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22nd June 2023
Perioperative pembrolizumab in patients with early-stage non-small cell lung cancer (NSCLC) leads to a significant improvement in event-free survival, but not overall survival, according to the findings of a recent randomised, placebo-controlled clinical trial.
Existing evidence points to an event-free survival benefit from using neoadjuvant durvalumab, an anti-programmed cell death-1 agent in resectable stage NSCLC. However, whether similar advantages would arise from the perioperative and adjuvant usage of pembrolizumab, a programmed cell death protein 1 inhibitor, in early stage NSCLC is uncertain.
Recently, an international research group published a randomised, placebo-controlled trial in the New England Journal of Medicine, to evaluate perioperative pembrolizumab in patients with early-stage NSCLC.
Eligible participants had resectable stage NSCLC and were randomised 1:1 to either perioperative pembrolizumab (200 mg) or placebo once every three weeks, with cisplatin-based chemotherapy. This was followed by surgery and then adjuvant pembrolizumab (200 mg) or placebo once every three weeks.
A dual primary endpoint of event-free survival and overall survival was used, with secondary endpoints of a major pathological response, pathological complete response and safety.
A total of 797 participants, of whom 397 were assigned to the pembrolizumab group, were included in the analysis.
The median time from randomisation to the data-cut-off date was 25.2 months. Event-free survival at 24 months was significantly higher in the pembrolizumab group compared to placebo (hazard ratio, HR, for progression, recurrence or death = 0.58, 95% CI 0.46 – 0.72, p < 0.001). In contrast, the estimated 24-month overall survival was not significantly different to placebo.
A major pathological response occurred in a significantly higher proportion of participants assigned to perioperative pembrolizumab (p < 0.0001). Similarly, there was a significantly higher pathological complete response (p = 0.0001).
Any treatment-related adverse events cross the treatment phases were reported in a similar proportion of patients (96.7% vs 95%, pembrolizumab vs placebo).
9th March 2023
Neoadjuvant pembrolizumab therapy given to patients with stage III or IV resectable melanoma provides superior 2-year event-free survival in comparison to using only adjuvant therapy according to the findings of randomised, Phase II trial by US researchers.
Cutaneous melanoma is the most serious form of skin cancer worldwide with an estimated 325,000 new cases and 57,000 deaths in 2020. In a randomised, placebo-controlled trial of patients with completely resected stage III melanoma, adjuvant treatment with the programmed death 1 (PD-1) inhibitor, pembrolizumab, significantly improved recurrence-free survival compared to placebo. Neoadjuvant therapy involves the provision of systemic treatment before surgery and is designed to improve surgical outcomes for such patients. In fact, work in animal models indicates that there is a significantly greater therapeutic efficacy from using neoadjuvant, compared with adjuvant, immunotherapy to eradicate distant metastases following primary tumour resection. However, the added value of using neoadjuvant pembrolizumab therapy in patients with either stage III or IV resectable melanoma compared to adjuvant treatment alone has not been tested.
In the current study, the US researchers undertook a randomised, Phase II, open-label trial, in patients with measurable stage IIIB to IVC melanoma that was amenable to surgical resection. Participants were randomised 1:1 to either three doses of neoadjuvant pembrolizumab, surgery followed by 15 doses of adjuvant pembrolizumab or to surgery followed by pembrolizumab for approximately 1 year (adjuvant-only group). The primary end point was set as event-free survival in the intention-to-treat population.
Neoadjuvant pembrolizumab and event-free survival
In total, 313 patients with a median age of 63 years (35% female) were randomised to either neoadjuvant (154) or adjuvant only therapy.
After a median follow-up of 14.7 months, event-free survival was significantly longer in the neoadjuvant group (p = 0.004).
After 2 years, event-free survival occurred in 72% (95% CI 64 – 80) of those given neoadjuvant pembrolizumab compared to 49% (95% CI 41 – 59) in the adjuvant only group. In addition, the incidence of treatment-related adverse events of grades 3 or higher was similar between the two groups (12 vs 14%, neoadjuvant vs adjuvant).
The authors concluded that giving pembrolizumab both before and after surgery resulted in significantly longer event-free survival compared to adjuvant therapy alone.
Citation
Patel SP et al. Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma. N Engl J Med 2023
12th December 2022
Tisagenlecleucel appears to remain effective for more than 3 years in paediatric and young adults who had relapsed or refractory acute lymphoblastic leukaemia according to the results of a follow-up study by an international research group.
B-cell acute lymphoblastic leukaemia (ALL) is a clonal malignant disease originated in a single cell and characterised by the accumulation of blast cells that are phenotypically reminiscent of normal stages of B-cell differentiation. Moreover, ALL is the most common childhood cancer and has a high survival rate when properly managed. Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy and in the ELIANA trial, after a single infusion, the drug provided durable remission with long-term (12 month) persistence in paediatric and young adult patients with relapsed or refractory B-cell ALL. Moreover, the trial reported an overall remission rate within 3 months of 81% and improvements in patient-reported quality-of-life scores were observed for all measures at month 3 after the infusion. However, what remains uncertain is the durability of the response to treatment observed in the ELIANA trial and in the present study, researchers provided an update on the efficacy of the drug.
Tisagenlecleucel longer-term efficacy
In the follow-up arm, 79 patients with a median age of 11 years (57% male), 92% of whom had experienced a treatment relapse, provided on-going data for a median follow-up of 38.8 months. Overall, participants had received a median of 3 previous lines of therapy.
In the updated analysis, the overall remission rate was 82% and the median event-free survival was 24 months. In addition, event-free survival was 44% (95% CI 31 – 57) and overall survival was 63% (95% CI 51 – 73) at 3 years with most events having occurred with the first two years. Researchers estimated the 3-year relapse-free survival with and without censoring for subsequent therapy to be 52% and 48% respectively. The estimated overall survival rate was 63% (95% CI 51 – 73%).
A total of 24 relapses were recorded and of which 6 had occurred 12 months after the Tisagenlecleucel infusion. Interestingly, there were no new or unexpected long-term adverse events reported although grade 3/4 adverse events were seen in 29% of patients more than 12 months after the infusion. However, grade 3/4 infection rates did not increase longer than 1 year after infusion. Patients also reported improvements in quality-of-life up to 36 months after infusion.
The authors concluded that these data demonstrated favourable long-term safety and suggested that tisagenlecleucel is a potentially curative treatment option for heavily pretreated paediatric and young adult patients with either relapsed or refractory acute lymphoblastic leukaemia.
Citation
Laetsch TW et al. Three-Year Update of Tisagenlecleucel in Pediatric and Young Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia in the ELIANA Trial J Clin Oncol 2022
18th February 2022
Adjuvant pembrolizumab added to chemotherapy post surgery significantly improves event-free survival compared to chemotherapy alone. This was the conclusion of a study by researchers from the Centre of Experimental Cancer Medicine, Barts Cancer Institute, London, UK.
Triple negative breast cancer constitutes 10-15% of female breast cancers and is a more aggressive cancer with more frequent recurrence and worse survival compared with the non-triple negative form.
Clinical trial data has revealed improved disease-free survival with postoperative chemotherapy in patients with either triple-negative or HER2-positive breast cancer who had residual disease after neoadjuvant chemotherapy.
Whether the addition of pembrolizumab to neoadjuvant chemotherapy would increase the proportion of patients with early triple-negative breast cancer who had a pathological complete response after surgery was unclear until publication in 2020, of the KEYNOTE-522 trial.
The trial concluded that the percentage of patients with a pathological complete response was significantly higher among those who received pembrolizumab plus neoadjuvant chemotherapy than among those who received placebo plus neoadjuvant chemotherapy.
For the present study, the authors have reported on an updated analysis of the KEYNOTE-522 trial and in particular, event-free survival as well as additional efficacy and updated safety information. Participants were adults with confirmed triple negative breast cancer or those with newly diagnosed and previously untreated non-metastatic disease with primary tumour and regional lymph node involvement.
During the adjuvant phase, patients with previously untreated stage II or III triple negative breast cancer, were randomised 2:1 to receive either pembrolizumab (the pembrolizumab–chemotherapy group) or placebo (the placebo–chemotherapy group), administered once every 3 weeks.
After surgery, patients received either pembrolizumab or placebo and chemotherapy every 3 weeks for up to nine cycles. The primary endpoint was pathological complete response and event-free survival.
Adjuvant pembrolizumab and event-free survival
A total of 1174 patients were randomly assigned to either arm and during follow-up, 123 (15.7%) patients assigned to the pembrolizumab arm had an event or died compared to 93 (23.8%) in the placebo-chemotherapy arm.
The estimated event-free survival after 36 months was 84.5% in the adjuvant pembrolizumab group and 76.8% in the placebo arm, giving a hazard ratio, HR, for an event or death = 0.63, 95% CI 0.48 – 0.82, p < 0.001.
Data on overall survival were described as immature at the time of the analysis and the estimated overall survival at 36 months was 89.7% in the adjuvant pembrolizumab group and 86.9% in the placebo-chemotherapy group. With respect to safety, the authors reported that the reported adverse events were consistent with the established safety profile of both pembrolizumab and chemotherapy.
The authors concluded that among those with early triple negative breast cancer, neoadjuvant pembrolizumab plus chemotherapy and then followed by adjuvant pembrolizumab after surgery, was associated with a significantly longer event-free survival than neoadjuvant chemotherapy alone.
Citation
Schmid P et al. Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer N Engl J Med 2022
16th December 2021
Ethic and socioeconomic disparities in survival outcomes have been highlighted in an analysis of newly diagnosed children and young adults with acute lymphoblastic leukaemia (ALL). This was the main finding from a study by researchers from Institute for Health Policy, Evaluation and Management, University of Toronto, Canada, presented at ASH 2021.
Health disparities are major issue for racial, ethnic, and socioeconomically disadvantaged groups and although outcomes in childhood ALL have steadily improved, disparities based on ethnicity and socioeconomic (SES) factors appear to persist.
For the present study, the Canadian team sought to identify the presence of any persistent inequities by race/ethnicity and SES in childhood ALL in the largest cohort ever assembled for this purpose. They identified a cohort of newly-diagnosed patients with ALL, ranging in age from 0 to 40 years enrolled in trials between 2004-2019. Race/ethnicity was categorised as non-Hispanic white vs. Hispanic vs. non-Hispanic Black vs. non-Hispanic Asian vs. Non-Hispanic other.
SES was proxied by insurance status: United States (US) Medicaid (public health insurance for low-income individuals) vs. US other (predominantly private insurance) vs. non-US patients (mainly jurisdictions with universal health insurance). Event-free and overall survival (EFS, OS) were compared across race/ethnicity and SES. The relative contribution of disease prognosticators (age, sex, white blood cell count, lineage, central nervous system status, cytogenetics, end Induction minimal residual disease) were examined with Cox proportional hazard multivariable models of different combinations of the three constructs of interest (race/ethnicity, SES, disease prognosticators) and examining hazard ratio (HR) attenuation between models.
Findings
The study cohort included 24,979 children, adolescents, and young adults with ALL. A total of 13,872 (65.6%) of the whole cohort were Non-Hispanic White patients, followed by 4354 (20.6%) Hispanic patients and 1517 (7.2%) non-Hispanic Black patients. Those insured with US Medicaid were 6944 (27.8%).
The 5-year EFS was 87.4% among non-Hispanic White patients vs. 82.8% among Hispanic patients (hazard ratio, HR = 1.37, 95% CI 1.26 – 1.49; p<0.0001] and 81.9% among non-Hispanic Black patients. The outcomes for non-Hispanic Asian patients were similar to those of non-Hispanic White patients.
US patients on Medicaid had inferior 5-year EFS as compared to other US patients (83.2% vs. 86.3%, HR = 1.21, 95% CI 1.12 – 1.30, p<0.0001) while non-US patients had the best outcomes, with a 5-year EFS of 89%.
There was substantial imbalance in traditional disease prognosticators (e.g. T-cell lineage) across both race/ethnicity and SES, and of race/ethnicity by SES. For example, T-lineage ALL accounted for 17.6%, 9.4%, and 6.6% of Non-Hispanic Black, Non-Hispanic White, and Hispanic patients respectively (p<0.0001).
Multivariable analysis showed how EFS among Hispanic patients was substantially attenuated by the addition of disease prognosticators and the hazard ratio reduced from HR 1.37 to 1.17 and was further (but not fully) attenuated by the subsequent addition of SES (HR 1.11).
In contrast, the increased risk among non-Hispanic Black children was minimally attenuated by both the addition of disease prognosticators and subsequent addition of SES (HR reduction of 1.45 to 1.38 to 1.32). Similarly, while the superior EFS of non-US insured patients was substantially attenuated by the addition of race/ethnicity and disease prognosticators (HR 0.79 to 0.94), increased risk among US Medicaid patients was minimally attenuated by the addition of race/ethnicity or disease prognosticators (HR 1.21 to 1.16).
OS disparities followed similar patterns but were consistently worse than in EFS, particularly among patients grouped as non-Hispanic other.
The authors concluded that there were substantial disparities in survival outcomes by race/ethnicity and SES and that these disparities varied between specific disadvantaged groups., adding that future studies are required to identify specific drivers of survival disparities that may be mitigated by targeted interventions.
Citation
Gupta S et al. Racial, Ethnic, and Socioeconomic Factors Result in Disparities in Outcome Among Children with Acute Lymphoblastic Leukemia Not Fully Attenuated By Disease Prognosticators: A Children’s Oncology Group (COG) Study. ASH Conference 2021
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