The OBR Blog

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 clinicaltrials.gov 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

 

One of biggest challenges in attending an annual ASCO meeting is time management. With over 2,000 abstracts submitted this year and a wide variety of new drugs and therapeutic targets, ASCO 2019 will be no different.

During a webinar last week sponsored by E-Squared Communications (a Conisus company), OBR and three renowned cancer experts helped identify some of the “high impact studies” that are sure to gain a lot of attention at this year’s ASCO Annual Meeting. For those of you who missed this increasingly popular annual webinar, the experts not only covered the important data but also provided some suggestions on where to go if you happen to play hooky for a day at ASCO. Don Sharpe, President and Founder of OBR, moderated the session, and the primary areas of focus included cervical, prostate, pancreatic, breast, lung, and advanced gastric/gastroesophageal junction cancers as well as multiple myeloma and hepatocellular carcinoma (HCC).

Pending its final outcome, the first trial highlighted in the webinar could well be a practice-changing study. This phase 3 Intergroup trial (E3A06) in patients with asymptomatic intermediate- or high-risk smoldering multiple myeloma is the largest randomized trial in this setting to date. The 182 patients who participated in this study were randomized to either receive lenalidomide alone or observation, with progression-free survival (PFS) being the primary endpoint. At a median of 28 months of follow-up, the 3-year PFS rate in the lenalidomide arm seems to be numerically trending in the right direction (91% vs. 66%). This data will be highlighted in an oral abstract (8001) session on Sunday, June 2nd.

Following an interesting review of a phase 2 study highlighting the use of LN-145 tumor infiltrating lymphocytes in patients with cervical cancer, the next phase 3 study highlighted by the experts was a late-breaking abstract. This Australian and New Zealand Urogenital (ANZUP) Cooperative Group trial (ENZAMET) evaluated enzalutamide as first-line androgen-deprivation therapy for metastatic hormone-sensitive prostate cancer. The abstract LBA2 will be presented at the plenary session on Sunday, June 2nd and is sure to draw comparisons to the earlier LATITUDE study of abiraterone in this setting.

Pancreatic cancer seems to be climbing into the spotlight as well this year, as the OBR experts identified the Adjuvant Treatment in Pancreatic Cancer Study (APACT) as an important one to watch. This study evaluated nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients with surgically resected pancreatic cancer. With 866 patients enrolled, this large clinical trial had a primary endpoint of disease-free survival; however, the authors noted that the overall survival (OS) results seen in this study may better support the rationale of using this combination in the adjuvant setting, especially for patients who are ineligible for FOLFIRINOX.

The PARP inhibitor olaparib was also discussed in the webinar as a potentially new therapeutic option for patients with pancreatic cancer. The phase 3 POLO trial of olaparib versus placebo as maintenance therapy in patients with germline BRCA-mutated metastatic pancreatic cancer whose disease had not progressed following first-line platinum-based chemotherapy will be highlighted during the plenary session on Sunday, June 2nd (LBA4). This study is the first positive phase 3 trial of any PARP inhibitor in germline BRCA-mutated metastatic pancreatic cancer.

Pembrolizumab was highlighted as well in two studies looking at gastric cancer and GEJ adenocarcinoma (KEYNOTE-062) and advanced HCC (KEYNOTE-240). In KEYNOTE-062, pembrolizumab met its primary endpoint by demonstrating OS noninferiority compared to chemotherapy in the intent-to-treat population. In KEYNOTE-240, pembrolizumab showed positive numerical trends but did not meet statistical significance for its co-primary endpoints of OS and PFS; however, it did show an improved response rate versus placebo (ORR 16.9% vs. 2.2%), and it will be interesting to see what impact this might have going forward.

Another important KEYNOTE study is KEYNOTE-189: Updated OS and progression after the next line of therapy (PFS2) with pembrolizumab (pembro) plus chemo with pemetrexed and platinum vs placebo plus chemo for metastatic nonsquamous NSCLC. KEYNOTE-001 is also a late-breaking abstract looking at 5-year long-term OS for patients with advanced non-small cell lung cancer treated with pembrolizumab.

There are certainly other important abstracts at this year’s ASCO Annual Meeting, but at the very least, this review should help narrow down your choices.

By Adrian Barfield, President, Medallion Healthcare

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