|Year : 2019 | Volume
| Issue : 5 | Page : 23-30
Molecularly targeted therapies in non-small cell lung cancer: The evolving role of tyrosine kinase inhibitors
DC Doval1, CJ Desai2, TP Sahoo3
1 Department of Medical Oncology/Hemato-Oncology Chair Medical Oncology and Chief of Breast and Thoracic Services, Rajiv Gandhi Cancer Institute, New Delhi, India
2 Consultant Oncologist and Director, Hemato Oncology Clinic, Vendanta Institute of Medical Sciences, Ahmadabad, Gujarat, India
3 Consultant Medical Oncologist, Silverline Hospital, Bhopal, Madhya Pradesh, India
|Date of Web Publication||29-Nov-2019|
D C Doval
Department of Medical Oncology/Hemato-Oncology Chair Medical Oncology and Chief of Breast and Thoracic Services, Rajiv Gandhi Cancer Institute, New Delhi
Source of Support: None, Conflict of Interest: None
Non-small cell lung cancer (NSCLC) is a major subtype of lung cancer. Patients with NSCLC are diagnosed at a locally advanced or metastatic stage where prognosis with palliative chemotherapy is poor. The discovery of epidermal growth factor receptor (EGFR) mutations has revolutionized cancer treatment for NSCLC by promoting the development of molecularly targeted therapies like tyrosine kinase inhibitors (TKIs). This review summarizes the clinical efficacy and tolerability of EGFR-TKIs, including osimertinib, in EGFR-mutated advanced NSCLC. EGFR-TKIs have demonstrated superior response and overall survival rates compared with chemotherapy in EGFR-mutated NSCLC. However, despite the initial rapid and durable clinical responses, acquired resistance to first- and second-generation TKIs eventually develops in most cases, with disease progression observed mostly within 12 months of treatment initiation. Osimertinib, a potent third-generation TKI, irreversibly inhibits mutated EGFR alleles, including T790M. In addition to longer survival and higher response rate, osimertinib has a favorable safety profile with a lower incidence of grade ≥3 treatment-related adverse events compared with other TKIs. Based on the efficacy and safety results, recently the National Comprehensive Cancer Network (NCCN) has included osimertinib as the “preferred first-line of treatment” in patients with metastatic EGFR mutationpositive NSCLC. Thus, osimertinib as first-line therapy for EGFRpositive patients irrespective of the T790M mutation status could be an ideal choice in the Indian setting where only 50% of patients opt for any second-line therapy after first-line failure.
Keywords: Epidermal growth factor receptor, non-small cell lung cancer, osimertinib, tyrosine kinase inhibitors
|How to cite this article:|
Doval D C, Desai C J, Sahoo T P. Molecularly targeted therapies in non-small cell lung cancer: The evolving role of tyrosine kinase inhibitors. Indian J Cancer 2019;56, Suppl S1:23-30
|How to cite this URL:|
Doval D C, Desai C J, Sahoo T P. Molecularly targeted therapies in non-small cell lung cancer: The evolving role of tyrosine kinase inhibitors. Indian J Cancer [serial online] 2019 [cited 2021 May 12];56, Suppl S1:23-30. Available from: https://www.indianjcancer.com/text.asp?2019/56/5/23/272013
| » Introduction|| |
Lung cancer is a leading cause of cancer-related mortality worldwide accounting for 18% (1.6 million) of all cancer-related deaths., In the Indian population, lung cancer is one of the most common cancers with incidence of 2-45 patients per 100,000 individuals.
Non-small cell lung carcinoma (NSCLC) is the major type of lung cancer.,, Most patients with NSCLC are diagnosed at a locally advanced or metastatic stage where prognosis with palliative chemotherapy is poor., This review discusses the role of epidermal growth factor receptor (EGFR)-based tyrosine kinase inhibitors (TKIs) for targeted treatment in NSCLC patients.
| » Discovery of Epidermal Growth Factor Receptor Sequence and Its Mutations|| |
Chromosomal rearrangements and gene mutations contribute to the constant activation of kinases, which play a critical role in carcinogenesis. Cancer cells depend on mutated genes for maintenance and survival; thereby, oncogene-targeting agents can inhibit cell growth and might even induce cell apoptosis. The existence of the EGFR family was first reported in 1975 and the sequence for EGFR was found in the 1980s. The discovery of EGFR sequence and its role led to the development of targeted therapies for cancer treatment. EGFR is a transmembrane receptor belonging to the family of tyrosine kinase receptors, which includes erbB1 (EGFR), erbB2 (HER2), erbB3, and erbB4. It is expressed in cells of epidermal, mesenchymal, and neurogenic origin. EGFR promotes tumor growth and progression by enhancing various functions including proliferation, survival, invasion, or immune evasion. After binding to a specific ligand, the normally functioning EGFR undergoes a structural change activating pathways that causes cell proliferation or cell maintenance by inhibition of cell death.
Overexpression of EGFR or mutations in the intracellular domain of EGFR has been implicated in several solid tumors, including NSCLC. In the past decade, the introduction of EGFR-based targeted therapies has radically affected lung cancer management with survival benefits in patients with metastatic NSCLC.,,,
| » EGFR Mutations in NSCLC|| |
Approximately 43-89% of patients with lung cancer exhibit overexpression of EGFR (75% of cases) or EGFR mutations (25% of cases). Most of these mutations occur in exon 19 or as point mutations in exon 21, the latter resulting in arginine replacing leucine at codon 858 (L858R). Other less common mutations are at exons 18 and 21.,,
The incidence of EGFR mutation differs by ethnicity, with 10-23% of adenocarcinomas in whites being driven by activating EGFR mutations, compared with 40-50% of adenocarcinomas in Asians.,,,, The frequency of EGFR mutations is mentioned in [Table 1]. The overall prevalence of EGFR mutations in NSCLC patient subgroups across different countries was 32.3% [95% confidence interval (CI): 30.9-33.7%] ranging from 14.1% (95% CI: 12.7-15.5%) in Europe to 38.4% (95% CI: 36.5-40.3%) in China.
|Table 1: Frequency of EGFR Mutations in Different NSCLC Patient Subgroups|
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The incidence of EGFR mutations is much higher in the Indian population than in whites and is closer to the incidence observed in East Asian countries. The EGFR mutation frequency in NSCLC of adenocarcinoma histology between Indian men and women was 23% and 32%, respectively. Geographically, there is uniform distribution in the EGFR mutation frequency within India. Furthermore, although exon 19 mutations are predominant among nonsmokers, higher incidence of exon 21 mutations exists among EGFR mutation-positive male smokers of Indian ethnicity than in whites.,,, Numerous clinical parameters that are associated with a high response rate to EGFR-TKIs and a relatively favorable prognosis including adenocarcinoma histology, women, nonsmokers, and Asian ethnicity. Subsequent studies showed that these clinical parameters are surrogates for the presence of specific activating mutations in the tyrosine kinase domain of the EGFR (exon 19 deletions, L858R point mutation in exon 21).
| » Development of EGFR-TKIs for NSCLC|| |
In earlier clinical trials with first-generation TKIs, gefitinib in unselected patients with NSCLC showed no overall survival (OS) benefit; however, there was a significant survival advantage in a subgroup of Asian nonsmokers with adenocarcinomas. This finding led to the discovery that tumors with activating mutations in exons 18-21 respond to EGFR-TKI therapy. Gefitinib and erlotinib were developed as the first-line EGFR-TKIs for the treatment of EGFR-mutated NSCLC. They bind reversibly to the EGFR extracellular domain to yield a durable response to provide better progression-free survival (PFS) and no OS benefit compared with chemotherapy with better quality of life. The second-generation EGFR-TKIs afatinib and dacomitinib bind irreversibly to the EGFR domain. Several first-line phase III studies on comparing first-generation (gefitinib, erlotinib) with second-generation (afatinib, dacomitinib) EGFR-TKIs showed objective response rate (ORR) and PFS to be 60-70% and 9-15 months, respectively. Development of osimertinib, a third-generation EGFR-TKI, was through targeted chemistry for irreversible binding to the common mutations of EGFR. [Table 2] mentions the approval status of various EGFR-TKIs for the treatment of EGFR-mutant NSCLC.
|Table 2: EGFR-TKIs with Approval Status for the Treatment of EGFR-mutant NSCLC|
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| » First- and Second-Generation EGFR-TKIs|| |
The superiority of EGFR-TKIs over chemotherapy has been demonstrated in several phase III trials [Table 3] in EGFR-mutated NSCLC in the first-line setting in terms of ORR and PFS, but not in OS. Erlotinib was the first EGFR-TKI to be approved by the Food and Drug Administration (FDA) for NSCLC as a secondline therapy after progression on the firstline platinumbased therapy based on a Canadian BR21 study, which compared the efficacy and safety of erlotinib versus placebo in patients with stage III or IV NSCLC. Compared with patients in the placebo group, those in the erlotinib group had a higher response rate, OS, and PFS. The first-line approval of erlotinib for treatment of NSCLC was based on results of EURTAC trial in patients with advanced EGFR mutation., Based on the results of the IPASS study, gefitinib, another first-generation EGFRTKI, was approved in 2009 by the European Medicines Agency (EMA) as firstline treatment for the treatment of adult patients with locally advanced or metastatic, EGFR-mutated NSCLC. Favorable results from a landmark phase IV study evaluating the effectiveness and tolerability of gefitinib in NSCLC patients with EGFR mutation established the role of gefitinib as first-line treatment in such cases. The mean OS and PFS in this study were 19.2 and 9.7 months, respectively. In a phase 2b, open-label, randomized controlled trial, afatinib showed a significant PFS benefit versus gefitinib where the median PFS was 11.0 months versus 10.9 months (HR 0.73, P = 0.017) but failed to show an OS benefit.
|Table 3: Phase III Trials Showing Superiority of EGFR-TKIs Over First-line Chemotherapy in EGFR-mutated NSCLC Patients|
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Safety and dose reductions
Drug tolerability is an issue with first- and second-generation TKIs. The most commonly observed adverse events (AEs) with TKIs are cutaneous AEs like skin rash and dermatitis and gastrointestinal AEs like diarrhea and stomatitis. AEs observed in clinical studies with first- and second-generation TKIs are summarized in [Table 4]. Dose reduction is usually required for first- and second-generation TKIs in patients with toxicity, poor performance status, or low body surface area. A recent meta-analysis reported that compared with erlotinib, gefitinib was associated with more grade 3/4 liver dysfunction, but it tended to cause lower rates of dose reduction, treatment discontinuation, total grade 3/4 AEs [relative risk (RR), 0.78; 95% CI: 0.65-0.94]. The rate of grade 3/4 AEs with afatinib was comparable to that with erlotinib but higher than that with gefitinib. However, the dose adjustment protocol for afatinib in case of treatment-related AEs does not report any effect on efficacy.
| » Drug Resistance To first- and Second-Generation TKIs|| |
Despite being a first-line therapy option for patients with EGFR-mutated NSCLC, acquired resistance to TKIs usually develops within 12 months of treatment. Drug resistance to EGFR-TKIs has been reported through the following mechanisms: development of acquired resistance, activation of bypass pathways, activation of downstream pathways, and histologic transformation [Figure 1]. Secondary or acquired resistance to treatment with EGFR-TKIs is defined as progression of disease while on continuous treatment. This type of resistance develops after 9-14 months of therapy. The most common mechanism of acquired resistance is T790M mutation, or the “gatekeeper” mutation. This accounts for 40-55% of all cases and is a result of substitution of threonine with methionine at amino acid position 790, which leads to increase in the affinity of receptors for adenosine triphosphate (ATP), such as the wild-type EGFRs, rendering first- and second-generation EGFR-TKIs ineffective. Other rare EGFR mutations involve L747S, D761Y, and T854A. Another reason for resistance is EGFR amplification, which occurs in almost 10% of cases.,,,,,
|Figure 1: Mechanisms of acquired resistance to first- and second-generation EGFR-TKIs. Frequencies (given in parentheses) are approximations|
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Activation of bypass mechanisms is another mechanism of resistance to EGFR-TKIs. EGFR tyrosine kinases rely upon RAS/Raf/MEK/ERK and PI3K/AKT/mTOR signal transduction pathways for further cellular activities. In bypass resistance, mesenchymalepithelial transition factor (MET) amplification is observed in almost 5% of cases and human epidermal growth factor receptor 2 (HER2) amplifications are observed in 8-13% of cases. Mutations in downstream pathways such as BRAF mutations, mitogen-activated protein kinase 1 amplifications, phosphoinositide-3-kinase, catalytic, alpha polypeptide-activating mutations, and loss or decrease of phosphatase and tensin homolog have been implicated in 5-10% of cases of EGFR mutations. Another important pathway for resistance is transformation of NSCLC to SCLC, which is observed in approximately 10% of cases. This results in decrease in EGFR expression and thus renders EGFR-TKIs ineffective.,
Patients with EGFR mutations are reported to have a higher prevalence of central nervous system (CNS) metastasis than patients without EGFR mutations. Approximately 30% of patients with NSCLC develop CNS metastasis after systemic therapy with TKIs, thereby reducing the therapy's effectiveness. Demographically, the prevalence of CNS metastases in patients with NSCLC is higher in Asians (39-63%) than in whites (2-40%). However, the prevalence of acquired resistance especially the T790M mutation is lower in metastasized tissue than in the primary site presumably because of lower penetration of first- and second-generation EGFR-TKIs. Poor bioavailability of first- and second-generation EGFR-TKIs in the brain contributes further to the emergence of resistance and thus restricts their efficacy in patients with CNS metastases.,,,
| » Confronting Drug Resistance and Development of Third-Generation Tkis|| |
Gefitinib and erlotinib are ineffective against the acquired T790M EGFR mutation, which has been observed in 50-60% of patients with mutant NSCLC. Three third-generation EGFRTKIs (rociletinib, olmutinib, and osimertinib) were identified to overcome the drug resistance mechanisms. However, the clinical development of rociletinib (CO-1686) was terminated due to lower than expected efficacy in the pooled analysis of all the phase I/II clinical studies on rociletinib., Olmutinib (HM61713) was also suspended due to three cases of severe skin toxicity, including two reports of toxic epidermal necrolysis (one fatal), and one case of non-fatal Stevens–Johnson syndrome. The third novel TKI is osimertinib that covalently and irreversibly binds to the cysteine 797 residue in the ATP binding site rendering activity against mutated EGFR alleles, including T790M, L858R, and ex19del.,
| » Efficacy and Safety of Osimertinib|| |
The clinical program of osimertinib included AURA and FLAURA studies. The clinical development and results of AURA and FLAURA studies are shown in [Figure 2] and [Table 5], respectively. The AURA study was composed of AURA phase I, AURA extension phase, AURA2, and AURA3 studies. The AURA extension phase and AURA 2 were phase II, openlabel, multicenter studies to assess the efficacy and safety of osimertinib in patients with locally advanced/metastatic NSCLC who have progressed following prior therapy with an EGFR-TKI therapy and with EGFR- and T790M mutation-positive tumors. Pooled analysis of AURA extension phase and AURA2 studies showed the ORR to be 66% (95% CI: 61-71%) and a PFS of 11 months. The OS in pooled analysis was 26.8 months (95% CI: 24.2-not calculated)., The AURA 3 study, a randomized, international, phase 3 trial reported a significantly longer PFS with osimertinib than with platinum therapy plus pemetrexed [10.1 vs. 4.4 months; hazard ratio (HR), 0.30; 95% CI: 0.23-0.41; P < 0.001] as well as a significantly better response rate in patients with T790M-positive advanced NSCLC. Additionally, the median duration of PFS per a blinded independent central review (BICR) was longer (11 months vs. 4.2 months; HR, 0.28; 95% CI: 0.20-0.38) for patient who received osimertinib than for patients who received platinum therapy plus pemetrexed. The ORR was significantly better with osimertinib than with platinum therapy plus pemetrexed (71% vs. 31%, 95% CI: 24-40; P < 0.001). In a subset of patients with CNS metastases, the PFS was significantly longer (8.5 months vs. 4.2 months, respectively; HR = 0.32; 95% CI: 0.21-0.49) and the ORR was higher [70% vs. 31%; odds ratio (OR) = 5.13; 95% CI: 1.44-20.64; P = 0.015] in the osimertinib group than in the platinum plus pemetrexed treatment group. On the basis of positive results from the AURA clinical program, osimertinib was approved worldwide for the treatment of patients with metastatic T790M-positive NSCLC who have disease progression during or after EGFR-TKI therapy.,,
Ramalingam et al. (2017) studied two EGFR-naïve cohorts in the AURA studies who were treated with osimertinib. Osimertinib demonstrated a significantly higher ORR (77%) and prolonged PFS (20.5 months) in treatment-naïve patients with EGFR mutationpositive advanced NSCLC. There was no evidence of the acquired EGFR T790M mutation in post-progression plasma samples., The phase 3 FLAURA trial was designed to assess the efficacy and safety of osimertinib versus gefitinib/erlotinib as the first-line treatment in patients with previously untreated EGFR mutation-positive advanced NSCLC. Osimertinib treatment resulted in significantly longer PFS than treatment with comparator (18.9 months vs. 10.2 months, respectively; HR = 0.46; 95% CI: 0.37-0.57; P < 0.001). The median duration of response was significantly higher in the osimertinib group than in the standard TKI group (17.2 months vs. 8.5 months, respectively). Despite a longer median duration of exposure with osimertinib, the safety profile of osimertinib was similar to that of standard EGFR-TKIs, but with relatively lower rates of grade ≥3 AEs. Based on the results of FLAURA and AURA first-line cohorts, the FDA and EMA have approved osimertinib as the first line of treatment in patients with metastatic EGFR mutation-positive NSCLC in 2018.
CNS efficacy in the FLAURA study demonstrated a nominal statistically significant improvement in CNS PFS (HR = 0.48; 95% CI: 0.26-0.86; P = 0.014). In another phase I trial (BLOOM) in patients with EGFR-mutated advanced NSCLC and leptomeningeal metastases, a confirmed intracranial response was observed in seven patients: two patients had a confirmed cerebrospinal fluid cytology clearance and five patients had neurological improvement.
Patient-reported outcomes of quality of life have become an important parameter in evaluating the efficacy of therapy, especially for conditions that require long-term care, such as cancer. Patient-reported parameters have been evaluated in the AURA3 and FLAURA studies. In both studies, there was significant improvement in global health/quality of life scores of the patients on osimertinib therapy. Specifically, there was improvement on parameters of cough, dyspnea, chest pain, appetite loss, and fatigue during the therapy., Patients with brain metastases usually show poor prognosis with EGFR-TKIs. Administration of osimertinib as first- or second-line treatment showed better outcomes and reduced frequency of CNS progression of disease than administration of other EGFR-TKIs did. The data on OS of patients in FLUARA are based on the interim analysis. However, the potential survival benefit of osimertinib as first-line treatment in NSCLC patients with EGFR mutations is encouraging.
| » Emerging Real-World Evidence for Osimertinib|| |
Real-world evidence studies have gained importance in ascertaining the effectiveness of treatment in the general population. The data for effectiveness of osimertinib available from three real-world studies are encouraging, although osimertinib is mostly used as a second-line therapy. The preliminary results of ASTRIS study in T790M-positive NSCLC with >1,200 patients showed an investigator-assessed response rate of 64% (95% CI: 61-67%), which is comparable to the rate in clinical trial results., Another study from Austria reported a clear clinical and radiographic response in 85% of patients, of which 17% of patients reached complete remission and 68% of patients showed partial response after treatment with osimertinib after disease progression on EGFR-TKIs. No new safety signals were identified during these studies, indicating a good safety profile of osimertinib in a real-world setting as well. In another real-world study, the CNS efficacy of osimertinib was comparable to that previously documented clinical study findings (ORR was 70% with no isolated CNS progression). In Indian studies, osimertinib has shown a similar efficacy profile with an ORR of approximately 71% and better CNS penetration compared with other EGFR-TKIs. The safety profile of osimertinib was also comparable in these studies.,
The National Comprehensive Cancer Network (NCCN) recommends testing for EGFR mutations at presentation of NSCLC either with biopsy or with alternative sources, such as plasma (ctDNA) and urine, particularly when tumor tissue is not available., With increase in the sensitivity of mutation testing, T790M mutations can be detected in up to 79% of tumor biopsies before start of EGFR-TKI therapy. Testing for the T790M mutation can be performed at the presentation of the disease to circumvent the need for rebiopsy at progression. If the T790M mutation is detected at presentation, osimertinib can be used as a first-line therapy.
| » Incorporating Osimertinib as A first-Line Option in the Clinic|| |
Data from phase 3 trials and real-world evidence show that only one-third to one-half of patients with NSCLC actually opt for any second-line therapy. Given the higher mortality rates expected in such cases, it is important to take away the uncertainty of the patient actually harboring the T790M mutation especially in countries such as India. Thus, administering osimertinib as a first-line therapy may be the ideal choice for EGFR-mutated NSCLC because of the drug's predictable and durable efficacy. This is evidenced by the FLAURA study interim findings in which EGFR-TKI-naïve patients treated with osimertinib had better PFS and RR over first-generation EGFR-TKI in the first-line setting. The 2019 NCCN guidelines for patients also enlist osimertinib as the preferred firstline of treatment for EGFR mutation-positive metastatic NSCLC.
Results in an Asian subset of patients with EGFR-madvanced NSCLC were consistent with the overall results of the FLAURA study. Moving osimertinib to a first-line therapy in Indian scenario might be better suited for addressing the challenges in lung cancer therapy.
| » Countering Newer Resistance Mechanisms: Combination Therapy or Fourth-Generation TKIs|| |
Although third-generation EGFR-TKIs are highly effective, resistance eventually develops. In case of osimertinib when used as a second-line therapy, patients are likely to develop resistance and disease progression after 10 months. The development of resistance may be due to EGFR-dependent or EGFR-independent resistance mechanisms. In EGFR-dependent mechanisms, C797S mutations have been commonly observed in almost 25% of cases. Other forms of EGFR mutations include L718Q, L844V, and C979G. Amplification of EGFR ex19del and wild-type EGFR and loss of EGFR T790M was observed in osimertinib-resistant patients. A comprehensive study of mutation profiles of a large cohort of osimertinib-resistant lung cancer patients identified C797 mutations and novel secondary mutations of EGFR L718 and L792 residues that confer osimertinib resistance, bothin vitro and in vivo. EGFR-independent mutations include HER2 and MET amplification and increased dependence on RAS signaling.,, The analysis of resistance mechanisms to osimertinib in the AURA3 and FLAURA trials were recently presented in ESMO 2018. The major mechanism of resistance to osimertinib were MET amplification (19% and 15%), EGFR C797S mutation (15% and 7%), and other mutations like HER2 amp, PIK3CA, and RAS mutations (9% and 2-7%).,
Resistance to third-generation EGFR-TKIs has prompted the development of fourth-generation EGFR-TKIs. Another strategy is using an effective combination of clinically approved drugs, which might overcome resistance to irreversible TKIs in clinical settings. The studies identified a combination of three clinically approved drugs, cetuximab, trastuzumab (an anti-HER2 monoclonal antibody), and osimertinib (low dose), as an effective and long-lasting treatment, which may prevent the onset of resistance to osimertinib. A continuous schedule of concurrent treatment was sufficient for effective tumor inhibition and prevention of relapses.
More recent findings from a clinical study emphasize the usefulness of first- and third-generation EGFR-TKI combinations and mention that this upfront combinational therapy will be effective in suppressing both C797S and T790M mutations during EGFR-TKI treatment. According to the study, compared with afatinib (a second-generation EGFR-TKI), gefitinib might be a preferable second-line option to C797S/activating mutation emerging after first-line osimertinib treatment in patients with NSCLC.
A meta-analysis of efficacy endpoints from various clinical studies revealed that a combination of radiotherapy with EGFR-TKIs provided better outcomes in terms of RR, OS, and PFS in NSCLC patients with CNS metastases with a tolerable safety profile. In a subgroup analysis, an Asian population with EGFR mutation adenocarcinoma had better prognosis with this treatment. In another meta-analysis, second-line pemetrexed chemotherapeutic regimens provided significantly longer PFS and OS than non-pemetrexed chemotherapeutic regimens after failure with EGFR-TKI treatment.
| » Conclusion|| |
In addition to longer PFS and higher response rate, osimertinib has a favorable safety profile, with a lower incidence of grade ≥3 treatment-related AEs compared with other TKIs in EGFR mutation-positive NSCLC. With recent evidence, selecting osimertinib as a first-line treatment option would help clinicians provide their patients the most effective and safe therapeutic option, without undergoing risk of serious toxicities and mortality associated with other regimens in a timely manner.
The authors thank AstraZeneca Pharma India Ltd for providing medical writing assistance in the development of this manuscript, in collaboration with Sciformix Technologies Pvt. Ltd.
Financial support and sponsorship
Financial support to authors - Nil.
The supplement issue in which this article has been published has been sponsored by AstraZeneca Pharma India Ltd.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]