Startseite Kongressberichte 2018 AACR Annual Meeting 2018, April 14-18, Highlights presented at the Press Conference Sunday, April 15

Sunday, April 15, 2018

Louis M. Weiner, MD, co-chair of the AACR Annual Meeting Clinical Trials Committee and director of the Georgetown Lombardi Comprehensive Cancer Center, will moderate a press conference highlighting the following research:

 

 

 

KEYNOTE-189 Met its Dual Primary Endpoints of Overall Survival and Progression-free Survival

Pembrolizumab Reduced the Risk for Recurrenceof Stage 3 Melanoma

CHICAGO—A one-year course of 18 doses of pembrolizumab (Keytruda) significantly reduced the risk of recurrence for patients with stage 3 melanoma who were at high risk of recurrence after surgery,  according to data from the KEYNOTE-054/EORTC 1325-MG phase III clinical trial, presented at the AACR Annual Meeting 2018, April 14–18.

“Patients with stage 3 melanoma have metastatic disease in one or more regional lymph nodes,”said Alexander M. M. Eggermont, MD, PhD,director general ofGustave RoussyCancer Campus Grand Paris inVillejuif, France. “A patient’s risk of recurrence depends on the number of lymph nodes affected and the tumor load. Those classified as having a high risk of recurrence have one or more regional lymph nodes with melanoma metastasis. In the case of a single positive node, the diameter must be greater than 1 millimeter.

“We were pleased to see that adjuvant pembrolizumab, given as a flat dose of 200 milligrams every three weeks after surgery for up to a year, which is 18 doses, significantly reduced the risk of recurrence for patients with high-risk stage 3 melanoma that has been completely resected,” continued Eggermont.“We hope that these data will lead to regulators in the United States and Europe approving pembrolizumab as a new treatment option for these patients.”

For all the patients randomized to pembrolizumab, the 12-month recurrence-free survival rate was 75.4 percent, compared with 61.0 percent for all those randomized to placebo. Thus, overall, patients randomized to pembrolizumab were 43 percent less likely to have recurrence.  

The FDA approved ipilumumab (Yervoy) and nivolumab (Opdivo) for use as an adjuvant treatment for patients with high-risk stage 3 melanoma that has been completely resected in October 2015 and December 2017, respectively.

Eggermont and colleagues enrolled 1,019 patients with stage 3 melanoma who were at high risk of recurrence after complete resection of their tumors in the KEYNOTE-054/EORTC 1325-MG phase III clinical trial. Patients were randomized 1:1 to a flat dose of 200 milligrams of pembrolizumab or placebo every three weeks for a total of 18 doses or until disease recurrence or unacceptable toxicity.

After a median follow-up of 1.25 years, 135 of the 514 patients randomized to pembrolizumab and 216 of the 505 patients randomized to placebo had been diagnosed with recurrent disease or had died.

The benefits of pembrolizumab were similar when patients with PD-L1-positive and PD-L1-negative tumors were analyzed separately. Among the 852 patients with PD-L1-positive tumors, those randomized to pembrolizumab were 46 percent less likely to have a recurrence or death event compared with those randomized to placebo. Among the 116 patients with PD-L1-negative tumors, those randomized to pembrolizumab were 53 percent less likely to have a recurrence or death event.

“An important aspect of this trialis that patients randomized to placebo who have recurrence are offered access to pembrolizumab,” said Eggermont. “This cross-over design is unique in the world of adjuvant trials in melanoma and will permit us to analyze if adjuvant therapy with pembrolizumab right after surgery is better or not than treating only those who relapse and start treatment at relapse.    

”According to Eggermont, the main limitation of the study is that we need more time before we can determine whether these positive recurrence-free survival results will lead to improvement in overall survival for the patients.

This study was conducted by the European Organisation for Research and Treatmentof Cancer (EORTC) and sponsored by Merck. Eggermont has received honoraria for scientific advisory board and data monitoring board functions from Actelion, Agenus, Bayer, Bristol-MyersSquibb, GlaxoSmithKline, HalioDx, Incyte, ISA Pharmaceuticals, Merck, MerckSerono, Nektar, Novartis, Pfizer, and Sanofi.

 

ABSTRACT CT001:

A. M. M. Eggermont, et al. Pembrolizumab versus placebo after complete resection of high-risk stage III melanoma: Efficacy and safety results from the EORTC 1325-MG/Keynote 054 double-blinded phase III trial.

Background: The checkpoint inhibitors ipilimumab and nivolumab are approved by FDA as adjuvant therapy for patients with resected high-risk stage III melanoma. We conducted the phase 3 double-blind EORTC 1325/KEYNOTE-054 trial to evaluate pembrolizumab vs placebo in patients with resected high-risk stage III melanoma.

Methods: Eligible patients included those ≥18 years of age with complete resection of cutaneous melanoma metastatic to lymph node(s), classified as stage IIIA (excluding lymph node metastasis ≤1 mm), IIIB or IIIC (excluding those with in-transit metastasis). A total of 1019 patients were randomized (stratification by stage and region) to pembrolizumab at a flat dose of 200 mg (N=514) or placebo (N=505) every 3 weeks for a total of 18 doses (~1 year) or until disease recurrence or unacceptable toxicity. In the absence of brain metastases, patients with recurrence were eligible for cross-over or re-challenge (those who received pembrolizumab and recurred more than 6 months after completing 1 year of therapy).

The 2 co-primary endpoints were recurrence-free survival (RFS) in the intention-to-treat overall population and in patients with PD-L1-positive tumors. A total of 409 RFS events were needed to provide 92% power to detect a hazard ratio (HR) for recurrence or death of 0.70 (1-sided alpha=1.4%). The interim analysis was performed at 1-sided alpha=0.8% (O’Brien-Fleming alpha error spending function) in the overall patient population, and at 2.5% in the PD-L1 positive population.

Results: Overall, 15%/46.5%/37.5% of patients had stage IIIA/IIIB/IIIC. At 1.25 yr median follow-up, pembrolizumab (135 events) compared with placebo (216 events) significantly prolonged RFS in the overall population (12-month RFS rate: 75.4% vs 61.0%; HR 0.57, 98.4% CI 0.43-0.74; P<0.0001). Same was true in those with a PD-L1-positive tumor (N=852; HR 0.54, 95% CI 0.42-0.69; P<0.0001) or a PD-L1-negative tumor (N=116; HR 0.47, 95% CI 0.47 (0.26, 0.85); P=0.01). RFS was consistently prolonged across subgroups. Drug-related grade 3 to 5 adverse events were reported in 14.7% (N=75) in the pembrolizumab group and 3.4% (N=17) in the placebo group. There was only one pembrolizumab-related death due to myositis. The highest incidence of immune-related adverse events (irAEs), mostly grade 1 to 2, observed in the pembrolizumab vs placebo group were endocrine disorders (23.4% versus 5.0%) [hypothyroidism (14.3% vs 2.8%), hyperthyroidism (10.4% vs 1.2%), thyroiditis (3.1%) vs 0.2%)]. The incidence of grade 3-4 irAEs was 7.1% vs 0.6%: colitis (2.0% vs 0.2%), pneumonitis (0.8% vs 0%), hepatitis (1.4% vs 0.2%), all others had incidences < 1%.

Conclusions: As adjuvant therapy for resected high-risk stage III melanoma pembrolizumab 200 mg every 3 weeks, for up to 1 year, resulted in significantly prolonged RFS with a favorable benefit-risk profile.

ORIGINAL ARTICLE NEJM:

Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma

A.M.M. Eggermont and Others

 

SelectiveInhibitor Shows Early Promise in Patients With RET-altered Cancers

CHICAGO — BLU-667, a next-generation inhibitor that selectively targets the oncogenic receptor tyrosine kinase RET, was well tolerated and had broad clinical benefit in patients with advanced cancer that had progressed on previous therapies including multikinase inhibitor therapy. Proof-of-concept data will be presented from an ongoing phase I clinical trial at the AACR Annual Meeting 2018, April 14-18, in Chicago.

“RET-altered cancers across multiple tumor types represent a high medical need, as there are no approved agents that selectively target this oncogene,” said Vivek Subbiah, MD, assistant professor, Department of Investigational Cancer Therapeutics, Divisionof Cancer Medicine,and Associate Medical Director, The Clinical Center for Targeted Therapy, The University of Texas MD Anderson Cancer Center, Houston.“Current therapies for RET-altered cancers are restricted to multikinase inhibitors and chemotherapy, which are nonspecific and display significant off-target toxicity. In an effort to revolutionize treatment for these cancers, BLU-667 was designed to specifically target oncogenic RET fusions and activating mutations.”

Prior preclinical work found that BLU-667 potently inhibits oncogenic RET and displays anti-tumor activity in a variety of RET-driven cancers, Subbiah noted. In addition, the inhibitor was 100 times more selective for the RET kinase relative to more than 350 human kinases tested, and it potently inhibited gatekeeper mutations shown to confer resistance to multikinase therapies, he explained.

Subbiah and colleagues tested BLU-667 in an open-label, first-in-human study. As of Feb. 13, 2018, they had enrolled 43 patients with unresectable, advanced solid tumors, with 26 patients having RET-mutant medullary thyroid cancer (MTC), 15 patients having non-small cell lung cancer (NSCLC) with RET fusion, and two patients with non-RET cancers. Patients had a median of one prior anti-neoplastic therapy; prior therapies ranged from zero to eight treatments.

BLU-667 doses ranging from 30 to 400 mg were administered orally every day.The maximum tolerated dose (MTD) was not reached.

BLU-667 demonstrated broad antitumor activity with a best overall response rate of 37 percent in the 30 patients with RET alterations who received doses ≥60mg and had at least one post-baseline response assessment. Patients with NSCLC and MTC had a best overall response rate of 45 and 32 percent, respectively. As of the data cutoff, 33 of 43 enrolled patients remained on study. BLU-667 was well-tolerated; grade 1 constipation was the most commonly reported adverse event (23 percent). Three dose-limiting toxicities (DLTs) were documented, and there were no grade 4-5 adverse events. The dose escalation portion of the trial is still underway.

Additional data are expected to be presented at the AACR Annual Meeting 2018.

“This ongoing phase I study has shown proof-of-concept of this selective RET inhibitor,” said Subbiah. “Although it’s very early in clinical testing, we observed promising antitumor activity in NSCLC and MTC.

“Precision targeted therapy with RET inhibition can have a powerful impact in patients whose cancer is induced by these oncogenic drivers, even in early clinical trial testing,” noted Subbiah. “I encourage all cancer patients to undergo genomic testing, as tumors with rare genomic aberrations may have effective drugs that are in clinical trials that could be beneficial to them.”

This study is sponsored and managed by Blueprint Medicines. Subbiah receives research funding for clinical trials from Blueprint Medicines, Novartis, Bayer, GSK, Nanocarrier, Vegenics, Northwest Biotherapeutics, Boston Biomedical, Berghealth, Incyte, Fujifilm, PharmaMar, D3, Pfizer, Multivir, Amgen, AbbVie, LOXO, Roche/Genentech, NCCN, and NCI-CTEP.

 

ABSTRACT CT043:

V. Subbiah, et al. Highly potent and selective RET inhibitor, BLU-667, achieves proof of concept in aphase I study of advanced,RET-altered solid tumors.

Background: The receptor tyrosine kinase, RET, activated via point mutation or genomic rearrangement, is a bona fide oncogene in multiple cancers, including medullary thyroid cancer (MTC)and non-small cell lung cancer (NSCLC). However, no approved therapies target RET potently and selectively. We initiated a phase 1 study (NCT03037385) in advanced solid tumors to define the MTD, safety, pharmacokinetics (PK) and anti-tumor activity of BLU-667, a highly potent and selective oral inhibitor that targets oncogenic RET-fusions, point mutations and resistance mutations.

Methods: Adult patients (pts) with unresectable, advanced solid tumors received BLU-667 once daily on a 4-week cycle following a Bayesian Optimal Interval design, which allowed additional accrual to dose levels declared safe. Adverse events (AEs), PK, biomarkers, and radiographic anti-tumor activity were assessed. 

Results: At a 13 FEB 18 cutoff, 43 pts (15 RET-fusion NSCLC [7 KIF5B,4 CCDC6, 5 other]; 26 RET-mutant MTC [15 M918T, 7 other]; 2 non-RET) have been treated with BLU-667 at doses of 30 to 400 mg/day. The median number of prior anti-neoplastic therapies was 1 (range 0-8). BLU-667 showed broad anti-tumor activity across multiple RET genotypes at doses ≥ 60 mg with radiographic tumor reductions (-2 to -70% ) demonstrated in 83% (25/30) of RET-altered pts with at least 1 post baseline response assessment. The best overall response rate per RECIST 1.1 was 37% (11/30 pts; 95% CI 20% -56%) with 5 PR (4 confirmed) in 11 NSCLC pts and 5 PR (3 confirmed) and 1 CR (pending confirmation) in 19 MTC pts. Rapid decline in blood (calcitonin; RET ct-DNA) and tumor (RET pathway mRNAs) biomarkers accompanied anti-tumor activity. PK showed rapid BLU-667 absorption (Tmax 2-4 h), long half-life (> 12 hours) and exposure (AUC and Cmax) in the expected therapeutic range based on tumor xenograft models.      

An MTD has not been reached and dose escalation continues. Most AEs were CTCAE grade (gr) 1, these included constipation (23%), ALT increase (16%), AST increase (16%), diarrhea (14%) fatigue, creatinine increase, WBC decrease, and hypertension (12% each). 3 DLTs were observed (1 gr 3 ALT increase, 1 gr 3 tumor lysis syndrome and 1 gr 3 hypertension). There were no gr 4/5 BLU-667-related AEs. 10 pts discontinued treatment (6 PD, 2 AEs [1 drug-related], 1 death [not drug-related], 1 other ); 33 remain on treatment with duration 21-11 cycles.

Conclusion: BLU-667, a highly potent and selective RET inhibitor has been well tolerated and demonstrates promising clinical activity in RET-altered solid tumors, including pts who have failed multikinase inhibitor therapy. These encouraging phase 1 data validate selective targeting of RET and warrant expanded clinical testing of BLU-667 in RET-altered cancers.

 
 

Children with Non-chromosomal Birth Defects Face Higher Risk of Several Childhood Cancers

Children with Non-chromosomal Birth Defects Face Higher Risk of Several Childhood Cancers

CHICAGO—Children with non-chromosomal birth defects such as congenital heart disease had a significantly higher risk of developing childhood cancer than children who did not have birth defects, according to a study presented at the AACR Annual Meeting 2018, April 14-18.

“Approximately one in 33 children is born with a birth defect,” said the study’s lead author, Jeremy M. Schraw, PhD, a postdoctoral fellow at Texas Children’s Cancer Center, Texas Children’s Hospital, and Department of Medicine, Section of Epidemiology and Population Science, Baylor College of Medicine in Houston.

“While we know that children with certain chromosomal conditions, like Down syndrome, have an increased risk of cancer, the majority of birth defects have no known chromosomal or genetic cause, but less is known about cancer risk in these children. There is growing evidence that non-chromosomal birth defects may predispose children to cancer, and we are trying to learn more about this connection so that we can potentially identify children who may benefit from early cancer detection,” Schraw continued.

In this study, the researchers pooled statewide registry data from Texas, Michigan, North Carolina, and Arkansas for the period 1992-2013, and linked information from birth certificates, birth defects registries, and cancer registries. They used Cox proportional hazardmodels to evaluate associations between 60 birth defects and 31 childhood cancers.

Beginning with a population of more than 10 million live births, Schraw and colleagues identified 517,548 children with non-chromosomal birth defects and 14,774 children with cancer. They found that the risk of any cancer was 2.6 times higher in children with non-chromosomal birth defects than in those without a defect. 

Certain cancers were strongly associated with certain birth defects. For example, children with ventricular septal defects, which cause a hole in the wall between the heart’s lower chambers, were at significantly higher risk (10-fold increased risk) of hepatoblastoma, a rare form of cancer that starts in the liver. Children with craniosynostosis and right ventricular outflow tract defects were significantly more likely (more than three-and seven-fold increased risk, respectively) to have neuroblastoma. 

Some birth defects, including the fairly common cleft palate and cleft lip, had no association with childhood cancer, Schraw said.

Schraw emphasized that childhood cancer is rare and, therefore, the risk that a child with a non-chromosomal birth defect will develop cancer during childhood is low.

“This study cannot establish a cause-and-effect relationship between birth defects and childhood cancers, and it is much too soon to make clinical recommendations based on this information,” Schraw said. “We do hope our findings spur additional inquiries into these associations, so that we may better understand the biology underlying these associations.” 

He added that if confirmed in future research, these findings could provide justification for increased cancer surveillance protocols in children with non-chromosomal birth defects.

Schraw said that he and his colleagues are planning to expand this study into other states. They are also conducting genomic sequencing in families where a child has both a birth defect and cancer to explore whether there are shared genetic origins underlying these associations. He said this additional genomic information could also shed light on why certain cancer types were more strongly associated with certain birth defects. 

Schraw said that because the study was based on registry data, the researchers had little information on the children’s health between birth and cancer diagnosis. Also, because the researchers did not have biological samples from the children, they could not fully discern the molecular features of their cancers.

Philip J. Lupo, PhD, MPH, an associate professor at Baylor College of Medicine and co-director of the EpiCenter at Texas Children’s Cancer Center, was the principal investigator and senior author of this paper. Sharon E. Plon, MD, PhD, a professor at Baylor College of Medicine, Texas Children’s Cancer Center, and Texas Children’s Hospital, co-supervised the study.

This study was supported by the Cancer Prevention Research Institute of Texas and Alex’s Lemonade Stand Foundation. Plon is a member of the scientific advisory panel of Baylor Genetics Laboratory.  

 

ABSTRACT LB-161:

J. M. Schraw, et al. A population-based assessment of cancer risk among children with non-chromosomal birth defects in 10 million live births.

Purpose: While cancer risk is increased among children with chromosomal birth defects, less is known about associations between specific non-chromosomal structural birth defects and specific childhood cancers. To investigate these, we established a population-based retrospective cohort of >10 million children by pooling statewide registry data from four U.S. states (Texas, Michigan, North Carolina,and Arkansas) for the period 1992-2013.

Methods: Individual level data from birth certificates, birth defects registries, and cancer registries were linked in each state; demographic and diagnostic variables were harmonized; and the data were pooled for the overall analysis. We used Cox proportional hazards models to evaluate associations between 60 birth defects and 31 childhood cancers when there were five or more comorbid cases. A hazard ratio (HR) and 95% confidence interval (CI) was calculated for eachbirth defect-childhood cancer (BD-CC) pairwise combination, adjusted for maternal age, infant sex, and state. The false discovery rate (FDR) was computed via the Benjamini-Hochberg procedure to account for multiple comparisons.

Results: We identified 517,548 children with non-chromosomal structural birth defects and 14,774 children with cancer. The risk of any cancer was increased among children with any non-chromosomal structural defect compared to children without any birth defect (HR=2.6, 95% CI 2.4-2.7). Of 2,511 potential BD-CC combinations, we tested 606 where there were ≥5 comorbid cases and identified 496 BD-CC associations with significantly elevated HRs at a 5% FDR. No significant inverse associations were identified for any BD-CC combination. Notably, hepatoblastoma, astrocytoma, ependymoma, and extracranial germ cell tumors were each strongly associated with several birth defects. For example, the risk of hepatoblastoma was increased among children with atrial septal defects (HR=12.5, 95% CI 7.9-19.7) and craniosynostosis (HR=15.4, 95% CI 7.6-31.3). Astrocytoma and ependymoma were associated with central nervous system (CNS) defects (HR=6.7, 95% CI 4.6-9.8 and HR=7.4, 95%CI 3.5-15.7, respectively). Elevated risk of extracranial germ cell tumors was observed among children with CNS defects (HR=22.5, 95% CI 10.9-46.4) and obstructive genitourinary defects (HR=32.4, 95% CI 16.2-64.6).

Conclusions: By pooling registry data across four U.S. states, we were able to evaluate specific BD-CC patterns and report several novel associations. Our findings suggest that children with non-chromosomal birth defects have a significantly elevated risk of several childhood cancers. These findings may inform research into the etiologies of childhood cancer, as well as new cancer surveillance protocols for children with non-chromosomal birth defects. This work was supported by the Cancer Prevention Research Institute of Texas.