Release Date: March 22, 2019
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Study Supports TKI Response as Predictor of Survival in HCC
Patients with previously untreated hepatocellular carcinoma (HCC) lived twice as long if they responded to tyrosine kinase inhibitor therapy compared with patients who did not achieve an objective response, according to a retrospective analysis of a phase III randomized trial.
Response to lenvatinib (Lenvima) or sorafenib (Nexavar) was associated with a median overall survival (OS) of 22.4 months versus 11.4 months for patients who did not achieve a partial or complete response.1 Multivariate analysis identified response to treatment as an independent predictor of OS.
The survival difference between responding and nonresponding patients emerged as early as 2 months and persisted throughout follow-up, Masatoshi Kudo, MD, of the Kindai University Faculty of Medicine in Osaka, Japan, reported at the 2019 Gastrointestinal Cancers Symposium.
“Objective response by modified RECIST criteria was an independent predictor of overall survival in patients with hepatocellular carcinoma, regardless of treatment,” Kudo said in conclusion. “The association between objective response and overall survival was consistent with results reported in previous studies.… Therefore, patients who achieve an objective response can potentially expect a longer overall survival.”
Nonetheless, additional studies are needed to validate the association between objective response and survival, he added.
Several studies demonstrated a significant association between objective response and survival in HCC. Data from the phase III REFLECT trial, comparing lenvatinib and sorafenib, afforded an opportunity to validate and possibly clarify the nature of the association.
The REFLECT trial demonstrated noninferiority of lenvatinib versus sorafenib in patients with previously untreated HCC. The results showed a median overall survival of 13.6 months among patients treated with lenvatinib and 12.3 months for patients randomized to sorafenib.2 Additionally, results for the overall patient population showed a doubling of median progression-free survival from 3.7 months with sorafenib to 7.4 months with lenvatinib. These later results were by investigator review according to mRECIST criteria.
Treatment with lenvatinib led to an investigator-assessed overall response rate of 24% versus 9% for the sorafenib arm. By independent review, response rates were 41% with lenvatinib and 12% with sorafenib. Both analyses used modified RECIST criteria.
The REFLECT trial was a global, randomized, open-label study powered to demonstrate the noninferiority of lenvatinib versus sorafenib for untreated HCC. The post hoc analysis reported by Kudo evaluated survival by response status, including landmark analyses of objective response status at 2, 4, and 6 months.
The analysis of overall survival by objective response provided confirmation for previous data, showing a 39% reduction in the risk of death among patients who responded to assigned treatment (95% CI, 0.49-0.76, P <.001). The landmark analysis of response at 2, 4, and 6 months showed a significant survival advantage for patients who responded to treatment, ranging from about 5 to 7 months (P = .033 to P = .009).
A multivariate analysis confirmed objective response as an independent predictor of improved overall survival (HR, 0.611; P <.0001).
- Kudo M, Finn RS, Qin S, et al. Analysis of survival and objective response (OR) in patients with hepatocellular carcinoma in a phase III study of lenvatinib (REFLECT). J Clin Oncol. 2019;37(suppl; abstr 186).
- Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163-1173. doi: 10.1016/S0140-6736(18)30207-1.
Biliary Tract Cancer
Dabrafenib/Trametinib Combo Induces High Responses in BRAF V600E-Mutant Biliary Tract Cancer
The combination of dabrafenib (Tafinlar) and trametinib (Mekinist) induced responses in nearly half of patients with BRAF V600E–mutated biliary tract cancer (BTC) who participated in a phase II basket trial that enrolled patients with BRAFV600E–mutated rare cancers.
Results of the ROAR trial, which were presented during the 2019 Gastrointestinal Cancers Symposium, showed that the BRAF/MEK inhibitor combination was associated with an overall response rate (ORR) of 42% by investigator assessment, a median progression-free survival (PFS) of 9.2 months (95% CI, 5.4-10.1), and a median overall survival (OS) of 11.7 months (95% CI, 7.5-17.7) in the BTC cohort of the study, said Zev Wainberg, MD, co-director of the GI Oncology Program at the University of California, Los Angeles. This efficacy is comparable with that obtained with first-line chemotherapy, comprising of gemcitabine and cisplatin.
“These results represent the first prospectively analyzed cohort of patients with BRAF V600E-mutated BTC treated with a combination of BRAF and MEK inhibition,” he said. “BRAF V600 is one of several actionable driver mutations in this disease, and should be considered for routine testing in patients with BTCs.”
The combination “should be considered a meaningful therapeutic option” for patients with BRAF-mutant BTC, Wainberg said. BRAF mutations have been identified in 5% to 7% of patients with BTC, primarily in the cohort with intrahepatic disease, he noted. The dabrafenib/trametinib combination has previously demonstrated efficacy in other BRAF-mutated cancers, including melanoma in the adjuvant and metastatic settings, non–small cell lung cancer, and anaplastic thyroid cancer.
ROAR also demonstrated the heterogeneous genetic backgrounds of BTC tumors that were “consistent with other reports in this tumor type,” he said.
Most patients with BTC present with advanced disease, and the 5-year survival rate is approximately 15%, said Wainberg. Beyond surgical resection, the standard of care includes chemotherapy with gemcitabine and cisplatin, which is associated with a PFS of 8.0 months and a median OS of 11.7 months.
ROAR is open-label, nonrandomized, multicenter study that enrolled patients with rare cancers that harbor BRAF V600E mutations. The data presented at the 2019 Gastrointestinal Cancers Symposium were from the BTC cohort that included 35 patients. Only patients with histologically confirmed advanced or metastatic disease and no available standard treatment options were eligible for enrollment.
Treatment options for BTC after first-line therapy are not well defined. The median PFS in second-line BTC is <5 months. Activating BRAF V600E mutations have been reported in up to 20% of BTCs.
The median age in the BTC cohort of ROAR was 57 years. Ninety-seven percent of patients had an ECOG performance status of 0 or 1. The predominant histology was adenocarcinoma, which was present in 74% of patients. All 35 patients had measurable disease at screening, and 74% of patients had stage III disease at enrollment. Their time since diagnosis was a median of 1.1 years. Some 80% had received ≥2 lines of prior systemic therapy, with 100% receiving prior gemcitabine and 63% prior cisplatin. Some 57% of patients had undergone surgery and 11% received radiation.
The median duration of exposure to dabrafenib plus trametinib was 6 months (range, 2-32 months) and 86% were on the study medications for >3 months. Twelve patients (34%) were continuing treatment with each agent at the time of data analysis. Sixty percent discontinued treatment with dabrafenib and 60% with trametinib because of disease progression. Twenty-two (63%) patients required dose interruption of dabrafenib and 21 (60%) required dose interruption of trametinib.
Patients received dabrafenib at 150 mg twice daily plus trametinib at 2 mg once daily on a continuous basis. Treatment was continued until unacceptable toxicity, disease progression, or death, and the primary endpoint was investigator-assessed ORR by RECIST v1.1. Secondary endpoints included PFS, duration of response (DOR), OS, and safety.
In the intent-to-treat/evaluable population (n = 33), with a median duration of follow-up of 8 months, the ORR was 42% by investigator assessment and 36% by independent review. All responses were partial responses (PRs). The stable disease (SD) rate was 45% by investigator assessment and 39% by independent review.
“Nearly every patient had some tumor reduction, with only 4 patients having progression of disease as their best response,” said Wainberg.
The investigator-assessed DOR at 6 months was 66%; 7 of 14 patients who achieved a PR had a duration of response >6 months and 5 patients had a response that was ongoing at data cutoff. Many of the patients who achieved stable disease but didn’t achieve a PR still had durable clinical benefit, he said.
Sixteen baseline tissue samples were successfully analyzed by targeted next-generation sequencing of 570 cancer-specific genes. “There were a number of genetic alterations seen in these patients, both mutations and amplifications, and there’s little in common between them,” supporting the diverse molecular phenotype, he said. Copy-number variant (CNV) analysis demonstrated loss of CDKN2A/B as the most common finding, which was identified in 6 of 11 (55%) patients with any CNV.
Molecular analyses also demonstrated low mutational burden, consistent with other reports in this tumor type. All patients had <6 mutations/megabase. Correlative analysis of pathway signatures showed that gene expression levels of MAPK pathway members were higher in 2 patients with a best overall response of progressive disease compared with patients with a best overall response of stable disease.
Of the 35 patients in the BTC cohort, 11 received at least 1 posttreatment therapy, including chemotherapy in 20%, surgery in 14%, small molecule targeted therapies in 11%, immunotherapy in 6%, biologic therapy in 6%, and radiotherapy in 3%. The median time from study discontinuation to the start of subsequent treatment was 6.6 weeks.
All-cause grade 3/4 adverse events (AEs) were reported in 57% of patients. The most frequent treatment-related AEs were pyrexia (40%), rash (29%), nausea (23%), diarrhea (23%), fatigue (23%), and chills (20%).
- Wainberg ZA, Lassen UN, Elez E, et al. Efficacy and safety of dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600E–mutated biliary tract cancer (BTC): a cohort of the ROAR basket trial. In: Proceedings from the 2019 Gastrointestinal Cancers Symposium; January 17-19, 2019; San Francisco, CA. Abstract 187.
Triplet Regimen Shows Durable Responses in BRAF V600E–Mutant Metastatic CRC
Clinical outcomes with the combination of encorafenib (Braftovi), binimetinib (Mektovi), and cetuximab (Erbitux) exceeded historical responses in patients with BRAF V600E–mutant metastatic colorectal cancer, according to preliminary efficacy findings from the safety lead-in (SLI) phase of the BEACON CRC trial. Updated results from 29 patients showed an estimated median progression-free survival (PFS) of 8.0 months and an estimated median overall survival (OS) of 15.3 months, with a median duration of follow-up of 18.2 months,1 Scott Kopetz, MD, PhD, reported at the 2019 Gastrointestinal Cancers Symposium, held January 17 to 19 in San Francisco, California.
The overall response rate (ORR) was 48% by local assessment, with 3 patients achieving a complete response (CR). Up to 15% of patients with metastatic colorectal cancer have BRAF V600E mutations, which confer a poor prognosis. Standards of care for second-line therapy, generally with a cetuximab-based regimen, have historically demonstrated ORRs under 10%, median PFS of about 2 months, and median OS of just 4 to 6 months.1,2
“We know that these patients have very poor survival; their median survival from the diagnosis is about 12 months,” said Kopetz, associate professor, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center in Houston. In BEACON, “the ORR of 48% and median OS of 15 months with reasonably mature data are substantially better than historical controls. This is encouraging because these were patients who received either second- or third-line treatment, and we’re seeing survivals that would exceed even what a first-line population would expect. This sets the stage for the phase III BEACON CRC results,” he said.
The rationale for the triplet is the minimal effectiveness of BRAF inhibitors alone in colorectal cancer, “due in part to feedback [activation] through growth factor receptors such as epidermal growth factor receptor [EGFR],” Kopetz said. “The EGFR inhibitor is blunting that feedback. That feedback results in MAP kinase pathway activation. Importantly, when we look at patients who are progressing on BRAF/EGFR inhibition, we’re seeing reactivation of the MAP kinase pathway through acquired alterations, including upstream. The addition is binimetinib, which is a MEK inhibitor that’s also in the MAP kinase pathway, and you get optimal pathway inhibition and blunt at least some of the mechanisms of potential acquired resistance that could occur.”
BEACON CRC is a randomized, open-label, 3-arm, phase III study evaluating the triplet compared with irinotecan-based chemotherapy plus cetuximab and encorafenib plus cetuximab in patients with BRAF V600E–mutant metastatic colorectal cancer after 1 or 2 prior lines of treatment in the metastatic setting. Enrollment was completed in 2018. The SLI portion of BEACON was conducted to evaluate safety and efficacy of the triplet prior to randomizing patients to the phase III portion.
The primary endpoint of BEACON CRC is OS associated with the triplet combination compared with the control arm.
Previously, as reported at the 2018 Gastrointestinal Cancers Symposium, the triplet combination was generally well tolerated in the SLI. Of 2 treatment discontinuations due to adverse events (AEs), 1 was considered related to treatment. The most common grade ≥3 AEs were fatigue (n = 4), urinary tract infection (n = 3), an increase in the level of aspartate aminotransferase (n = 3), and an increase in the level of blood creatine kinase (n = 3). At that report, in the 29 patients with a BRAF V600E mutation, the estimated median PFS was 8 months and the confirmed ORR was 48%, with 3 patients achieving CRs.2
According to information presented at the 2019 Gastrointestinal Cancers Symposium, the 30 patients treated in the SLI portion of the study received encorafenib at 300 mg daily, binimetinib at 45 mg twice daily, and cetuximab at the standard weekly dose of 400 mg/m2, then 250 mg/m2 once weekly. Of the 30 patients, 29 had a BRAF V600E mutation. Median patient age was 59 years. Sixty percent had received 1 prior line of therapy, and 40% had received 2 prior lines. Forty-three percent had received prior irinotecan. At the data cutoff of September 2, 2018, 6 patients remained on treatment.
Efficacy was evaluated in the 29 patients with BRAF V600E mutations, who were on study treatment for a median of 7.9 months. The confirmed 48% ORR by local assessment consisted of 3 CRs, 11 (38%) partial responses (PRs), and 13 (45%) with stable disease (SD). The 41% ORR by central assessment included 2 CRs, 10 (34%) PRs, and 13 (45%) patients with SD. The median duration of response was 5.5 months by local assessment and 8.2 months by central assessment. The duration of response estimate was ≥6 months in 43% of the responders by local assessment and 73% by central assessment. “We’re encouraged by the durability of the regimen, acknowledging that durability with doublets is on the shorter side,” said Kopetz.
When response was stratified by number of previous lines of therapy, the ORR by local assessment was 59% with 1 previous line (8 PRs and 2 CRs) and 33% (3 PRs and 1 CR) with 2 previous lines, and by central assessment, the ORR was 53% (8 PRs and 1 CR) with 1 previous line of therapy and 25% (2 PRs and 1 CR) with 2 previous lines. The 6-month OS was 86.2%, and the 12-month OS was 62.1%.
AEs were similar to those previously reported with BRAF, MEK, and EGFR inhibitors. The most common grade 3/4 AEs were fatigue (n = 4); anemia, increased level of creatine kinase, increased levels of aspartate aminotransferase, and urinary tract infection (n = 3 for each AE); dyspnea (n = 2); and gastrointestinal toxicities such as nausea, vomiting, and decreased appetite (n = 2 for each). Six patients (20%) had at least 1 drug discontinued because of AEs, 1 of whom discontinued all 3 drugs because of grade 2 fatigue.
- Kopetz S, Grothey A, Yaeger R, et al. Updated results of the BEACON CRC safety lead-in: encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CETUX) for BRAFV600E-mutant metastatic colorectal cancer (mCRC). Presented at: 2019 Gastrointestinal Cancers Symposium; January 17-19, 2019; San Francisco, CA. Abstract 688.
- Van Cutsem, E, Cuyle P-J, Huijberts S, et al. BEACON CRC study safety lead-in (SLI) in patients with BRAFV600E metastatic colorectal cancer: Efficacy and tumor markers. Presented at: 2018 Gastrointestinal Cancers Symposium; January 18-20, 2018; San Francisco, CA. Abstract 627.
- Gina Columbus
Esophageal Gastric Cancer
PD-1 Inhibitor Shows OS Benefit in PD-L1+ Esophageal Cancer