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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

May 15, 2019 - 10:05 pm Posted in ASCO Conference Coverage Posted in Breast Posted in Multiple Myeloma Posted in Pediatric (includes Adolescents and Young Adults) comments0 Comments

In conjunction with the release of the abstracts for the upcoming 2019 ASCO Annual Meeting, a virtual press cast previewed five noteworthy studies that showcase the range of research that will be presented at the meeting.

Topics included the effect of a low-fat diet on breast cancer mortality, identification of a greater than expected number of targetable molecular alterationsin a pediatric MATCH trial, response of rare pediatric tumors with certain gene fusions to the targeted agent entrectinib, optimization of chemotherapy for frail and/or elderly patients with advanced esophageal cancer, and reduction of progression of smoldering to active multiple myeloma by lenalidomide.

Here are summaries of the key findings.

Low-Fat Diet Associated with Reduced Breast Cancer Mortality (Abstract 520)

Observational studies of the effect of dietary fat on breast cancer have produced equivocal results. To address this, the Women’s Health Initiative (WHI) Dietary Modification (DM) trial, a randomized, controlled study looked at the influence of diet breast cancer incidence and mortality.

The WHI-DM trial (NCT00000611) enrolled 48,835 post-menopausal women age 50 to 79 years who were randomly assigned to dietary intervention (n=19,541) or usual diet (comparison group, n=29,294) from 1993 to 1998. Dietary intervention, which continued for 8.5 years, included reducing fat intake to 20% of calories and increasing intake of vegetables, fruit, and grains, similar to the DASH (dietary approaches to prevent hypertension) diet.

Trial endpoints included deaths from and after breast cancer. Cumulative follow-up data have been collected for a median of 19.6 years. Baseline fat intake was at least 32% of calories. Most women in the diet group increased daily intake of vegetables, fruit, and grains and reduced daily fat consumption to 25% of calories; most did not reach the 20% goal.

In the diet group versus the comparison group, there was a significantly lower risk of death from breast cancer (HR, 0.85; 95% CI, 0.74, 0.96; P=.01) and from any cause after a diagnosis of breast cancer (HR, 0.79; 95% CI, 0.64, 0.96; P=.025).

The authors call this the only study providing randomized clinical trial evidence that an intervention can reduce a woman’s risk of dying from breast cancer, although this analysis was not pre-specified in the original trial design, dietary components were assessed by participant recall, and there was no way to measure adherence to the diet.

At the meeting, the effect of the same dietary modification in a subgroup of women with poor metabolic function, defined as obesity, diabetes, elevated cholesterol, or hypertension, will also be presented (Abstract 1539).

More Actionable Targets than Expected Found in Pediatric MATCH Trial (Abstract 10011)

The NCI-COG (Children’s Oncology Group) Pediatric MATCH (Molecular Analysis for Therapy Choice) trial was designed to address whether a precision oncology approach, i.e., treating tumors with agents selected to target specific genetic alterations, would be useful in the pediatric cancer setting.

NCI-COG Pediatric MATCH will enroll at least 1000 children with tumors that have not responded to standard treatment. The initial step is to screen tumors for potential targets, followed by treatment with therapy matched to alterations found in the tumors independent of tumor type. Treatment is in individual phase 2 clinical trials, of which there are currently 10, one for each current single-agent targeted therapy being tested.

There were 422 patients enrolled, from 93 of the 124 COG sites that had the study open, between July 24, 2017 and the data cutoff for this analysis at the end of last year. Tumor samples were received from 92% of enrolled patients and accounted for over 60 different tumor types including central nervous system (CNS) and non-CNS tumors. Turnaround time was 15 days from tumor receipt to treatment assignment.

Study researchers projected a match rate of 10% based on adult data. So far, 24% of screened patients with cancer that did not respond to treatment were eligible for treatment with a targeted agent. Of these, 39 patients (10%) have enrolled in a treatment trial. The trial is ongoing and is expected to add at least four additional single targeted agents. Combination therapies are being considered for future trials.

Rare Pediatric Tumors with Gene Fusions Respond to Entrectinib in Early Trial (Abstract 10009)

Fusions and alterations in intracellular signaling pathways such as TRKA/B/C, ROS1, and ALK genes act as drivers in some tumors by “locking” the pathways in the “on” position. Entrectinib is an oral inhibitor of these pathways and has the additional advantage of being able to cross the blood-brain barrier to enter the CNS.

Pediatric tumors with mutations in TRKA/B/C, ROS1, and ALK genes are rare, and are being identified more frequently as next-generation sequencing is becoming more common. STARTRK-NG (RXDX-101-03) is phase1/1b clinical trial investigating entrectinib in children with recurrent or refractory solid tumors with these gene alterations. Most had undergone prior surgery and radiation.

Of 29 patients enrolled, 16 were in the phase 1 dose-finding part; an additional 13 patients have been enrolled in the ongoing basket phase 1b part at a dose level of 550 mg/m2(initial recommended dose, n=7) or 400 mg/m2for those unable to swallow intact capsules. Diagnoses included primary CNS tumors (n=6), neuroblastoma (n=3), and extracranial solid tumors (n=4). Median patient age is 7 years.

Responses have been seen in all patients whose tumor had a target gene alteration and no responses were seen in patients whose tumors lacked aberrations in target kinases. Therefore, the trial will continue only for patients with target fusions. Presenter Giles W. Robinson, MD, St. Jude Children’s Research Hospital, Memphis, Tennessee, said, “It gives me great pleasure as pediatric brain tumor doctor to show response in CNS tumors” that would otherwise probably have been fatal.

Dose-limiting toxicities included elevated creatinine, dysgeusia, fatigue, and pulmonary edema. Weight gain, problematic for some patients, also occurred as an on-target drug effect. Side effects have resulted in dose reduction to 400 mg/m2.

Dose-Modified Chemotherapy for Frail and/or Elderly Patients with Advanced Gastroesophageal Cancer (Abstract 4006)

Although the average age of patients at the time of diagnosis of advanced, inoperable gastroesophageal cancer is 75 years, and many patients are frail, standard of care chemotherapy has been developed in trials in patients with an average age of 65 years who are generally not frail. This study was motivated by the finding that a survey of oncologists in the UK used reduced dose chemotherapy regimens that were not evidence-based to treat frail and/or elderly patients with gastroesophageal cancer.

A prior phase 2 trial indicated that a 2-drug regimen was preferable to 3-drug or single agent regimens in this setting. The GO2 phase 3 trial was designed to optimize doses of 2-drug chemotherapy regimens and assess benefits and risks.

Patients (n=514) with a median age of about 76 years who were fit for chemotherapy but not for full-dose, 3-drug regimens were enrolled. There were 2 randomization schemes based on whether the patient was considered either certain or likely to benefit from chemotherapy and basic supportive care (BSC) was not appropriate (certain randomization), or would derive uncertain benefit from chemotherapy with BSC possibly appropriate (uncertain randomization). Presenter Peter S Hall, PhD, University of Edinburgh, Edinburgh, UK, discussed the certain randomization option, where patients were randomly assigned to one of 3 dose levels of combinations of oxaliplatin plus capecitabine.

In addition to assessing progression-free survival (PFS), and a non-inferiority boundary agreed upon by a patient focus group and clinicians, the study also determined which dose level resulted in the best “overall treatment utility (OTU),” a novel concept developed in phase 2, which included cancer control, severity of side effects, patient quality of life (QoL), and oncologist’s assessment of benefit.

The lower doses of chemotherapy were non-inferior to the highest dose for median PFS (4.9 months for the highest dose, 4.1 months for the intermediate dose, and 4.3 months for the lowest dose), as well as for median overall survival (7.5 months, 6.7 months, and 7.6 months, respectively). The lowest dose was associated with the best OTU scores, as a result of fewer side effects and better quality of life (QoL).

Lenalidomide Reduces the Risk of Progression from Smoldering to Active Multiple Myeloma (Abstract 8001)

Smoldering or asymptomatic multiple myeloma (SMM) is a precursor to symptomatic MM. The goal of the phase 2/3 E3A06 trial was to determine if early intervention in intermediate or high risk SMM using low-intensity, single-agent lenalidomide could prevent progression to MM. The primary endpoint was time to develop MM.

In phase 2, the safety of 25 mg daily of lenalidomide for 3 out of every 4 weeks was determined. Phase 3 randomly assigned patients to the same dose of lenalidomide (n=90) or to observation (n=92). Prophylactic aspirin was administered with the lenalidomide.

Time to develop MM was delayed with the use of lenalidomide (2-year PFS probability 0.93; 95% CI, 0.88-0.99) compared with observation (2-year PFD probability 0.76; 95% CI 0.66-0.87). Treatment-related grade 3 and 4 hematologic and non-hematologic adverse events were observed with lenalidomide; 51% of patients in the phase 3 portion discontinued due to toxicity, although there was no difference in QoL reported between the 2 groups.

Three-year PFS was 91% in the lenalidomide group, compared with 66% in the observation group (HR 0.28, P=.0005). Follow-up is too short to determine the effect of treatment on overall survival. The investigators will follow patients who discontinued to see if limited doses of lenalidomide can delay progression of SMM to MM. This study shows early intervention, at least in patients with higher risk SMM, can prevent MM and its associated end organ damage.

By Lynne Lederman, PhD

PS – Don’t forget to sign up for our ASCO ’19 Preview webinar featuring Lee Schwartzberg, MD, Zev Wainberg, MD, and Rich Leff, MD. Register here.

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