Background: A Phase IV, single-arm study was conducted to assess the safety of osimertinib in Indian patients with epidermal growth factor receptor (EGFR) T790M mutation-positive stage IV non-small cell lung cancer (NSCLC). Methods: Enrolled patients received 80 mg osimertinib for six cycles or until disease progression or unacceptable toxicity or withdrawal. Primary safety variables included treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events (AEs) leading to discontinuation/interruption/change (D/I/C) of drug dose, and AEs of special interest (AESIs). AEs were summarized by the percentage of patients experiencing at least one occurrence of each event. Results: Of the 60 enrolled patients (median age 58 [range: 34–81] years; 51.7% women) at eight sites, nine patients were discontinued prematurely due to disease progression (n = 7) and death (n = 2); median (range) duration of treatment was 126 (1–134) days. Median age of patients was 58 (34–81) years; 51.7% (n = 31) were women; 86.7% (n = 52) were nonsmokers; and most of them (98.3%) had adenocarcinoma. About 75% (n = 45) of patients experienced any of the TEAEs, with the most frequent being fatigue and creatine phosphokinase (CPK) increase (n = 6, 10% each). TEAEs in 11 (18.3%) patients were judged as study treatment related, with CPK increase being the most common (n = 4, 6.7%). TEAEs led to D/I/C of drug dose in eight (13.3%) patients, with one being study treatment related. Nine (15%) patients had AESIs of dyspnea (n = 6), chest pain (n = 2), and cardiorespiratory arrest (n = 1); two of them had a fatal outcome. One AESI (mild dyspnea) was considered study drug related. TEAEs of grade ≥3 were reported in seven (11.7%) patients, including dyspnea in two (3.3%), followed by diarrhea, mucosal inflammation, cardiorespiratory arrest, and others (n = 1, 1.7% each). None of the SAEs and fatal events were considered as study treatment related. Seven (11.7%) patients had abnormal electrocardiogram (ECG; not clinically significant) at the end of the study. Conclusion: Our study confirms the favorable safety profile of osimertinib without any new safety concerns in Indian patients with EGFR T790M mutation-positive stage IV NSCLC. ClinicalTrials.gov Identifier: NCT03853551 CTRI registration no. CTRI/2018/10/015941

Background: Molecular tissue testing in non-small cell lung cancer (NSCLC) is done for the assessment of epidermal growth factor receptor (EGFR) mutation. EGFR mutation status is the basis for deciding the targeted treatment option for patients with metastatic NSCLC. The nonavailability of tissue samples and contraindications for biopsy pose a significant challenge. Hence, circulating tumor DNA (ctDNA) by liquid biopsy can be a viable alternative for NSCLC patients. Methods: This study was conducted at 15 sites across India. EGFR mutation testing from plasma was done as part of the study at the central laboratory by the next-generation sequencing (NGS) method, and EGFR mutation test results from tissue samples (done as part of routine practice) were recorded for all the patients. Results: Out of the total patients enrolled (N = 245), the majority (64.5%, n = 158) were men. The median age of patients was 58.0 (range: 26–84) years. The concordance between plasma and tissue testing was found to be 82.9% (95% confidence interval [CI]: 77.55, 87.45). The sensitivity and specificity of NGS were 68.4% (95% CI: 56.92, 78.37) and 90.1% [95% CI: 84.36, 94.21), respectively. Plasma testing detected 1.2% (n = 3) and tissue sample testing detected 2.4% (n = 6) positive status of exon 20 T790M EGFR mutation. Out of the total number of patients enrolled, 25 were tissue positive and plasma negative, while 16 were plasma positive and tissue negative. Conclusions: This real-world study in Indian patients suggests that plasma testing for EGFR mutation analysis is a viable diagnostic option in newly diagnosed advanced/metastatic NSCLC patients. The noninvasive plasma procedure in patients without available/evaluable tumor sample may enable more patients to receive appropriate targeted therapies by providing clinicians with valuable insights into the patient's tumor mutation status. ClinicalTrials.gov Identifier: NCT03562819

To gain insights on the diverse practice patterns and treatment pathways for prostate cancer (PC) in India, the Urological Cancer Foundation convened the first Indian survey to discuss all aspects of PC, with the objective of guiding clinicians on optimizing management in PC. A modified Delphi method was used, wherein a multidisciplinary panel of oncologists treating PC across India developed a questionnaire related to screening, diagnosis and management of early, locally advanced and metastatic PC and participated in a web–based survey (WBS) (n = 62). An expert committee meeting (CM) (n = 48, subset from WBS) reviewed the ambiguous questions for better comprehension and reanalyzed the evidence to establish a revote for specific questions. The threshold for strong agreement and agreement was ≥90% and ≥75% agreement, respectively. Sixty-two questions were answered in the WBS; in the CM 31 questions were revoted and 4 questions were added. The panelists selected answers based on their best opinion and closest to their practice strategy, not considering financial constraints and access challenges. Of the 66 questions, strong agreement was reached for 17 questions and agreement was achieved for 22 questions. There were heterogeneous responses for 27 questions indicative of variegated management approaches. This is one of the first Indian survey, documenting the diverse clinical practice patterns in the management of PC in India. It aims to provide guidance in the face of technological advances, resource constraints and sparse high-level evidence..

Lung cancer is reported as the leading cause of cancer-related mortality worldwide. Non-small cell lung cancer (NSCLC) constitutes 80%–85% of all lung cancers. Diagnosis of NSCLC is a complex multistep process. The prognosis of NSCLC is poor as most of the patients are presented at the metastatic stage. The management of these patients needs the expertise of different specialists. A multidisciplinary team (MDT) comprising specialists from different disciplines has a substantial role in improving outcomes in these patients. This is feasible through extensive discussions, accurate evaluation of patients, reviewing medical records, implementing ideal treatment strategies, and merging local treatments with systemic treatment concepts. Therefore, the MDT approach for stage III NSCLC management can enable early treatment initiation, optimal treatment modalities, and reduce healthcare expenditure. Studies have shown that MDT can provide multimodality care facilitating the diagnosis and treatment of stage III NSCLC, resulting in survival benefit of these patients. Thus, it is imperative to collate scientific evidence to get an insight into the MDT approach in advanced NSCLC treatment. This review aims to summarize the impact of MDT on treatment rates, survival outcome, treatment guideline adherence, and quality of life (QoL) of stage III NSCLC patients.

Ovarian cancer (OC) is one of the most lethal gynecological cancers with a 5-year survival rate that ranges from 30% to 40%. Breast cancer genes (BRCA1 and BRCA2) play a key role in maintaining genomic stability. Mutations in BRCA1/2 genes lead to the accumulation of double-strand breaks, resulting in tumorigenesis. The risk of developing OC in women with BRCA1 and BRCA2 mutations is 39% and 11%, respectively, by 70 years of age. BRCA1/2 mutation testing is thus important to identify women at greatest risk of developing OC in addition to its impact on diagnosis, prognosis, and targeted therapy. Genetic testing is required to identify the BRCA mutations and thus select patients who can benefit from polyadenosine diphosphate (ADP)–ribose polymerase (PARP) inhibitor therapy. Tumor BRCA mutation testing can detect both germline and somatic mutations allowing implementation of preventive strategies on a broader population. Various international guidelines recommend BRCA1/2 mutation genetic testing in all OC patients irrespective of age and family history. This review focuses on the role of BRCA mutation testing in OC.

EGFR-TKIs have changed the landscape of metastatic NSCLC treatment with a significant improvement in survival of EGFRm patients compared to wild-type EGFR. Even with the newer third generation EGFR TKIs like, Osimertinib, which has proven efficacy against the resistance mutation of EGFRm T790M, progression eventually occurs. There are limited treatment options for patients with metastatic EGFRm NSCLC with other acquired resistance. Therefore, novel therapeutic combination strategies are being researched to overcome potential resistance to EGFR-TKI-targeted therapy. The ICIs targeting the programmed cell death-1 pathway in patients with EGFRm NSCLC were greatly anticipated based on preclinical studies showing increased PD-L1 expression. In clinical settings, this increased expression did not translate into a survival benefit. Treatment with ICIs failed to positively affect EGFRm patients because of multiple reasons: nonsynonymous tumor mutational burden, lower PD-L1 expression in tumors, and cancer cells utilizing alternate immune escape mechanisms. The NCCN guidelines currently do not recommend immunotherapy in patients with metastatic EGFRm NSCLC. Recently, a subgroup analysis in the IMpower150 study provided a signal for overall survival of atezolizumab with bevacizumab plus chemotherapy in EGFRm-TKI progressed patients. Based on these encouraging findings, several combinations of ICIs and EGFR-TKIs are being evaluated in TKI-failed EGFRm patients. These regimens might provide a favorable therapeutic effect by combining higher response rates of TKIs and durable disease control of ICIs. However, further research is warranted to understand the exact underlying molecular and cellular mechanisms responsible for the clinical benefits. In this article, we explored the TKI failed metastatic EGFRm NSCLC, reviewed the available clinical data of ICI use in metastatic EGFRm NSCLC, and discussed its emerging role as a combination regimen in this patient population.

Evidence from several studies has shown improved progression-free survival (PFS) with first- or second-generation epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitors (TKIs) compared with chemotherapy for advanced NSCLC patients. But resistance to first or second-generation TKI therapies after 9 to 12 months of treatment initiation is a concern. Osimertinib is a third-generation, irreversible, oral EGFR-TKI that potently and selectively inhibits both EGFRm (epidermal growth factor receptor mutated) and EGFR T790M and has demonstrated efficacy in NSCLC central nervous system (CNS) metastases. Trials have reported significantly longer PFS and higher median duration of response with osimertinib compared with first-generation EGFR-TKIs (erlotinib, gefitinib) and chemotherapy, respectively. And relatively lower rates of discontinuation due to adverse events (AEs). Significant improvement in overall survival was also observed when used as first-line treatment. Because EGFR-mutated tumors are highly dependent on EGFR signaling, optimal sequence of available TKIs – erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib – is necessary. The sequencing of EGFR-TKIs has changed over the past decade and depends on factors such as expected efficacy, CNS activity, tolerability, and options available after progression. Third-generation TKI may be the preferred first-line treatment because patients may not opt for or die before the start of second-line therapy, and it is difficult to predict which patients will eventually develop T790M mutation. The favorable tolerability profile alongside a longer time to disease progression makes osimertinib a preferred first-line treatment. Though clinical practice guidelines do not provide clear consensus on the most preferred EGFR-TKI, recent updates recommend osimertinib as a first-line treatment for advanced NSCLC patients. Also, improved patient selection incorporating clinical and molecular characteristics will help translate to better survival outcomes and improved quality of life. This review aims to determine the optimal sequence of administration of the EGFR-TKIs considering toxicity, quality of life, and survival outcomes among advanced NSCLC patients.

Lung cancer is one of the deadliest cancers globally and accounts for most of the cancer-related deaths in India. Comprehensive data on lung cancer in India are lacking. This review aimed to discuss the epidemiological trends of lung cancers and driver mutations as well as the recent advancements in molecular diagnostics and therapeutic options primarily in non–small cell lung cancer (NSCLC) in India. Electronic databases, such as PubMed and Google Scholar, were searched to retrieve the relevant literature published in the past 5 years. As per the GLOBOCAN 2018 report, lung cancer was ranked the fourth leading cause of cancer (5.9% cases) in India, in all ages and sexes. Furthermore, 63,475 of all cancer-related deaths (8.1%) were attributed to lung cancer (cumulative risk 0.60), making it the third leading cause of cancer-related mortality. The common targets for treatment in lung cancer patients mainly include EGFR mutation, ALK and ROS1 rearrangements and PDL1 expression. In India, EGFR and ALK re-arrangement are commonly reported, but there is limited data of PD-L1 expression. Molecular testing has gained importance as several biomarkers are being targeted to treat lung cancer patients. Surgery, radiotherapy, systemic chemotherapy, and personalized molecular-targeted therapy prolong the overall survival (OS) in patients with NSCLC. Although chemotherapy and molecular-targeted therapies have greatly improved the clinical outcomes, prolonged disease control could not be attained in most NSCLC patients. In this situation, immunotherapy seems to be potentially beneficial to obtain long-lasting disease control with minimal adverse events.

Despite a better understanding of the pathophysiology and development of newer therapeutic options, cancer remains an area with several unmet needs. Although overall survival (OS) remains a gold standard endpoint for all cancer therapies, it poses challenges such as the requirement of a long-term follow-up, a higher number of patients, and a higher financial burden. Therefore, surrogate endpoints such as progression-free survival, time to progression, duration of response, and objective response rate are being investigated and used in oncology studies. Patient-related outcomes that measure the patient's overall health, quality of life, and satisfaction in the long term are crucial surrogate endpoints considered for drug approval. Surrogate endpoints shorten oncology clinical studies and accelerate the evaluation and implementation of newer therapies. Emerging surrogate endpoints such as biomarkers, immune-related response criteria, minimal residual disease, and pathological complete response are increasingly being considered in oncology trials. Validation of surrogate endpoints enables their substitution for OS and gain market approval. The selection of surrogate endpoints for an oncology trial depends on cancer type and stage, the purpose of treatment, and expected duration of survival for the relevant disease. With the advent of individualized approach and complex study designs, the field of oncology is currently undergoing a paradigm shift. The use of newer surrogate endpoints will aid in accelerating the drug development process, making patient care for oncology more accessible.

Standard therapy for advanced ovarian cancer (OC) consists of radical debulking cytoreductive surgery followed by adjuvant chemotherapy. An important risk factor for OC is genetic predisposition, with BRCA1 or BRCA2 mutations accounting for the majority of hereditary OC. Mutation in BRCA ultimately causes accumulation of genetic alterations because of the failure of cells to arrest and repair DNA damage or to undergo apoptosis, resulting in tumorigenesis. Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as a promising approach for managing BRCA-associated cancers, especially high-grade OC and breast cancers. They lead to synthetic lethality in BRCA-mutated cells by stalling the replication forks in homologous recombination-deficient (HR) cells. Four PARP inhibitors (olaparib, niraparib, rucaparib, and talazoparib) are currently approved by the Food and Drug Administration for OC, breast, and pancreatic cancer indications and are being evaluated for other BRCA-associated cancers. Despite their clinical efficacy, cancer cells generally develop resistance to them through several mechanisms. Understanding these mechanisms is crucial for developing strategies to counter resistance and identify the basic mechanisms of DNA damage response. This review focuses on the mechanism of action of PARP inhibitors, understanding various causes of resistance, and building strategies to overcome PARP inhibitor resistance.

Human epidermal growth factor receptor 2 (HER2)-negative subset is the most heterogeneous group of metastatic breast cancers (MBCs) as it includes both hormone receptor (HR)-positive and HR-negative breast cancer (or TNBC), which have different therapies and treatment challenges. Though endocrine therapy (ET) remains the treatment backbone in HR-positive HER2-negative cases, about 40% of the patients show intrinsic or acquired resistance to ET due to multiple mechanisms. Combining different therapies such as ET and other targeted therapies with or without chemotherapy fails to give continued benefit, unlike cyclin-dependent kinase (CDK) 4/6 inhibitors that have shown a great benefit. TNBC has conventionally been treated ineffectively with systemic chemotherapy. Recently, poly (ADP-ribose) polymerase inhibitors (PARPi) have emerged for HER2-negative breast cancer (BC) patients, including TNBC. Olaparib and talazoparib have recently been approved in germline BRCA-mutated (gBRCAm) HER2-negative MBC. Additionally, ongoing trials of PARPi in combination with various therapies are expected to provide more and better treatment options for gBRCAm HER2-negative breast cancer.

Androgen deprivation therapy (ADT) using gonadotropin-releasing hormone agonist (s) (GnRH-A) remains the backbone of advanced prostate cancer treatment. In this review, we assessed the efficacy, safety, and convenience of administration of various GnRH-A. All GnRH-A (goserelin, triptorelin, buserelin, histrelin, and leuprorelin) have comparable potential to suppress testosterone (T) levels (≤50 ng/dL in a month and ≤20 ng/dL in 3 months). However, goserelin has shown better efficacy in maintaining T levels ≤50 ng/dL compared with leuprolide. The incidences of T escape are lower with goserelin and leuprolide than buserelin. Goserelin also has maximum benefit in prostate-specific antigen suppression. In neoadjuvant setting, when only goserelin was used, the 10-year overall survival (OS) rate was 42.6% to 86%. When either goserelin or leuprolide was used, the 10-year OS rate was 62%. As an adjuvant to radical prostatectomy, goserelin had a 10-year survival rate of 87%, and triptorelin had an 8-year survival rate of 84.6%. Goserelin further showed an absolute survival rate of 49% when used as an adjuvant to radiotherapy. The survival rates further improved when GnRH-A are used as combined androgen blockade compared with monotherapy. The frequency and severity of adverse events (hot flushes, fatigue, sexual dysfunction) are comparable among the GnRH-A. Goserelin appears to be the most convenient of all the GnRH-A for administration. Lack of conclusive comparative evidence makes it imperative to have a holistic approach of considering the patient profile and the disease characteristics to select the appropriate GnRH-A for ADT in prostate cancer.

Luteinizing hormone–releasing hormone agonist (LHRH-A), goserelin, and antagonist, degarelix, are both indicated for the treatment of advanced prostate cancer (PCa); however, large comparative trials evaluating their efficacy and safety are lacking. In this review, we assessed the available evidence for both the drugs. Although degarelix achieves an early rapid decline in testosterone (T) and prostate-specific antigen (PSA) levels, median T and PSA levels, in addition to prostate volume and International Prostate Symptom Scores, become comparable with goserelin over the remaining treatment period. Degarelix causes no initial flare, therefore it is recommended in patients with spinal metastases or ureteric obstruction. Goserelin achieves lower PSA, improved time to progression, and better survival outcomes when administered adjunctively to radiotherapy compared with radiotherapy alone, with significant results even over long-term follow-up. The evidence supporting adjuvant degarelix use is limited. Goserelin has better injection site safety, single-step delivery, and an efficient administration schedule compared with degarelix, which has significantly higher injection site reactions and less efficient administration mechanism. There is conflicting evidence about the risk of cardiovascular disease (CVD), and caution is required when using LHRH-A in patients with preexisting CVD. There is considerable long-term evidence for goserelin in patients with advanced PCa, with degarelix being a more recent option. The available comparative evidence of goserelin versus degarelix has several inherent limitations related to study design, sample size, conduct, and statistical analyses, and hence warrants robust prospective trials and long-term follow-up.