Osimertinib after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC.

BACKGROUND: Osimertinib is a recommended treatment for advanced non-small-cell lung cancer (NSCLC) with an epidermal growth factor receptor (EGFR) mutation and as adjuvant treatment for resected EGFR-mutated NSCLC. EGFR-tyrosine kinase inhibitors have shown preliminary efficacy in unresectable stage III EGFR-mutated NSCLC. METHODS: In this phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with unresectable EGFR-mutated stage III NSCLC without progression during or after chemoradiotherapy to receive osimertinib or placebo until disease progression occurred (as assessed by blinded independent central review) or the regimen was discontinued. The primary end point was progression-free survival as assessed by blinded independent central review. RESULTS: A total of 216 patients who had undergone chemoradiotherapy were randomly assigned to receive osimertinib (143 patients) or placebo (73 patients). Osimertinib resulted in a significant progression-free survival benefit as compared with placebo: the median progression-free survival was 39.1 months with osimertinib versus 5.6 months with placebo, with a hazard ratio for disease progression or death of 0.16 (95% confidence interval [CI], 0.10 to 0.24; P<0.001). The percentage of patients who were alive and progression free at 12 months was 74% (95% CI, 65 to 80) with osimertinib and 22% (95% CI, 13 to 32) with placebo. Interim overall survival data (maturity, 20%) showed 36-month overall survival among 84% of patients with osimertinib (95% CI, 75 to 89) and 74% with placebo (95% CI, 57 to 85), with a hazard ratio for death of 0.81 (95% CI, 0.42 to 1.56; P = 0.53). The incidence of adverse events of grade 3 or higher was 35% in the osimertinib group and 12% in the placebo group; radiation pneumonitis (majority grade, 1 to 2) was reported in 48% and 38%, respectively. No new safety concerns emerged. CONCLUSIONS: Treatment with osimertinib resulted in significantly longer progression-free survival than placebo in patients with unresectable stage III EGFR-mutated NSCLC. (Funded by AstraZeneca; LAURA ClinicalTrials.gov number, NCT03521154.).

Adjuvant Osimertinib vs. Placebo in Completely Resected Stage IA2-IA3 EGFR-Mutated NSCLC: ADAURA2.

INTRODUCTION: Osimertinib is a third-generation, irreversible, oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-TKI sensitizing and EGFR T790M resistance mutations, with demonstrated efficacy in EGFR mutation-positive (EGFRm) non-small cell lung cancer (NSCLC), including central nervous system (CNS) metastases. Here we present the rationale and study design for ADAURA2 (NCT05120349), which will evaluate adjuvant osimertinib vs. placebo in patients with stage IA2-IA3 EGFRm NSCLC, following complete tumor resection. PATIENTS AND METHODS: ADAURA2 is a phase III, global, randomized, double-blind, placebo-controlled study. Patients will be adults aged ≥18 years with resected primary nonsquamous NSCLC stage IA2 or IA3 and central confirmation of an EGFR exon 19 deletion or L858R mutation. Patients will be stratified by pathologic risk of disease recurrence (high vs. low), EGFR mutation type (exon 19 deletion vs. L858R) and race (Chinese Asian vs. non-Chinese Asian vs. non-Asian), and randomized 1:1 to receive osimertinib 80 mg once daily (QD) or placebo QD until disease recurrence, treatment discontinuation, or a maximum treatment duration of 3 years. The primary endpoint of this study is disease-free survival (DFS) in the high-risk stratum. Secondary endpoints include DFS in the overall population, overall survival, CNS DFS, and safety. Health-related quality of life and pharmacokinetics will also be evaluated. RESULTS: Study enrolment began in February 2022 and interim results of the primary endpoint are expected in August 2027.

Osimertinib Maintenance After Definitive Chemoradiation in Patients With Unresectable EGFR Mutation Positive Stage III Non-small-cell Lung Cancer: LAURA Trial in Progress.

The LAURA trial (NCT03521154) will evaluate the efficacy and safety of osimertinib as maintenance therapy in patients with locally advanced, unresectable, epidermal growth factor receptor mutation-positive (EGFRm), stage III non-small-cell lung cancer (NSCLC) without disease progression during/following definitive platinum-based chemoradiation therapy (CRT). Eligible patients include adults aged ≥ 18 years (≥ 20 years in Japan) with locally advanced, unresectable, stage III NSCLC with local/central confirmation of an EGFR exon 19 deletion/L858R mutation. Patients must have received ≥ 2 cycles of concurrent/sequential platinum-based CRT, have no investigator-assessed progression, and have creatinine < 1.5 × upper limit of normal and creatinine clearance ≥ 30 mL/min. In this phase III trial, patients will be randomized 2:1 to once-daily osimertinib 80 mg or placebo, until objective radiological disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, confirmed by blinded independent central review (BICR). The primary objective is to assess the efficacy of osimertinib per BICR-confirmed progression-free survival (PFS). Secondary objectives include central nervous system PFS, overall survival, PFS by mutation status and safety. Patients with BICR-confirmed disease progression (or investigator-confirmed progression if after primary PFS analysis) may be unblinded and receive open-label osimertinib; all will have post-progression follow-up. Serious adverse events and adverse events of special interest will be collected throughout the trial and survival follow-up. The first patient was enrolled in July 2018, with results expected in late 2022.

Antineoplastic Drug Contamination on the Outside of Prepared Infusion Bags.

Eight Dutch hospital pharmacies took wipe samples of prepared infusion bags containing 5 fluorouracil just before distribution to the wards. The samples were tested with high-performance liquid chromatography and triple quadrupole mass spectroscopy. The limit of detection was 10 ng per swipe. None of the 146 samples had a detectable amount of 5-fluorouracil. The outside of infusion bags containing antineoplastic drugs prepared in these eight Dutch hospital pharmacies were not contaminated and, therefore, were not a risk factor with regard to exposure of hospital workers to antineoplastic drugs.

Translation, psychometric validation, and baseline results of the Patient-Reported Outcomes Measurement Information System (PROMIS) pediatric measures to assess health-related quality of life of patients with pediatric lymphoma in Malawi.

INTRODUCTION: Internationally validated tools to measure patient-reported health-related quality of life (HRQoL) are available, but efforts to translate and culturally validate such tools in sub-Saharan Africa (SSA) are scarce, particularly among children. METHODS: The Patient-Reported Outcomes Measurement Information System 25-item pediatric short form (PROMIS-25) assesses six HRQoL domains-mobility, anxiety, depression, fatigue, peer relationships, and pain interference-by asking four questions per domain. There is a single-item pain intensity item. The PROMIS-25 was translated into Chichewa and validated for use in Malawi using mixed qualitative and quantitative methods. The validity and reliability of the PROMIS-25 was assessed. RESULTS: Fifty-four pediatric patients with lymphoma completed the PROMIS-25. Structural validity was supported by interitem correlations and principal component analysis. Reliability of each scale was satisfactory (range alpha = 0.71-0.93). Known group validity testing showed that anemic children had worse fatigue (P = 0.016) and children with poor performance status had worse mobility (P < 0.001) and pain interference (P = 0.005). Compared to children with cancer in the United States, children from Malawi reported lower levels of mobility, higher anxiety, higher depressive symptoms, higher fatigue, better satisfaction with peer relationships, and higher pain interference. CONCLUSION: Translation and cultural validation of the PROMIS-25 into Chichewa for Malawi was successful. Baseline HRQoL for patients with pediatric lymphoma in Malawi is poor for all domains except peer relationships. This emphasizes an urgent need to address HRQoL among children undergoing cancer treatment in SSA using self-reported instruments validated within the local context.

Risk factors and reasons for treatment abandonment among children with lymphoma in Malawi.

PURPOSE: Lymphoma is the commonest pediatric cancer in sub-Saharan Africa (SSA). Frequent treatment abandonment contributes to suboptimal outcomes. We examined risk factors and reasons for treatment abandonment for this population in Malawi. METHODS: We conducted a mixed methods study among children < 18 years old with newly diagnosed lymphoma, prospectively enrolled during 2013-2016. All children received standardized diagnosis and treatment, and were followed for up to 2 years. Treatment abandonment was defined as failure to attend prescribed chemotherapy within 4 weeks, or post-treatment visit within 3 months. Child, guardian, and household characteristics associated with treatment abandonment were assessed. Semi-structured interviews were conducted with primary caregivers of children experiencing treatment abandonment. RESULTS: Of 121 children with newly diagnosed lymphoma, 72 (60%) had complete information regarding child, guardian, and household characteristics. Of these, 56 (78%) had Burkitt's and 16 (22%) Hodgkin's lymphoma. Forty-nine (68%) were male, median age was 10.6 years (interquartile range [IQR] 7.9-13.0), and 26 (36%) experienced treatment abandonment. Lack of guardian education and travel time ≥ 4 h to clinic were independently associated with treatment abandonment, with adjusted hazard ratio (aHR) 3.8 [95% confidence interval (CI) 1.5-8.9, p = 0.005] and aHR 2.9 (95% CI 1.2-6.9, p = 0.019), respectively. Commonest reasons for treatment abandonment endorsed by 15 guardians were community influence, suboptimal clinic environment, logistical challenges, transport costs, treatment toxicities, loss of hope, alternative healers, and beliefs about cure. CONCLUSIONS: These findings highlight families at risk for treatment abandonment, underlying reasons, and opportunities to improve retention in care for pediatric cancer patients in SSA.

Extranodal natural killer/T-cell lymphoma in Malawi: a report of three cases.

BACKGROUND: Extranodal NK/T-cell lymphoma (ENKTCL) reports from sub-Saharan Africa (SSA) are remarkably rare, despite early childhood acquisition and high prevalence of the causative infectious agent, Epstein-Barr virus (EBV), and frequent occurrence of other lymphoproliferative disorders causally associated with EBV. CASE PRESENTATIONS: At a national teaching hospital in Malawi, three patients of African descent were seen with ENKTCL between 2013 and 2014. Patients were aged between 29 and 60 years, two with craniofacial involvement and one with a primary abdominal tumor, and all were HIV-negative. All had systemic B symptoms, and two severely impaired performance status. On histologic review, morphology and immunophenotyping demonstrated classical ENKTCL features in all cases, including diffuse proliferations of intermediate-to-large atypical lymphocytes with high mitotic activity and extensive background necrosis, positivity for CD3 and CD56, and negativity for CD20. By in situ hybridization, all three tumors were positive for EBV-encoded RNA (EBER). Baseline plasma EBV DNA was also markedly elevated for all three patients. Due to radiotherapy and chemotherapy limitations, patients were treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) with rapid disease progression. All three patients died from progressive lymphoma within 3 months of initial diagnosis. CONCLUSIONS: Our experience with these three patients in Malawi can highlight that ENKTCL does indeed occur in SSA, increase familiarity with ENKTCL among clinicians and pathologists throughout the region, and emphasize the need for better diagnosis and treatment for this neglected population.

Salvage chemotherapy for adults with relapsed or refractory lymphoma in Malawi.

BACKGROUND: Lymphoma is highly associated with HIV in sub-Saharan Africa (SSA), which contributes to worse outcomes relative to resource-rich settings, and frequent failure of first-line chemotherapy. However, there are no second-line treatment descriptions for adults with relapsed or refractory lymphoma (RRL) in SSA. METHODS: We describe HIV+ and HIV- patients with RRL receiving salvage chemotherapy in Malawi. Patients were prospectively treated at a national teaching hospital in Lilongwe, with the modified EPIC regimen (etoposide, prednisolone, ifosfamide, cisplatin) between June 2013 and May 2016, after failing prior first-line chemotherapy. RESULTS: Among 21 patients (18 relapsed, 3 refractory), median age was 40 years (range 16-78), 12 (57%) were male. Thirteen patients (62%) were HIV+, of whom 12 (92%) were on antiretroviral therapy (ART) at initiation of salvage chemotherapy, with median CD4 cell count 139 cells/µL (range 12-529) and 11 (85%) with suppressed HIV RNA. Median number of EPIC cycles was 3 (range 1-6), and the commonest toxicity was grade 3/4 neutropenia in 19 patients (90%). Fifteen patients responded (3 complete, 12 partial, overall response rate 71%), but durations were brief. Median overall survival was 4.5 months [95% confidence interval (CI) 2.4-5.6]. However, three patients, all HIV+, experienced sustained remissions. Tolerability, response, and survival did not differ by HIV status. CONCLUSIONS: The appropriateness and cost-effectiveness of this approach in severely resource-limited environments is uncertain, and multifaceted efforts to improve first-line lymphoma treatment should be emphasized, to reduce frequency with which patients require salvage chemotherapy. TRIAL REGISTRATION: NCT02835911. Registered 19 January 2016.

Short Communication: CD4 Count and HIV RNA Trends for HIV-Associated Lymphoproliferative Disorders in Malawi.

Given scarce data from sub-Saharan Africa (SSA), we sought to describe CD4 count and HIV RNA trends over time among patients with HIV-positive lymphoproliferative disorders in Malawi. We prospectively enrolled HIV-positive individuals with pathologically confirmed lymphoproliferative disorders between 2013 and 2016. Chemotherapy was standardized with concurrent antiretroviral therapy (ART). We assessed CD4 count and HIV RNA at baseline and every 6 months for up to 2 years. Of 72 HIV-positive patients, 59 had non-Hodgkin lymphoma (NHL), 5 classical Hodgkin lymphoma (CHL), and 8 multicentric Castleman disease (MCD). Median age was 43 years (range 23-64). Fifty-five patients (76%) were on ART at enrollment for a median 47 months (range 1-387), with median CD4 count of 138 cells/µl (range 2-2,235) and median HIV RNA of 2.2 log10copies/ml (range 0.3-7.3). MCD patients had longer median ART durations, higher median CD4 counts, and lower median HIV RNA at baseline than NHL or CHL patients. CD4 count and HIV RNA steadily improved during follow-up, with different patterns in different histological groups. Twelve-month overall survival (OS) was 55% [95% confidence interval (CI) 42%-66%]. There were trends toward baseline CD4 count <100 cells/µl and HIV RNA >2.0 log10copies/ml being associated with worse OS. However, CD4 count and HIV RNA improvements during follow-up were independent of possible effects on OS. Distribution of HIV-positive lymphoproliferative disorders may change with continued ART scale-up in SSA. Chemotherapy and concurrent ART can lead to good immunological and virological outcomes.

Plasma Epstein-Barr virus DNA for pediatric Burkitt lymphoma diagnosis, prognosis and response assessment in Malawi.

Point-of-care tools are needed in sub-Saharan Africa (SSA) to improve pediatric Burkitt lymphoma (BL) diagnosis and treatment. We evaluated plasma Epstein-Barr virus (pEBV) DNA as a pediatric BL biomarker in Malawi. Prospectively enrolled children with BL were compared to classical Hodgkin lymphoma (cHL) and nonlymphoma diagnoses. Pediatric BL patients received standardized chemotherapy and supportive care. pEBV DNA was measured at baseline, mid-treatment, and treatment completion. Of 121 assessed children, pEBV DNA was detected in 76/88 (86%) with BL, 16/17 (94%) with cHL, and 2/16 (12%) with nonlymphoma, with proportions higher in BL versus nonlymphoma (p < 0.001) and similar in BL versus cHL (p = 0.69). If detected, median pEBV DNA was 6.1 log10 copies/mL for BL, 4.8 log10 copies/mL for cHL, and 3.4 log10 copies/mL for nonlymphoma, with higher levels in BL versus cHL (p = 0.029), and a trend toward higher levels in BL versus nonlymphoma (p = 0.062). pEBV DNA declined during treatment in the cohort overall and increased in several children before clinical relapse. Twelve-month overall survival was 40% in the cohort overall, and for children with baseline pEBV detected, survival was worse if baseline pEBV DNA was ≥6 log10 copies/mL versus <6 log10 copies/mL (p = 0.0002), and also if pEBV DNA was persistently detectable at mid-treatment versus undetectable (p = 0.041). Among children with baseline pEBV DNA detected, viremia was the only significant risk factor for death by 12 months in multivariate analyses (adjusted hazard ratio 1.35 per log10 copies/mL, 95% CI 1.04-1.75, p = 0.023). Quantitative pEBV DNA has potential utility for diagnosis, prognosis, and response assessment for pediatric BL in SSA.

Quantifying bias in survival estimates resulting from loss to follow-up among children with lymphoma in Malawi.

Pediatric lymphoma is common in sub-Saharan Africa, where survival estimates are often based on limited follow-up with incomplete retention, introducing potential for bias. We compared follow-up and overall survival (OS) between passive and active tracing within a prospective cohort of children with lymphoma in Malawi. Median follow-up times were 4.4 months (interquartile range [IQR] 2.0-9.4) and 10.8 months (IQR 6.2-20.6) in passive and active follow-up, respectively. Twelve-month overall survival (OS) was 69% (95% confidence interval [CI] 54-80) in passive and 44% (95% CI 34-54) in active follow-up. Passive follow-up significantly overestimated the OS and underestimated the mortality. Efforts to improve retention in regional studies are needed.

Applying quality by design principles to the small-scale preparation of the bone-targeting therapeutic radiopharmaceutical rhenium-188-HEDP.

INTRODUCTION: Rhenium-188-HEDP ((188)Re-HEDP) is a therapeutic radiopharmaceutical for treatment of osteoblastic bone metastases. No standard procedure for the preparation of this radiopharmaceutical is available. Preparation conditions may influence the quality and in vivo behaviour of this product. In this study we investigate the effect of critical process parameters on product quality and stability of (188)Re-HEDP. METHODS: A stepwise approach was used, based on the quality by design (QbD) concept of the ICH Q8 (Pharmaceutical Development) guideline. Potential critical process conditions were identified. Variables tested were the elution volume, the freshness of the eluate, the reaction temperature and time, and the stability of the product upon dilution and storage. The impact of each variable on radiochemical purity was investigated. The acceptable ranges were established by boundary testing. RESULTS: With 2ml eluate, adequate radiochemical purity and stability were found. Nine ml eluate yielded a product that was less stable. Using eluate stored for 24h resulted in acceptable radiochemical purity. Complexation for 30min at room temperature, at 60°C and at 100°C generated appropriate and stable products. A complexation time of 10min at 90°C was too short, whereas heating 60min resulted in products that passed quality control and were stable. Diluting the end product and storage at 32.5°C resulted in notable decomposition. CONCLUSION: Two boundary tests, an elution volume of 9ml and a heating time of 10min, yielded products of inadequate quality or stability. The product was found to be instable after dilution or when stored above room temperature. Our findings show that our previously developed preparation method falls well within the proven acceptable ranges. Applying QbD principles is feasible and worthwhile for the small-scale preparation of radiopharmaceuticals.