Immunotherapy in PD-L1–Positive Advanced Cervical Cancer
Pembrolizumab (Keytruda) treatment was active in patients with programmed cell death ligand 1 (PD-L1)–positive advanced cervical cancer enrolled in the phase Ib KEYNOTE-028 trial. The findings were reported by Jean-Sebastien Frenel, MD, of the Institut de Cancerologie de l’Ouest, Centre Rene Gauducheau, Saint-Her-blain, and colleagues in the Journal of Clinical Oncology.
Jean-Sebastien Frenel, MD
In the advanced cervical cancer cohort, 24 patients received pembrolizumab at 10 mg/kg every 2 weeks for up to 24 months. Re-sponse according to the Response Evaluation Criteria in Solid Tumors v1.1 was assessed every 8 weeks for the first 6 months and every 12 weeks thereafter. The primary end-point was overall response rate. The median age of patients was 42 years (range = 26–62 years); 92% had received prior radiation therapy; and 63% had received at least 2 lines of therapy for advanced disease, including bevacizumab (Avastin) in 42%. PD-L1 positivity was defined as membranous staining ≥ 1%; 18 patients were PD-L1–positive in the tumor only and 6 were PD-L1–positive in the tumor and stroma.
Response Rate and Adverse Events
At data cutoff, the median follow-up was 11.0 months (range = 1.3–32.2 months). Partial response was observed in four patients (17%), with an additional three patients (13%) having stable disease. The median time to response was 1.9 months (range, 1.7–8.2 months). The median duration of response was 5.4 months (range, 4.1–7.5 months), with 2 patients hav-ing response > 6 months. All four responders had PD-L1 expression on the tumor only. The median progression-free survival was 2 months, with rates of 21% and 4% at 6 and 12 months. Median overall survival was 11 months, with rates of 67% and 40% at 6 and 12 months. Treatment-related adverse events of any grade occurred in 75% of patients, with the most common being rash (21%) and pyrexia (17%). Treatment-related grade ≥ 3 adverse events occurred in five patients (21%, all grade 3), with rash occurring in 8%. Treatment-related serious adverse events occurred in four patients (17%), including one case each of rash, colitis, Guillain-Barré syndrome, and pyrexia. Treatment was discontinued due to treatment-related adverse events in two patients (8%), consisting of colitis and Guillain-Barré syndrome. Immune-mediated adverse events occurred in six patients (25%), including rash in two, colitis in one, Guillain-Barré syndrome in one, hyperthyroidism in one, and hypothyroidism in one. No treatment-related deaths were observed. The investigators concluded: “In patients with programmed [cell] death ligand 1–positive advanced cervical cancer, pembrolizumab demonstrated antitumor activity and exhibited a safety profile consistent with that seen in other tumor types.”
Frenel JS, et al: J Clin Oncol. November 2, 2017 (early release online).
FGFR Kinase Inhibitor in FGFR-Altered Advanced Cholangiocarcinoma
In a phase II trial reported in the Journal of Clinical Oncology by Milind Javle, MD, of the Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, and colleagues found that the oral pan-fibroblast growth factor receptor (FGFR) kinase inhibitor BGJ398 was active in FGFR-altered advanced cholangiocarcinoma. It is estimated that FGFR2 fusions/translocations are present in 13% to 17% of cases of intrahepatic cholangiocarcinoma.
In the study, 61 patients (57% women; median age, = 57 years) with disease progression on prior therapy received BGJ398 at 125 mg once daily for 21 days with 7 days off. Among the 61 patients, 48 had FGFR2 fusion, 8 had a mutation, and 3 had amplification. The primary endpoint was investiga-torassessed overall response rate.
Response Rate and Adverse Events
The overall response rate was 14.8%. All responses occurred in patients with FGFR2 fusions (response rate, 18.8%). The disease control rate was 75.4% among all patients and 83.3% in those with FGFR2 fusions. Median progression-free survival was 5.8 months. Common adverse events of any grade included hyperphosphatemia (72%), fatigue (36%), stomatitis (30%), and alopecia (26%). Grade 3 or 4 treatment-related adverse events occurred in 41%, including hyperphosphatemia in 16%, stomatitis in 7%, and palmar-plantar erythrodysesthesia in 5%.
The investigators concluded: “BGJ398 is a first-in-class FGFR kinase inhibitor with manageable toxicities that shows clinical activity against chemotherapy-refractory cholangiocarcinoma containing FGFR2 fusions. This promising antitumor activity supports continued development of BGJ398 in this highly selected patient population.”
Javle M, et al: J Clin Oncol. November 28, 2017 (early release online).
Quality of Life With Neoadjuvant Chemoradiotherapy in Esophageal or Esophagogastric Junction Cancer
An analysis of the Dutch Chemoradiotherapy for Esophageal Cancer Followed by Surgery Study (CROSS) reported by Bo Jan Noordman, MD, of the Department of Surgery, Erasmus MC–University Medical Center, and colleagues in the Journal of Clinical Oncology showed no adverse effect of neoadjuvant chemoradiotherapy vs surgery alone on post-surgery health-related quality of life in patients with esophageal or esophagogastric junction cancer.
The CROSS study showed significant improvement in overall survival with neoadjuvant chemoradiotherapy (carboplatin plus paclitaxel with concurrent 41.4-Gy radiotherapy) vs surgery alone. In the current analysis, health-related quality of life was assessed by the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire–Core 30 (QLQ-C30) and –Oesophageal Cancer Module (QLQ-OES24) questionnaires prior to treatment and at 3, 6, 9, and 12 months after surgery; the neoadjuvant therapy group also received preoperative questionnaires. QLQ-C30 physical functioning and QLQ-OES24 eating prob-lems were predefined primary endpoints. Secondary endpoints were QLQ-C30 global quality of life and fatigue and QLQ-OES24 emotional problems.
Changes in Health-Related Quality of Life
Among 363 patients included in the analysis, no statistically significant differences between groups were observed in any measures in the postoperative period. In the neoadjuvant therapy group, significant declines in physical functioning, eating problems, global quality of life, fatigue, and emotional problems were observed 1 week after neoadjuvant therapy (all P ≤ .001).
All endpoints significantly worsened at 3 months vs baseline in both groups (all P < .001), with continuous gradual improvement thereafter. Whereas eating problems, global quality of life, and emotional problems returned to baseline values by the end of follow-up, significant impairment in physical functioning and fatigue persisted at 1 year after surgery in both groups of patients (both P < .001).
Conclusion
The investigators concluded: “Although [health-related quality of life] declined during [neoadjuvant chemoradiotherapy], no effect of [neoadjuvant chemoradiotherapy] was apparent on postoperative [health-related quality of life] compared with surgery alone. In addition to the improvement in survival, these findings support the view that [neoadjuvant chemoradiotherapy] according to the Chemoradiotherapy for Esophageal Cancer Followed by Surgery Study regimen can be regarded as a standard of care.”
Noordman BJ, et al: J Clin Oncol. November 21, 2017 (early release online).
Constructing a Risk Stratification Model for Pediatric Acute Lymphoblastic Leukemia
In a study reported in the Journal of Clinical Oncology, O’Connor and colleagues combined genetic subtypes and minimal residual disease as a continuous variable to construct a risk stratification model for pediatric acute lymphoblastic leukemia (ALL). Anthony V. Moorman, MD, of Wolfson Childhood Cancer Research Centre, Newcastle University, is the correspond-ing author of the Journal of Clinical Oncology article.
Anthony V. Moorman, MD
The study involved a population-based cohort of 3,113 patients treated in a clinical trial (UKALL2003), with a median follow-up of 7 years. Minimal residual disease was evaluated by polymerase chain reaction analysis of Ig/TCR gene rearrangements. Immuno-phenotype, cytogenetics, and fluorescence in situ hybridization were used to segregate patients into four exclusive genetic subtypes: cytogenetic good, intermediate, and high risk and T-cell acute lym-phoblastic leukemia (T-ALL).
Integrated Risk Model
Minimal residual disease value distributions dif-fered according to the distinct genetic subtypes (P < .001). Overall, the risk of relapse was reduced by 20% for each log reduction in minimal residual disease level (hazard ratio = 0.80, P < .001). The risk of relapse was directly proportional to the minimal residual disease level with-in each genetic risk group, but absolute relapse rates associated with specific minimal residual disease values varied by genetic subtype.
Integrated risk groups were constructed according to the following criteria: standard risk = good-risk cytogenetics and minimal residual disease < 0.1% plus intermediaterisk cytogenetics and minimal residual disease < 0.01% plus T-ALL with undetectable minimal residual disease; intermediate risk = good-risk cytogenetics and minimal residual disease ≥ 0.1% and < 5% plus intermediate-risk cytogenetics and minimal residual disease ≥ 0.01% and < 1% plus T-ALL with minimal residual disease > 0% and < 5%; and high risk = minimal residual disease ≥ 5% plus high-risk cytogenetics plus intermediaterisk cytogenetics and minimal residual disease ≥ 1%. Relapse rates at 5 years were 4%, 13%, and 33% in the three integrated risk groups (P < .001), with 5-year event-free survival of 94%, 83%, and 58% (P < .001), respectively.
The investigators concluded: “A single threshold for assigning patients to a [minimal residual disease] risk group does not reflect the response kinetics of the differ-ent genetic subtypes. Future risk algorithms should integrate genetics with [minimal residual disease] to accurately identify patients with the lowest and highest risk of relapse.” ■
O’Connor D, et al: J Clin Oncol. November 13, 2017 (early release online).
