Does dose reduction of afatinib affect treatment outcomes of patients with EGFR-mutant metastatic non-small cell lung cancer in real-world clinical practice?

Background: Afatinib can be started at a dose lower than the recommended starting dose of 40 mg/day for the treatment of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), however treatment outcomes in real-world clinical practice remains unclear. Methods: This retrospective study of patients with NSCLC from 18 major hospitals (public, private or university teaching hospitals) enrolled in Malaysia's National Cardiovascular and Thoracic Surgical Database (NCTSD) assessed the efficacy of lower doses of afatinib on treatment outcomes in a real-world clinical practice. Data on clinical characteristics, afatinib dosing, and treatment outcomes for patients included in NCTSD from 1st January 2015 to 31st December 2020 were analyzed. Results: Of the 133 patients studied, 94.7% had adenocarcinoma. Majority of the patients (60.9%) had EGFR exon 19 deletion and 23.3% had EGFR exon 21 L858R point mutation. The mean age of patients was 64.1 years and majority (83.5%) had Eastern Cooperative Oncology Group performance status of 2-4 at diagnosis. The most common afatinib starting doses were 40 mg (37.6%), 30 mg (29.3%), and 20 mg (26.3%) once daily (OD), respectively. A quarter of patients had dose reduction (23.3%) due to side effects or cost constraints. Majority of the patients had partial response to afatinib (63.2%) whilst 2.3% had complete response. Interestingly, the objective response rate was significantly higher (72.3%) with afatinib OD doses of less than 40 mg compared to 40 mg (54.0%) (P=0.032). Patients on lower doses of afatinib were two times more likely to achieve an objective response [odds ratio =2.64; 95% confidence interval (CI): 1.20-5.83; P=0.016]. These patients had a numerically but not statistically longer median time to treatment failure (TTF). Median TTF (95% CI) for the overall cohort was 12.4 (10.02-14.78) months. Median overall survival (95% CI) was 21.30 (15.86-26.75) months. Conclusions: Lower afatinib doses (<40 mg OD) could be equally effective as standard dose in patients with EGFR-mutant advanced NSCLC and may be more suited to Asian patients, minimizing side effects that may occur at higher dosages of afatinib leading to dose interruptions and affecting treatment outcomes.

Amivantamab plus Chemotherapy in NSCLC with EGFR Exon 20 Insertions.

BACKGROUND: Amivantamab has been approved for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertions who have had disease progression during or after platinum-based chemotherapy. Phase 1 data showed the safety and antitumor activity of amivantamab plus carboplatin-pemetrexed (chemotherapy). Additional data on this combination therapy are needed. METHODS: In this phase 3, international, randomized trial, we assigned in a 1:1 ratio patients with advanced NSCLC with EGFR exon 20 insertions who had not received previous systemic therapy to receive intravenous amivantamab plus chemotherapy (amivantamab-chemotherapy) or chemotherapy alone. The primary outcome was progression-free survival according to blinded independent central review. Patients in the chemotherapy group who had disease progression were allowed to cross over to receive amivantamab monotherapy. RESULTS: A total of 308 patients underwent randomization (153 to receive amivantamab-chemotherapy and 155 to receive chemotherapy alone). Progression-free survival was significantly longer in the amivantamab-chemotherapy group than in the chemotherapy group (median, 11.4 months and 6.7 months, respectively; hazard ratio for disease progression or death, 0.40; 95% confidence interval [CI], 0.30 to 0.53; P<0.001). At 18 months, progression-free survival was reported in 31% of the patients in the amivantamab-chemotherapy group and in 3% in the chemotherapy group; a complete or partial response at data cutoff was reported in 73% and 47%, respectively (rate ratio, 1.50; 95% CI, 1.32 to 1.68; P<0.001). In the interim overall survival analysis (33% maturity), the hazard ratio for death for amivantamab-chemotherapy as compared with chemotherapy was 0.67 (95% CI, 0.42 to 1.09; P = 0.11). The predominant adverse events associated with amivantamab-chemotherapy were reversible hematologic and EGFR-related toxic effects; 7% of patients discontinued amivantamab owing to adverse reactions. CONCLUSIONS: The use of amivantamab-chemotherapy resulted in superior efficacy as compared with chemotherapy alone as first-line treatment of patients with advanced NSCLC with EGFR exon 20 insertions. (Funded by Janssen Research and Development; PAPILLON ClinicalTrials.gov number, NCT04538664.).

Challenges and Strategies for Improving Access to Cancer Drugs in Malaysia: Summary of Opinions Expressed at the 2nd MACR International Scientific Conference 2022.

Considerable progress has been made in cancer drug development in recent decades. However, for people in low- and middle-income countries, including Malaysia, many of these drugs are not readily available. During the 2nd Malaysian Association for Cancer Research (MACR) International Scientific Conference, a forum discussion was held to address these challenges and explore strategies to improve access to cancer medicines in the country. This paper presents the results of the said forum discussion. A few challenges to cancer drug access were highlighted, including lengthy approval and regulatory practices, cost of medicines, and manufacturing barriers. Besides, a few strategies for mitigating some of these challenges were proposed, such as mechanisms for cost reduction, uptake of biosimilars and generics, local manufacturing, public-private partnerships, strengthening the role of insurance companies, funding and regulation, and advocacy for fair pricing, by drawing examples from cancer medicines access initiatives in Malaysia and initiatives for different disease groups. Overall, this paper provides a comprehensive overview of the challenges and strategies for improving access to cancer medicines in Malaysia and provides valuable insights for policymakers, healthcare providers, the pharmaceutical industry, cancer patients, cancer support groups, and other stakeholders working on this important issue.

Association between pre-existing cardiometabolic comorbidities and the pathological profiles of breast cancer at initial diagnosis: a cross sectional study.

The presence of comorbidities has been associated with later stages of breast cancer diagnosis. It is unclear whether biological mechanisms are partly responsible. We examined the association between the presence of pre-existing comorbidities and tumour profile at initial diagnosis with breast cancer. Data for the present analysis were derived from a prior inception cohort study comprising 2,501 multiethnic women, newly diagnosed with breast cancer between 2015 and 2017 in four hospitals across Klang Valley. At the inception of the cohort, medical and drug histories, height, weight and blood pressure were recorded. Blood samples were taken to measure serum lipid and glucose. Modified Charlson Comorbidity Index (CCI) was calculated using data extracted from medical records. The association of CCI as well as specific comorbidities, with pathological breast cancer profile was analysed. Higher comorbidity burden, namely cardiometabolic conditions were associated with unfavourable pathological features including larger tumours, involvement of >9 axillary lymph nodes, distant metastasis and human epidermal growth factor receptor 2 overexpression. These associations remained largely significant following multivariable analyses. Specifically, diabetes mellitus was independently associated with high nodal metastasis burden. Low level of high-density lipoprotein was associated with larger tumours (>5 cm), and distant metastasis. Evidence from this study seems to support the hypothesis that the later stages of breast cancer diagnosis in women with (cardiometabolic) comorbidities may be partially explained by underlying pathophysiological events.

Real-World Treatment and Outcomes of ALK-Positive Metastatic Non-Small Cell Lung Cancer in a Southeast Asian Country.

Purpose: Anaplastic lymphoma kinase (ALK) inhibitors are associated with good overall survival (OS) for ALK-positive metastatic non-small cell lung cancer (NSCLC). However, these treatments can be unavailable or limited by financial constraints in developing countries. Using data from a nationwide lung cancer registry, the present study aimed to identify treatment patterns and clinical outcomes of ALK-positive NSCLC in Malaysia. Methods: This retrospective study examined data of patients with ALK-positive NSCLC from 18 major hospitals (public, private, or university teaching hospitals) throughout Malaysia between January 1, 2015 and December 31, 2020 from the National Cardiovascular and Thoracic Surgical Database (NCTSD). Data on baseline characteristics, treatments, radiological findings, and pathological findings were collected. Overall survival (OS) and time on treatment (TOT) were calculated using the Kaplan-Meier method. Results: There were 1581 NSCLC patients in the NCTSD. Based on ALK gene-rearrangement test results, only 65 patients (4.1%) had ALK-positive advanced NSCLC. Of these 65 patients, 59 received standard-of-care treatment and were included in the analysis. Crizotinib was the most commonly prescribed ALK inhibitor, followed by alectinib and ceritinib. Patients on ALK inhibitors had better median OS (62 months for first-generation inhibitors, not reached at time of analysis for second-generation inhibitors) compared to chemotherapy (27 months), but this was not statistically significant (P=0.835) due to sample-size limitations. Patients who received ALK inhibitors as first-line therapy had significantly longer TOT (median of 11 months for first-generation inhibitors, not reached for second-generation inhibitors at the time of analysis) compared to chemotherapy (median of 2 months; P<0.01). Conclusion: Patients on ALK inhibitors had longer median OS and significantly longer TOT compared to chemotherapy, suggesting long-term benefit.

Development and Validation of a Dual-Language (English and Malay) Needs Assessment Tool for Breast Cancer (NeAT-BC).

Background: Needs assessment tools may be used to guide the optimisation of cancer survivorship services. We sought to develop and validate a dual-language needs assessment tool for women with breast cancer. Methods: The study comprised two phases; (I) co-design, and (II) psychometric testing. In Phase I, items were generated based on focus group discussions with patients and a literature review. These items were then translated into the Malay language. Content and face validation were undertaken with an expert panel. In phase II, 315 Malaysian women living with breast cancer were recruited. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were conducted to determine construct validity and reliability. Criterion validity was assessed using the EORTC QLQ-C30 questionnaire. Results: We co-designed and validated a 48-item dual-language needs assessment tool for breast cancer (NeAT-BC). Five underlying constructs were revealed in the EFA: (1) emotional support, (2) social and intimate relationships, (3) hospital appointments, (4) personal care and health, and (5) information and services. The NeAT-BC demonstrated good reliability across all constructs (Cronbach's alpha: 0.90 to 0.96). CFA also demonstrated acceptable convergent and divergent validity, composite reliability ≥ 0.87, and Heterotrait−Monotrait index < 0.85 for all constructs. Criterion validity was established given the significant negative correlation between overall needs and quality of life (r = −0.14; p = 0.02). The NeAT-BC took approximately 25 min to be completed and could be interviewer-administered or self-administered. Conclusion: The utilization of the NeAT-BC is expected to guide establishment of evidence-based cancer survivorship services in Malaysia, with wider potentials for adoption in other multi-ethnic and/or low-and-middle income settings.

Outcomes of Patients with EGFR-Mutant Advanced NSCLC in a Developing Country in Southeast Asia.

Background: Although first- and second-generation EGFR TKIs are considered first-line treatment in EGFRm+ NSCLC, most patients develop resistance and progress, commonly, EGFR T790M mutation. The third-generation EGFR-TKI has demonstrated efficacy in patients with progressive disease harboring the T790M mutation and in the first-line setting, bypassing this mode of resistance. The primary objectives of this study are to describe the proportion of EGFRm+ NSCLC patients treated with first-, second- and third-generation EGFR TKIs, and cytotoxic chemotherapy in the first-line setting, and the time on treatment for each category. Secondary objectives are to determine the dropout rate, the rates for T790M mutation testing at disease progression and the type of subsequent treatment. Methods: This multicenter retrospective study utilized data from the Malaysian Lung Cancer Registry that actively registers all lung cancer patients ≥18 years, with primary lung cancer confirmed histologically or cytologically. All patients diagnosed with advanced stages (ie stages IIIB, IIIC and IV) EGFRm+ NSCLC from 1st of January 2015 to 31st December 2019 were included. Results: Of 406 patients with EGFRm+ NCSLC, 351 were treated. Types of first-line treatment were as follows: EGFR-TKIs (first generation - 54.1%, second generation - 25.6% and third-generation - 12.5%) and chemotherapy (7.7%). The median time of treatment for each generation of EGFR-TKI was 12 months, 12 months and 24 months, and 2 months for chemotherapy. The dropout rate was 28.7% (n = 101). Nearly half (49.4%) of patients who were on first- or second-generation EGFR-TKI had further genetic testing via liquid or tissue biopsies upon disease progression. About 24.9% of those who developed disease progression after first- or second-generation EGFR TKI were started on a third-generation EGFR TKI. Conclusion: In the real-world, the management of EGFRm+ advanced NSCLC patients in an Asian cost-restrictive setting may adversely affect the choice of first-line therapy, time on each line of treatment and subsequently the overall survival of patients.

Programmed death-ligand 1 expression and use of immune checkpoint inhibitors among patients with advanced non-small-cell lung cancer in a resource-limited country.

INTRODUCTION: Immune checkpoint inhibitor (ICI) therapy is an established treatment for advanced non-small-cell lung cancer (NSCLC) and programmed death ligand-1 (PD-L1) expression is a recognized biomarker to determine response to therapy. We retrospectively analyzed NSCLC patients in the Malaysia Lung Cancer Registry (MLCR) and report on the clinical characteristics associated with PD-L1 expression and ICI use in Malaysia, a low- to middle-income country. METHODS: All 901 NSCLC patients in the MLCR who were diagnosed from January 1, 2017 to December 31, 2020 from 14 hospitals across the country were analyzed. RESULTS: Out of 901 patients, 505 had PDL-1 testing done with complete data available only in 489 patients. The most common histology was adenocarcinoma (84.7%) followed by squamous cell carcinoma (10.2%). The majority (95%) presented with stage 3 or 4. The number and percentage of patients with PDL-1 tumor proportion scores of ≥50%, 1-49%, and <1% were 138 (28.2%), 158 (32.3%), and 193 (39.5%), respectively. In multivariate analysis, the presence of genomic mutation is the only independent characteristic associated with negative PD-L1 expression (crude odds ratio 0.579, 95% confidence interval 0.399-0.840, p = 0.004). Of 292 patients eligible for ICI therapy, only 100 patients (34.2%) received ICIs. Seventy-eight patients received ICI therapy as first-line treatment, 15 patients as second-line treatment, and 7 patients as third-line treatment. CONCLUSIONS: This is the first analysis on PD-L1 expression and ICI use in Malaysia. Despite the proven efficacy of ICI therapy, only 56% of our patients had PD-L1 tests performed and only 34.2% of eligible patients received ICIs.

Management of advanced prostate cancer in a middle-income country: real-world consideration of the Advanced Prostate Cancer Consensus Conference 2017.

OBJECTIVE: To examine the results of the Malaysian Advanced Prostate Cancer Consensus Conference (MyAPCCC) 2018, held for assessing the generalizability of consensus reached at the Advanced Prostate Cancer Consensus Conference (APCCC 2017) to Malaysia, a middle-income country. METHODS: Six key sections were chosen: (1) high-risk localized and locally advanced prostate cancer, (2) oligometastatic prostate cancer, (3) castration-naïve prostate cancer, (4) castrate resistant prostate cancer, (5) use of osteoclast-targeted therapy and (6) global access to prostate cancer drugs. There were 101 consensus questions, consisting of 91 questions from APCCC 2017 and 10 new questions from MyAPCCC 2018, selected and modified by the steering committee; of which, 23 questions were assessed in both ideal world and real-world settings. A panel of 22 experts, comprising of 11 urologists and 11 oncologists, voted on 101 predefined questions anonymously. Final voting results were compared with the APCCC 2017 outcomes. RESULTS: Most voting results from the MyAPCCC 2018 were consistent with the APCCC 2017 outcomes. No consensus was achieved for controversial topics with little level I evidence, such as management of oligometastatic disease. No consensus was reached on using high-cost drugs in castration-naïve or castration-resistant metastatic prostate cancer in real-world settings. All panellists recommended using generic drugs when available. CONCLUSIONS: The MyAPCCC 2018 voting results reflect the management of advanced prostate cancer in a middle-income country in a real-world setting. These results may serve as a guide for local clinical practices and highlight the financial challenges in modern healthcare.

Malaysian Consensus Statement for the Diagnosis and Management of Acromegaly.

In Malaysia, acromegaly is under-recognised with only 10-15% of the expected number of cases from prevalence estimates, having been diagnosed and managed in established endocrine centres with access to multidisciplinary care. This is mainly due to lack of awareness and standardised approach in diagnosing this disease resulting in delay in diagnosis and management with suboptimal treatment outcomes. This first Malaysian consensus statement on the diagnosis and management of acromegaly addresses these issues and is based on current best practices and latest available evidence so as to reduce the disease burden on acromegaly patients managed in the Malaysian healthcare system.

Symptom Prevalence and Related Distress in Cancer Patients Undergoing Chemotherapy.

BACKGROUND: Much has been done to examine the psychological impact of cancer treatment, but it remains unclear to what extent anxiety and depression is related to symptom prevalence. The present study concerned the characteristics and frequency of distress as related to symptom prevalence in cancer patients undergoing chemotherapy in Malaysia. MATERIALS AND METHODS: Participants were 303 consecutive adult cancer patients undergoing chemotherapy in an academic medical center. The short form Memorial Symptom Assessment Scale (MSAS-SF), which covers three domains of symptoms (global distress, physical- and psychological symptoms) was used to cross-sectionally measure symptom frequency and associated distress via self-reporting. One-way ANOVA and t-tests were used to test mean differences among MSAS-SF subscale scores. RESULTS: Complete data were available for 303 patients. The mean number of symptoms was 14.5. The five most prevalent were fatigue, dry mouth, hair loss, drowsiness and lack of appetite. Overall, symptom burden and frequency were higher than in other published MSAS-SF studies. Higher symptom frequency was also found to be significantly related to greater distress in cancer patients undergoing chemotherapy. CONCLUSIONS: Patients undergoing chemotherapy suffer from multiple physical and psychological symptoms. Better symptom control or palliative care is needed. Greater frequency of reported symptoms may also indicate a subconscious bid by patients for care and reassurance - thus tailored intervention to manage distress should be offered.