, there were no statistically significant differences between laparoscopic and open surgery for median survival (80 vs 81 months), median recurrence-free survival (19 vs 16 months), 5-year survival (57% vs 56%), 5-year recurrence-free survival (29% vs 31%), rate of complete tumor removal, or amount of tissue removed beyond the observable tumor. Patients were able to have recurrent tumors surgically removed if necessary.

ASCO Expert Nancy Baxter, MD, said, “This is an excellent example of high-quality evidence that will guide patient care. The essential thing is everybody who has a potentially curable disease should receive surgery,” regardless of which technique is used.

Enfortumab vedotin continues to show promise in previously treated advanced urothelial cancer (LBA4505)

Enfortumab vedotin (EV) is an antibody-drug conjugate targeting Nectin-4, a protein found in most urothelial cancers. EV-201 is a single arm, open-label, phase 2 trial enrolling individuals with locally advanced or metastatic urothelial cancer who had received platinum-based chemotherapy plus checkpoint inhibitors (cohort 1) or checkpoint inhibitors only (no platinum chemotherapy; cohort 2) (NCT03219333). Preliminary results were reported today for cohort 1. Cohort 2 is ongoing.

Of 125 patients treated in cohort 1, 44% had a confirmed objective response, of which 12% were complete responses. Median overall survival was 11.7 months (95% CI, 9.1-not reached), median progression-free survival was 5.8 months, (95% CI, 4.9-7.5), and median duration of response was 7.6 months (95% CI, 0.95-11.3).

Of those whose cancer had not previously responded to checkpoint inhibitor treatment, 41% had a response to EV; 38% of patients with liver metastases also had a response. EV was well-tolerated. The most common treatment-related adverse events were fatigue (50%), alopecia (49%), and decreased appetite (44%).

Planned trials of EV include EV-301, a randomized, phase 3 trial versus standard of care in previously treated, advanced urothelial cancer after platinum chemotherapy (NCT03474107), and EV-103, a trial of EV in combination with pembrolizumab and/or chemotherapy (NCT032884545).

EV is associated with durable responses in a heavily pretreated population. “When you see activity there you know there is something real going on. To what extent will require the randomized trial that is ongoing. From an unmet need perspective there is no question that this is a real drug with benefit for patients,” said ASCO Expert Robert Dreicer, MD.

Broader trial enrollment criteria could double eligible patients with advanced NCSLC (LBA108)

Clinical trial enrollment in the US is abysmally low. ASCO and Friends of Cancer Research propose expanding clinical trial eligibility to accelerate accrual, allow more patients to participate in clinical research, and enroll trial populations more representative of patient populations.

This retrospective electronic health record (EHR) review looked at the potential effect of broadened clinical trial inclusion criteria on enrollment in clinical trials of adults with advanced non-small cell lung cancer (NSCLC). Adults with advanced NSCLC who had ≥2 visits to an oncologist and ≥1 dose of a systemic treatment after diagnoses were identified from ASCO’s CancerLinQ database records from 2011 to 2018.

The suggested broadened inclusion criteria analyzed here included allowing individuals with brain metastases, another previous or concurrent cancer diagnosis, or a creatinine clearance as low as 30 mL/min. Traditional criteria exclude brain metastases, prior or concurrent cancer diagnosis, and creatinine clearance <60 mL/min.

Of 10,500 individuals with advanced NSCLC who were identified, 47.7% (5,005 people) would not meet standard trial eligibility criteria. The adoption of expanded criteria would exclude only 1.5% (154 people), expanding the potential trial population by 4,851 individuals. The adoption of expanded criteria therefore nearly double the potential NSCLC trial population compared with traditional criteria.

Finally, also at the press briefing, Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence introduced Project Facilitate, a pilot program to provide health-care professionals with continuous support throughout the expanded access (EA) process for oncology drugs. Ellen Sigal, PhD, introduced the Reagan-Udall EA Navigator designed to increase patient awareness of trial sponsor policies and listings.

by Lynne Lederman, PhD

Today, four plenary sessions dropped at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting featured results from three phase 3 trials: ENZAMET, ANNOUNCE, and POLO as well as encouraging data about the impact of Medicaid expansion under the Affordable Care Act (ACA).

Medicaid Expansion Closes Racial Disparities Gap (Abstract LBA1)

When the ACA was implemented in 2010, states were permitted to expand Medicaid access. A retrospective study found that states that expanded Medicaid had a reduction in racial disparities in time to cancer treatment.

Using data from electronic health records, researchers observed timely treatment (ie, treatment initiation within 30 days of diagnosis) for adult patients younger than 65 with a diagnosis of advanced or metastatic cancer. The study population included more than 30,000 patients, and depending on the Medicaid expansion status of the state in which they lived, patients were labeled as participating in Medicaid expansion or not.

When Medicaid was not expanded, a significantly lower percentage of African American patients received timely treated compared with white patients (43.5% vs 48.3%; P<0.001). When Medicaid was expanded, this racial disparity gap did not exist (49.6% vs 50.3%; P=0.63).

“The disparities disappeared under the expansion,” summed up study presenter Amy Davidoff, PhD, Yale University.

Enzalutamide for the Win in Metastatic Prostate Cancer (Abstract LBA2)

Enzalutamide outperformed standard non-steroidal anti-androgens for men with metastatic hormone-sensitive prostate cancer, according to data from an interim analysis of the randomized, phase 3 ENZAMET trial.

Patients (n=1,125) received a testosterone-suppressing medicine followed by treatment with enzalutamide or a standard of care non-steroidal anti-androgen: bicalutamide, nilutamide, or flutamide.

For the overall patient population, the 3-year overall survival (OS) rate was 79% for men treated with enzalutamide; 72% for men treated with bicalutamide, nilutamide, or flutamide. This resulted in a 33% reduced likelihood in risk of death for men treated with enzalutamide (HR=0.67; 95% CI, 0.52-0.86; P=0.002).

In particular, an OS benefit for enzalutamide was seen among men with high volume disease (HR=0.74; 95% CI, 0.55-1.01) or no planned early docetaxel (HR=0.51; 95% CI, 0.36-0.73), but not for those with planned early docetaxel (HR=0.90; 95% CI, 0.62-1.31).

“There is a delay in progression with an improvement in overall survival, but there is toxicity,”  cautioned study presenter Christopher Sweeney, MBBS, a medical oncologist at the Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute. “Ezalutamide actually increased the docetaxel-related toxicity.”

Olaratumab Flops in Phase 3 for Advanced Soft Tissue Sarcomas (Abstract LBA3)

Despite encouraging survival data in the previous phase 1b/2 trial, olaratumab in combination with doxorubicin failed to improve survival in patients with advanced soft tissue sarcomas in the phase 3 ANNOUNCE trial. Olaratumab in combination with doxorubicin was granted accelerated approval in 2016, but in light of the ANNOUNCE trial results, olaratumab is in the process of being withdrawn from the market.

No clear reason was offered for the failure of olaratumab in the phase 3 trial, but a few possibilities were floated, such as the control arm having a particularly high OS and not limiting study entry to treatment-naïve patients.

Offering a partial explanation for the initial survival benefit seen in the early-phase trial, study discussant Jaap Verweij, MD, PhD, Erasmus University Medical Center, said, “A critical issue in phase 2 studies, certainly in a group of diseases as heterogenous as soft tissue sarcomas, are small numbers of patients.”

Olaparib Hits its Target in BRCA-Positive Metastatic Pancreatic Cancer (Abstract LBA4)

Maintenance therapy with olaparib, a PARP inhibitor, after first-line, platinum-based chemotherapy extended progression-free survival (PFS) for patients with germline BRCA-positive metastatic pancreatic cancer, according to the results of the phase 3 POLO trial. Final OS results are still maturing.

The trial included metastatic pancreatic cancer patients with a BRCA1 or BRCA2 germline mutation who received chemotherapy for at least 16 months and then were randomly assigned maintenance therapy with either olaparib or placebo.

The median PFS was 7.4 months for the olaparib arm and 3.8 months for the placebo arm, resulting in a 47% reduced risk of progression for patients receiving olaparib (HR=0.53; 95% CI, 0.35 – 0.82; P=0.0038).

The objective response rate was 23.1% (18 of 78 patients) for the olaparib arm and 11.5% (6 of 52 patients) for the placebo arm, with two patients on olaparib achieving a complete response; both complete responses are ongoing. The median duration of response was 24.9 months for the olaparib arm and 3.7 months for the placebo arm.

“We conclude that a strategic approach of first-line, platinum-based chemotherapy followed by maintenance olaparib treatment should become a new standard of care for patients with metastatic pancreatic cancer who have a germline BRCA mutation,” said the study presenter Hedy Kindler, MD, Professor of Medicine, University of Chicago Medicine.

by Christina Bennett, MS

June 01, 2019 - 06:06 pm Posted in ASCO Conference Coverage Posted in Breast Posted in Lung (includes NSCLC, SCLC, Mesothelioma) Posted in Ovarian Posted in Stomach (Gastric) Cancer comments0 Comments

Several late-breaking studies made a splash today at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting. During the press conference this morning, results from the phase III MONALEESA-7 and KEYNOTE-062 trials were presented as well as long-term survival data from the KEYNOTE-001 trial. In the afternoon, a poster session featured a late-breaking study about the impact of the Affordable Care Act (ACA) in ovarian cancer.

Adding Ribociclib to Endocrine Therapy Improves Survival (Abstract LBA1008)

The addition of ribociclib, an oral CDK 4/6 inhibitor, to frontline endocrine therapy significantly extended overall survival (OS) for premenopausal women with advanced hormone receptor-positive/HER2-negative breast cancer, according to data from the phase III MONALEESA-7 trial.

Participants (N=672) were randomly assigned to received endocrine therapy plus ribociclib or endocrine therapy plus placebo. At a median follow-up of 34.6 months, 35% of patients in the ribociclib arm and 17% in the placebo arm were still receiving the assigned treatment.

The median OS was not yet reached for the ribociclib arm and 40.9 months for the placebo arm, resulting in a 29% relative reduction in risk of death for the ribociclib arm (HR=0.712; 95% CI, 0.535 – 0.948; P=0.00973). At 42 months of follow-up, the estimated OS rate was higher for the ribociclib arm compared with the placebo arm (70.2% vs 46.0%).

“This is the first time a statistically significant improvement in overall survival has been observed with a CDK 4/6 inhibitor in combination with endocrine therapy in patients with hormone receptor-positive advanced disease,” said study presenter Sara A. Hurvitz, MD, Director of the Breast Cancer Clinical Research Program at UCLA Jonsson Comprehensive Cancer Center.

Pembrolizumab in Gastric Cancer May be Safer Than Chemo (Abstract LBA4007)

Compared with chemotherapy, pembrolizumab alone had similar survival and less toxicity in the first-line setting for patients with PD-L1−positive, HER2-negative, advanced gastric or gastroesophageal junction (G/GEJ) cancer in the phase III KEYNOTE-062 trial. A survival benefit with pembrolizumab was seen in patients with tumors that had high PD-L1 expression—defined as a combined positive score of at least 10.

In terms of toxicity, 54.3% of patients who received pembrolizumab had a treatment-related adverse event and 16.9% had a grade 3 or higher adverse event. In contrast, 91.8% of patients who received chemotherapy had a treatment-related adverse event and 69.3% had a grade 3 or higher adverse event.

“For patients with advanced gastric or gastroesophageal cancer, pembrolizumab should really, in many cases, replace chemotherapy as a first-line treatment for this population,” said ASCO Expert Richard L. Schilsky, MD, Senior Vice President and Chief Medical Officer of ASCO.

5-Year Survival Rates for NSCLC Leap Forward with Pembrolizumab (Abstract LBA9015)

Pembrolizumab improved 5-year survival rates for advanced non-small cell lung cancer patients (NSCLC), according to long-term data from the multicohort phase Ib KEYNOTE-001 trial. At 5 years of follow-up, 18% of trial participants (100 of 550) were still alive. By comparison, before the advent of pembrolizumab, the average 5-year survival rate for advanced NSCLC was 5.5%.

Higher PD-L1 tumor proportion score (TPS) was linked to better survival, particularly among treatment-naïve patients—29.6% with a PD-L1 TPS of 50% or greater were still alive 5 years later compared with 15.7% with a PD-L1 TPS between 1% and 49%.

Among patients who received at least 2 years of pembrolizumab treatment and were still alive at data cutoff (n=46), the 5-year OS rate was 78.6% for treatment-naïve patients and 75.8% for previously treated patients. The objective response rate was 86% for treatment-naïve patients and 91% for previously treated patients.

ACA Linked to Better Diagnosis and Treatment of Ovarian Cancer (Abstract LBA5563)

After the implementation of the ACA in 2010, women with ovarian cancer had an increased likelihood of being diagnosed at an early stage and receiving treatment within 30 days of diagnosis, a poster reported.

The study researchers used data from the National Cancer Database and assessed early stage at diagnosis (I/II vs III/IV) and time to treatment (<30 days vs ≥30 days) in women aged 21 to 64 with ovarian cancer (n=72,987) and compared that to women aged 65 or older with ovarian cancer (N=59,499). The study time period defined 2006 to 2009 as before the ACA and 2011 to 2014 as after the ACA.

A difference-in-differences (DD) approach showed a trend toward increased diagnosis among younger women (DD=1.7%; 95% CI, 0.7 – 2.7; P=0.001) and reduction in delays in treatment of 30 days or greater (DD=−1.6%; 95% CI, −0.7 to −2.7; P=0.001) after the ACA was implemented.

“As stage and treatment are major determinants of survival, these gains under the ACA may have long-term impacts on women with ovarian cancer,” concluded the investigators.

Christina Bennett, MS


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