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  In this article
 »  Abstract
 » Introduction
 » Methods
 »  Expert Opinions ...
 » Conclusions
 »  References

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  Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 54  |  Issue : 5  |  Page : 31-36
 

Advanced therapeutic options and importance of rebiopsy in epidermal growth factor receptor-tyrosine kinase inhibitor-progressed nonsmall cell lung carcinoma patients: An expert opinion


1 Director, Medical Oncology, Jaslok Hospital & Research centre, Mumbai, India
2 Professor of Medicine and Head Division of Medical Oncology, Birla Cancer Centre, SMS Medical College & Hospital, Jaipur, India
3 Professor, Department of Medical Oncology Christian Medical College & Hospital Vellore, Tamil Nadu, India
4 Consultant, Medical Oncology, Jaslok Hospital and Research Centre, Mumbai, India
5 Professor & Head, Department of Medical Oncology, Amrita Institute of Medical Sciences and Research Center, Cochi, India
6 Consultant, Medical Oncology, Apollo Gleneagles Hospital, Kolkata, India
7 Chief Coordinator-Oncology Services, Medica Super Specialty Hospital, Kolkata, India
8 Assistant Professor, Department of Medicine, Chirayu Medical College & Hospital, Bhopal, India
9 Consultant Oncologist, Department of Oncology and Haematology, Apollo Hospitals International Limited, Ahmedabad, Gujarat, India

Date of Web Publication29-Dec-2017

Correspondence Address:
Dr. Suresh H Advani
Director, Medical Oncology, Jaslok Hospital & Research centre, Mumbai,
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_520_17

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 » Abstract 


Advanced nonsmall cell lung cancer (NSCLC) treatment is primarily based on platinum-based chemotherapy. Although epidermal growth factor receptor (EGFR) targeting has shifted the treatment paradigm toward personalized tyrosine kinase inhibitors (TKIs), resistance develops inevitably and EGFR T790M is the most common acquired resistance mechanism. Rebiopsy of resistant NSCLC cases can provide additional information on the underlying resistant mechanisms and therefore can help clinicians in taking better management decisions. An expert panel meeting of renowned cancer oncologists was held to discuss the management of advanced-stage NSCLC. The present paper is based on the recommendations made by the expert panel and is supported by an exhaustive literature search. It was suggested that identification of driver mutation leads to better treatment decisions. TKIs have proven to be better treatment option in EGFR-positive patients as compared to chemotherapy. Third-generation TKIs (osimertinib) promise to bring optimal and improved care for NSCLC cases failing first-line TKI treatment.


Keywords: Nonsmall cell lung cancer, nonsmall cell lung cancer, epidermal growth factor receptor, tyrosine kinase inhibitor, osimertinib, rebiopsy, T790M, drug resistance


How to cite this article:
Advani SH, Malhotra H, Chacko RT, Basade M, Keechilat P, Mahapatra P N, Goswami C, Sahoo T P, Shah C. Advanced therapeutic options and importance of rebiopsy in epidermal growth factor receptor-tyrosine kinase inhibitor-progressed nonsmall cell lung carcinoma patients: An expert opinion. Indian J Cancer 2017;54, Suppl S1:31-6

How to cite this URL:
Advani SH, Malhotra H, Chacko RT, Basade M, Keechilat P, Mahapatra P N, Goswami C, Sahoo T P, Shah C. Advanced therapeutic options and importance of rebiopsy in epidermal growth factor receptor-tyrosine kinase inhibitor-progressed nonsmall cell lung carcinoma patients: An expert opinion. Indian J Cancer [serial online] 2017 [cited 2020 Jul 5];54, Suppl S1:31-6. Available from: http://www.indianjcancer.com/text.asp?2017/54/5/31/221923





 » Introduction Top


The worldwide incidence of lung cancer is estimated to be 224,390 in the year 2016. It was also reported to be the leading cause of cancer-related deaths with an estimated number of 1.69 million deaths in 2015.[1],[2] Nonsmall cell lung cancer (NSCLC) represents 85% of all lung cancer with an overall 5-year survival of 16%–20%.[1],[2],[3] Majority of the cancer patients are diagnosed at advanced stages, and treatment is directed toward delaying the progression, improving symptoms and quality of life, and extending life.[4],[5]

Surgical resection is the most successful treatment option for early-stage lung cancer but shows a high risk of relapse. With 70% of cases presenting as advanced and metastatic disease, chemotherapy has traditionally been the treatment of choice in patients with a good performance status (PS) who can tolerate the proposed surgical intervention. Although platinum (cisplatin and carboplatin)-based doublet chemotherapy with paclitaxel or docetaxel or gemcitabine is universally accepted, these therapies are associated with considerable toxicities with only marginal improvement in the survival rate.[6]

Among Asian population, about 30–40% of all NSCLC cases harbor mutations in epidermal growth factor receptor (EGFR) and TK domain (exon 19 deletions and exon 21 L858R substitution). Aberrant EGFR signaling, which can be attributed to gene mutation, increased gene-copy number and EGFR protein overexpression has been implicated in the pathogenesis of NSCLC and is associated with poor prognosis.[1],[7] EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib, and afatinib have demonstrated superior objective response rate (ORR), progression-free survival (PFS), and improved quality of life in various trials for NSCLC when compared to standard chemotherapeutic regimens.[8],[9],[10] Thus, targeting molecular pathways is a promising arena for personalized treatment of NSCLC patients.[11] However, despite initial treatment response and improved PFS, ORR, and quality of life with EGFR-TKIs, most patients show tumor progression and face the challenge of drug resistance.[12],[13],[14]

EGFR-TKI resistance can be primary or secondary in nature. De novo/primary resistance (i.e., lack of an initial response to therapy) to EGFR-TKI is approximately seen in 30% of NSCLC patients with an EGFR-activating mutation while tumor regression occurs in approximately 70% of the patients. Primary resistance results from drug-resistant EGFR mutations (exon 20 deletion/duplication, germline EGFR T790M mutation, and D761Y-EGFR mutation) and other genetic alterations that lead to increased phosphatidylinositol-3-kinase (PI3K), nuclear factor kappa B, and insulin-like growth factor 1 receptor (IGF1R) signaling which eventually promotes cancer cell survival. Among 70% of the initial responders, majority of EGFR-TKI recipients develop acquired resistance after a median of 10–14 months on therapy. This result primarily from different second-site mutations such as EGFR-T790M, exon 21 T854A mutation, exon 19 L747S mutation, and exon 19 D761Y mutation. Moreover, other mutations such as proto-oncogene MET amplification and epithelial mesenchymal transition. can also lead to EGFR-TKI resistance in NSCLC patients.[15],[16]

Locked nucleic acid/polymerase chain reaction/sequencing assay has revealed that approximately 68% of acquired resistance to first-generation TKIs is due to T790M.[17] In rebiopsy specimens, almost 51% of the resistant cases are reported to harbor T790M mutation.[18] EGFR-T790M not only provides resistance to EGFR-TKIs but also confers growth advantage to cancer cells.[19] The frequency of EGFR-T790M has been reported to vary from 1% to 35% at baseline, and minor subclones (<1%) are rarely identified in untreated patients.[20] Although prognostic significance of baseline EGFR-T790M has not been reported, its presence indicates favorable prognosis in patients with acquired resistance when compared to patients without the mutation after TKI failure.[18],[19],[20] Rebiopsy of resistant NSCLC cases can provide information on the underlying resistant mechanisms and can help in better management decisions.[21]

Management of NSCLC is expanding its horizon with recent progress in actionable biomarker-directed precision therapy and advanced multiplexed noninterventional clinical testing, both at initial diagnosis and disease progression. European Society for Medical Oncology currently recommends chemotherapy, immunotherapy (biologics), and TKIs (both first and second generation) for the management of NSCLC patients.[22] Even in a very few cases, a combination of chemotherapy and TKIs has been shown to be a viable first-line option for selected patients with unknown EGFR mutation status.[23] A third-generation TKI, osimertinib targeting EGFR T790M, L858R, and exon 19 deletion have been approved by Food and Drug Administration (FDA) for metastatic NSCLC patients.[24] Thus, repeat biopsies identifying dynamic alterations in plasma EGFR status and expanding treatment options with novel third-generation TKIs are beginning to play a greater role in multidisciplinary patient management.[25]

The present paper, thus, aims to provide an expert panel review on the upfront treatment of EGFR-TKI-progressed NSCLC patients with targeted therapy, current available therapeutic options, need for repeat biopsies, and use of third-generation TKIs in managing this unique subgroup of lung cancer patients.


 » Methods Top


Two separate expert panel meetings were organized by AstraZeneca in the month of May and September 2016 which led to the conception of the present manuscript. Twenty panel members comprising of Indian medical oncologists and clinical pathologists were involved in this report making. Experts were convened to review the current therapeutic options and management gaps in EGFR-TKI-progressed NSCLC patients. Based on the expert committee discussion and available literature review, the present report was formulated and distributed among the expert panel members. The members were requested to revert with their individual comments within a month following which all the concerns and comments were addressed by the writing group and the report was finalized.

Literature search and selection criteria

This report was formulated after critical analysis and discussion by the expert panel members. This was supported by an exhaustive literature search in PubMed from where relevant articles were analyzed and selected for the preparation of the present manuscript. The search terms were “NSCLC,” “NSCLC,” “T790M,” “rebiopsy,” “tyrosine kinase inhibitors,” “TKIs,” “gefitinib,” “afatinib,” “erlotinib,” “third-generation TKIs,” and “osimertinib” in combination with the Boolean operators “AND/OR.” Only the studies published after the year 2005 and conducted in human subjects were considered for this report. In total, 59 research articles, systematic reviews, or meta-analyses were used for the preparation of the manuscript.

The recommendations from the experts are presented regarding clinical guidelines and research priorities such as repeat biopsies at disease progression, upfront treatment with precision therapy, and use of promising third-generation TKIs in NSCLC patients showing resistance to first- and second-generation TKIs.


 » Expert Opinions and Rationale Top


  1. Identification of oncogenic driver mutation makes personalized treatment strategies more feasible in EGFR mutation-positive NSCLC patients.


  2. Recommendation

    The panelists discussed that although T790M is the main driver mutation in maximum number of NSCLC patients and is the reason behind acquired resistance, sensitive tests such as next-generation sequencing and liquid biopsy detect more than one mutation at the same time making it difficult to identify the causal driver mutation. An improved understanding of the underlying molecular pathway would lead to the development of better therapeutics targeting the causal driver mutation specifically and eventually bringing better treatment outcomes. The experts recommended that with newer sensitive methods coming into practice, testing for driver mutations in other genes apart from EGFR like anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1), and MET can be done. This will lead to more specific targeted therapeutic options ensuring improved clinical prognosis.

    Rationale

    Driver mutations are generally found on signaling protein-coding genes crucial for cell survival and proliferation. These are transformative in nature, i.e., they bring malignant transformation of noncancerous cells.[26] These drivers provide growth advantage to cancer cells leading to tumor progression. In NSCLC patients, there are four common oncogenic driver mutations – EGFR mutations in exon 18 (G719X), exon 19 (in-frame deletion mutation), exon 20 (T790M), and exon 21 (L858R and L861X); KRAS gene mutation at codons 12 and 13; EML4-ALK fusion genes; and MET signaling dysregulation.[27] Driver mutations in ALK gene are associated with a higher risk of cancer metastasis, and NSCLC patients harboring these mutations do not respond to EGFTR-TKIs.[28],[29],[30] Gautschi et al. reported a case where the NSCLC patient was positive for V600E-BRAF mutation and responded to treatment with vemurafenib (BRAF enzyme inhibitor).[31] Thus, identifying targetable oncogenes in NSCLC can help in better management of the disease with improved patient outcomes.

    Treatment of advanced stage NSCLC should, therefore, be based on both histology and mutation profile. A combined approach would lead to better prediction of malignant behavior and an improved patient management with better-targeted therapeutics.[27]

  3. First-line targeted therapy with EGFR-TKIs is superior when compared with standard chemotherapy in EGFR-positive NSCLC patients.


  4. Recommendation

    Upfront treatment of NSCLC patients either with standard chemotherapy or targeted therapy has been in debate. Some of the panelists recommended first-line chemotherapy for treatment of NSCLC patients, irrespective of EGFR status. They mentioned that in India, chemotherapy is the most feasible option for upfront treatment of lung cancer patients, while targeted therapy requires a longer time-period due to molecular tests needed and a lot of patients are lost during follow-up. Other experts supported the upfront treatment of advanced stage NSCLC patients with precision therapy. They argued that targeted therapy is readily accepted by these advanced-stage cancer patients and looking at their improved quality of life, targeted therapies with TKIs should always be preferred. They even pointed toward an evidence-based study (iPASS study) which supports the use of TKI (gefitinib) when compared with standard chemotherapy.[32] However, the group of panelists also mentioned that there is a high chance of false-negative results for a driver mutation in the tumor sample (due to methodic limitations).

    Rationale

    Empirical chemotherapy with a platinum doublet is the gold standard for advanced stage NSCLC patients. A double-blind, phase III, randomized controlled trial was conducted in 539 advanced nonsquamous NSCLC patients who received either continuation maintenance therapy with pemetrexed after induction therapy with pemetrexed plus cisplatin (n = 359) or placebo with best supportive care (n = 180). The study showed a significant reduction in the risk of disease progression (P< 0·0001) and a higher median PFS in the treatment group when compared to placebo (4.1 vs. 2.1 months).[33] American Society of Clinical Oncology recommends chemotherapy for NSCLC patients who do not have a genetic mutation on either the EGFR or ALK gene but warrants withdrawal of the agent if the patient displays disease worsening even after four cycles of treatment.[34]

    Based on the patient's PS and health condition, drug combinations can also be used to improve their quality of life. A randomized clinical trial showed that NSCLC patients with Eastern Cooperative Oncology Group PS of 2 and receiving combination chemotherapy with carboplatin and paclitaxel had higher ORR (37% vs. 15%), longer time to disease progression (4.6 vs. 3.5 months), and improved median survival time (8.0 vs. 6.6 months) when compared to patients randomized to receive a single agent (either gemcitabine or vinorelbine).[35]

    Various studies have shown targeted therapy to be better in advanced stage NSCLC patients as compared to the conventional chemotherapy. In a multicenter phase 3 trial, 86 advanced EGFR mutation-positive NSCLC patients who received erlotinib showed improved PFS (9.7 vs. 5.2 months) and limited toxicities (severe adverse events 6% vs. 20%) when compared with 87 patients receiving standard chemotherapy (cisplatin and docetaxel).[36] Similarly, a phase III study with afatinib displayed prolonged PFS (13.6 months) in metastatic lung adenocarcinoma patients when compared to a combination chemotherapy with cisplatin and pemetrexed (6.9 months).[37]

    Furthermore, LUX-LUNG 7 trial, a prospective randomized phase IIb study, assessed the safety and efficacy of afatinib (40 mg once daily) versus gefitinib (250 mg once daily) in NSCLC patients and demonstrated that ORR was significantly higher in patients treated with afatinib compared to those given gefitinib (70% vs. 56%). Similarly, mean duration of response was also longer in afatinib group as compared to gefitinib (10.1 vs. 8.4 months). The data for overall survival (OS) among both groups of NSCLC patients were not mature when the primary analysis was conducted at a median follow-up of 27.3 months (current hazard rate: 0.87, 95% confidence interval: 0.66–1.15).[38],[39]

    Some studies even emphasize the benefit of using TKIs along with chemotherapy in improving patient outcomes. A randomized clinical trial showed that sequential combination of erlotinib and chemotherapy (gemcitabine and carboplatin) showed OS benefit in NSCLC patients when compared with patients receiving either EGFR-TKI or chemotherapy (29.7 months vs. 20.7 or 11.2 months respectively; P < 0.0001).[40]

    Further, a study by Barlesi et al. reported molecular analysis of 17,664 NSCLC patients where the frequency of identified mutations was EGFR (11%), HER2 (1%), KRAS (29%), BRAF (2%), PIK3CA (2%), and ALK (5%).[41] In general, driver mutations are identified through sequence capture, amplification, and alignment. However, technical limitation might let driver mutations go unnoticed, and false negative rate of detecting a driver mutation might be as high as 37%.[42] Even sometimes, mutation signals are diluted due to its location in noncoding region and presence of stromal cells.[43]

  5. Rebiopsy is necessary to determine the constantly evolving molecular profile of advanced-stage NSCLC patients, following which the course of subsequent treatments can be rationalized and initiated.


  6. Recommendation

    The experts mentioned that until now, rebiopsy in patients who progressed after first- and second-generation EGFR-TKIs is not very popular because advanced and approved treatment options targeting resistant mutations are not available in the market. However, with the advent of advanced treatment options, sequential rebiopsies would witness a logarithmic increase in demand with more patients opting for mutation profiling. They also agreed that noninterventional techniques such as liquid biopsy which can detect circulating tumor biomarkers and rapidly reveal actionable mutations could be an alternative to image-guided biopsies which are interventional in nature, time-consuming, and painful.

    Rationale

    The mutational profile of EGFR-TKI-resistant patients is diverse with mutations constantly evolving. Reports suggest that T790M detection is not always consistent; patients initially positive for T790M (at first post-TKI biopsy) become negative in subsequent biopsies and vice versa.[43] Different driver mutations generally show up at different stages of disease progression and sometimes cancer cells could harbor more than one driver mutation.[26] Driver T790M mutation has been identified in around 52% of EGFR mutation-positive NSCLC patients at first post-TKI biopsy. NSCLC patients developing T790M mutation at post-TKI biopsy had longer median PFS and OS when compared to T790M-negative patients (14.2 vs. 11.1 months and 45.9 months vs. 29.8 months, respectively).[44] Thus, these mutations need to be constantly checked through additional biopsies. Once these mutations are identified, personalized targeted therapy can be used in resistant NSCLC patients to improve individual responses, patient outcomes, and eventually their quality of life.

    Moreover, noninterventional blood-based liquid biopsy, which can be repeatedly performed in EGFR-TKI-progressed patients, unveil tumor heterogeneity and may even identify missed clones (which is not possible with tissue biopsy) and thus has currently been approved by FDA for detecting gene mutations in advanced-stage NSCLC.[45],[46] It can be considered as an alternative to tissue biopsy and has shown to give respite to almost 60% of patients with T790M-positive NSCLC who currently undergo painful and risky tissue-based biopsy.[47]

  7. Use of third-generation TKI inhibitor, osimertinib (AZD9291) in T790M-positive NSCLC patients, and the FDA approved companion diagnostics.


Recommendation

The panel members unanimously agreed on the use of osimertinib in T790M mutation-positive NSCLC patients who failed treatment with first- and second-generation EGFR-TKIs. It was mentioned that in patients who tested positive for T790M in tissue biopsy or in liquid biopsy, osimertinib could be used for improving their PFS and quality of life.

Rationale

Advanced research is ongoing in the field of NSCLC treatment, and a number of third-generation TKIs are in different stages of development. Rociletinib (a third-generation TKI) showed promising (53% response rate) midstage results in EGFR-T790M-positive metastatic NSCLC patients, but its efficacy in pooled TIGER-X/TIGER-2 trial was not satisfactory (ORR 23–32%). The trial also highlighted the increased magnitude of serious adverse events and safety issues associated with rociletinib therapy. All these led to the termination of TIGER trials, and thus, the clinical development of rociletinib was stopped.[48],[49] Some of the other promising third-generation TKIs are HM61713 (ORR of 58.8%), ASP8273 (ORR of 28%), and EGF816 (ORR of 54.5%), but each one of these are in their initial trial phases and require bigger studies to substantiate their effectiveness in advanced-stage NSCLC patients.[50] Osimertinib is a potent, oral, irreversible third-generation TKI for sensitizing and resistant T790M mutation and has shown clinical efficacy in advanced-stage T790M-positive NSCLC patients progressed on/after first-generation EGFR TKI.[51],[52] A recent study by Ramalingam et al. reported the safety and efficacy results of osimertinib in 50 advanced stage EGFR mutation-positive NSCLC patients. The median PFS was demonstrated to be around 19 months with a disease control rate of 97% and manageable tolerability profile.[53] AURA phase I expansion study and two phase II studies (AURA extension and AURA II) demonstrated efficacy of osimertinib in 474 T790M-positive NSCLC patients who had progressed on/after EGFR-TKI therapy. In the phase I study, the ORR was 62%, while in the combined phase II study, it increased to 66%.[54] AURA phase III trial randomized 419 EGFR T790M-positive chemotherapy naïve NSCLC patients with confirmed progression on erlotinib, gefitinib, or afatinib in a 2:1 ratio to receive osimertinib (80 mg orally, once daily) versus platinum-based therapy (pemetrexed 500 mg/m2 + carboplatin at area under the plasma concentration-time curve AUC 5 or pemetrexed 500 mg/m2 + cisplatin 75 mg/m2). Patients receiving osimertinib demonstrated to have meaningful and improved ORR, disease control rate, and duration of response when compared to chemotherapy.[55],[56],[57]

Thus, FDA has approved osimertinib in 2015 for T790M-positive metastatic NSCLC patients.[58] European commission has also granted conditional marketing authorization to osimertinib in this class of patients regardless of prior EGFR-TKI treatment (Feb 2016). In addition, FDA has also approved companion diagnostics (the cobas EGFR Mutation Test v2) for osimertinib.[59]


 » Conclusions Top


This present report highlights a decade of research during which treatment of NSCLC, specifically of the advanced stage has evolved, providing many exciting treatment modalities which have improved survival rate and quality of life, rendering half of the NSCLC patients eligible for personalized medicine. With expanding horizons of therapeutic landscape and promising clinical trials, survival benefits (better treatment response and improved quality of life) of patients would witness a further improvement. Seamless interdisciplinary research encompassing early detection of resistant mutations underlying EGFR-TKI resistance and interventional and noninterventional rebiopsy techniques with accelerated biomarker testing can help in better management of advanced stages EGFR mutation-positive NSCLC patients failing first-line TKI treatment. Currently, the OS of NSCLC patients is roughly 2–3 years. However, with the advent of advanced generation TKIs (osimertinib), it is expected to improve further. Third-generation TKI (osimertinib) promises to bring optimal and improved patient care from bench to bedside.

Acknowledgments

The authors acknowledge AstraZeneca Pharma India Ltd and Turacoz Healthcare Solutions for medical writing and editing support.

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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