History and Examination
A 40-year-old female patient, non-smoker, with no comorbidities or family history of cancer and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1 presented to our hospital with complaints of pain in the left side of the chest and fever that persisted for 3 months.
Investigations and Diagnosis
Contrast-enhanced computed tomography (CECT) of the thorax revealed a left hilar mass measuring 3.2 × 3.8 × 4 cm, obstructing the left main bronchus with a collapsed left upper lobe and another lesion measuring 3.7 × 3.7 × 3.6 cm along the fissure, abutting the chest wall laterally. Positron emission tomography (PET)-CECT revealed a left upper lobe mass with multiple pleural deposits [Figure 1]. On immunohistochemistry (IHC), the tumor cells were found to be positive for thyroid transcription factor-1 (TTF-1) and negative for p40. A diagnosis of adenocarcinoma of pulmonary origin was made.
IHC on the tumor biopsy revealed strong granular cytoplasmic staining for the expression of anaplastic lymphoma kinase-1 (ALK-1) protein, which was observed using the Ventana D5F3 antibody clone approved by the United States Food and Drug Association (USFDA) for the detection of ALK-positive tumors [Figure 2]. A TaqMan Probe–based endpoint genotyping mutation analysis using the Easy® EGFR kit (Diatech Pharmacogenetics, Jesi, Italy) revealed an exon-19 in-frame deletion in the epidermal growth factor receptor (EGFR) gene. The assay detects the most frequent deletions between nucleotides 2235 and 2258 of exon 19 of EGFR, but does not distinguish between them.
EXCERPTS FROM THE DISCUSSION IN THE MOLECULAR TUMOR BOARD
The results of the diagnostic tests were discussed in our institution's molecular tumor board meeting. In light of the presence of ALK-1 protein expression, as detected via IHC, the molecular tumor board discussed the need for orthogonal testing to confirm the presence of ALK-1 rearrangement by fluorescence in situ hybridization (FISH). However, given the strong granular cytoplasmic staining on IHC for ALK-1, this was considered sufficiently diagnostic of ALK-1 positivity. Although brain metastasis was absent at the time of initial presentation, as both EGFR and ALK alterations are known to be associated with a higher risk of brain metastasis, the molecular tumor board recommended that brain imaging be performed along with close monitoring for the development of brain metastasis during the course of the disease. Therapeutically, the recommendation from the molecular tumor board was to target both the EGFR and ALK driver alterations.
Thus, given the presence of both, an EGFR exon-19 deletion and ALK-1 amplification, the patient was advised tyrosine kinase inhibitors (TKIs) targeting both the alterations, with very close monitoring for toxicity. Additionally, the molecular tumor board recommended the use of at least one oral TKI that could penetrate the blood–brain barrier, such as alectinib, lorlatinib, or osimertinib. However, as the patient could not afford these medicines, she was started on ceritinib 450 mg (with food) and gefitinib 250 mg orally, once daily.
One month after starting ceritinib and gefitinib, the patient complained of diarrhea and grade 1 rash. As a result, ceritinib was discontinued for one day and the patient was given doxycycline for three days. A follow-up CECT scan of the thorax and abdomen two months post treatment initiation revealed a significant decrease in the disease burden [Figure 3]. Therefore, the patient continued to receive ceritinib and gefitinib, and the treatment was well tolerated. At about three months post treatment initiation, the serum alanine aminotransferase and aspartate aminotransferase levels were within normal range at 19 and 27 U/L, respectively. However, 15 months post treatment initiation, the patient discontinued the use of ceritinib because of financial constraints and inability to reach our hospital during the COVID-19 pandemic. A follow-up CECT scan of the thorax two months after the discontinuation of ceritinib showed two new nodular opacities in the superior basal segment of the left lower lobe, suggesting disease progression [Figure 4]. The patient was advised to restart ceritinib and continue gefitinib. Imaging after two months of restarting the TKIs revealed a mild decrease in the nodular opacities. However, the patient now experienced grade 2 fatigue and anorexia and grade1 nausea and diarrhea along with skin rashes. The ECOG PS of the patient at this stage was 2. Additionally, she was found to have grade 3 hypokalemia. Therefore, she was advised to withhold ceritinib and gefitinib, and was given intravenous potassium supplementation. After the normalization of potassium levels, she was restarted on ceritinib at a dose of 300 mg once daily (with food) and gefitinib at a dose of 250 mg once daily. Currently, at 30 months from the diagnosis of adenocarcinoma of the lung, the patient is alive and continues to receive TKIs directed at both EGFR and ALK alterations, with control of symptoms and radiologically stable disease.
The discovery of actionable genetic alterations has changed the treatment paradigm of non–small cell lung cancers (NSCLCs). The most frequently altered gene in patients with NSCLC is EGFR. In Indian patients with lung cancer, the incidence of EGFR mutations is reported to be as high has 20%–23%,[2–4] whereas in western countries, the incidence is approximately 10%. Contrarily, alterations in ALK are less common and occur in about 5% of the patients with NSCLC. Therefore, testing for the presence of alterations in ALK and EGFR is routinely recommended in clinical practice.
Alterations in ALK and EGFR are usually mutually exclusive. However, recent reports have suggested that the incidence of concomitant ALK and EGFR alterations can range from 1.3%–15.4%.[9–11] The increasing frequency of concomitant ALK and EGFR alterations can be attributed to the increasing sensitivity of the various detection methods. Similar to NSCLCs with an ALK or EGFR alteration alone, concomitant EGFR and ALK alterations are more prevalent among women, Asians, and never smokers; our patient too was an Indian never-smoker female patient. While activation of ALK in EGFR-mutated NSCLCs and that of EGFR in ALK-rearranged NSCLCs are important mechanisms of acquired resistance in patients treated with EGFR- and ALK-TKIs, respectively, in our case, both ALK and EGFR alterations were present at baseline. Moreover, treatment outcomes with ALK- and EGFR-TKIs have been reported to be better in patients with lung adenocarcinomas harboring an ALK or EGFR mutation alone, respectively, than in those harboring concomitant ALK and EGFR alterations.
It has been shown that ALK and EGFR alterations can co-exist ab initio in the same tumor cells; however, the prevalence of each of these alterations may be different at various time points along the disease course, contributing to intracellular heterogeneity. Studies have also shown that concurrent alterations in ALK and EGFR could arise from two different cellular clones, thus contributing to tumor heterogeneity. In our case, it could not be determined whether the ALK and EGFR alterations were present in the same tumor cell or had arisen from two different cellular clones, as testing for the co-expression of the mutant proteins in the same tumor cell using single-cell genomics or transcriptomic techniques was not affordable.
Currently, there are no consensus guidelines for the treatment of patients with NSCLCs harboring concomitant ALK and EGFR alterations, and the response to TKIs is poorly understood in this subset of patients. Won et al., in their study, reported on 14 patients with NSCLC harboring concomitant ALK and EGFR alterations. Of these, seven received an ALK inhibitor, two received gefitinib, and one received gefitinib followed by crizotinib at disease progression. It was observed that patients with concomitant ALK and EGFR alterations were sensitive to ALK inhibitors but showed resistance to gefitinib. Of the two patients who received gefitinib alone, one had stable disease with a progression-free survival (PFS) of 6 months. The seven patients who received crizotinib showed either a partial response or had stable disease with a PFS ranging from 5–43 months. In a more recent case series of three patients with concomitant ALK and EGFR alterations, all the patients received EGFR-TKIs during first-line treatment. Of these, two patients also received ALK-TKIs in the second line. The three patients showed a partial response to EGFR-TKIs, while the second-line ALK-TKIs were found to be ineffective in both the cases. Based on these observations, Shin et al. suggested that in patients with concomitant ALK and EGFR alterations, EGFR-TKIs were possibly more effective than ALK-TKIs. Several other studies have also reported the sequential use of EGFR- and ALK-TKIs in patients with concomitant alterations. However, Russo et al., in their review of 100 cases of concomitant EML4-ALK rearrangement and EGFR mutation, suggested that simultaneous inhibition of ALK and EGFR could be an interesting approach to treating these patients. Similarly, a case of primary resistance to EGFR-TKI in an Indian patient with EGFR exon 21 mutant lung adenocarcinoma caused by a coexisting MET exon 14 skipping mutation at baseline was reported by Raut et al. In this patient, a combination of gefitinib and capmatinib led to a rapid and sustained response to treatment.
Based on the available literature and given the lack of consensus guidelines for the treatment of NSCLCs with concomitant ALK and EGFR alterations and the paucity of data related to the efficacy of ALK- and EGFR-TKIs used either alone or sequentially in this subset of patients, our molecular tumor board recommended targeting both the alterations together.
Preclinical studies have shown that the co-expression of ALK and EGFR alterations in vitro can lead to mutual resistance to single-agent EGFR- and ALK-TKIs. However, Yang et al., in their study on patients with NSCLC harboring concomitant ALK rearrangements and EGFR mutations, reported that these patients responded to either ALK- or EGFR-TKIs. Moreover, they observed that the efficacy of an EGFR-TKI in the first-line setting was associated with the level of phosphorylation of EGFR. In this study, of the four patients treated with both an ALK- and EGFR-TKI sequentially, two patients with a baseline low phospho-EGFR and high phospho-ALK expression level showed de novo or subsequent resistance to treatment with EGFR-TKI but responded to the ALK-TKI, crizotinib. The other two patients with a baseline low phospho-ALK and high phospho-EGFR expression level, showed partial responses to EGFR-TKIs in the first line setting, but had progressive disease or short-term stable disease post treatment with crizotinib. Thus, it appears that in patients with concomitant ALK and EGFR alterations, the efficacy of ALK and EGFR-TKIs depends on the relative level of activation of ALK and EGFR proteins at baseline. The levels of phospho-ALK and phospho-EGFR proteins were not evaluated in our patient. Thus, in light of the preclinical and clinical findings related to the development of resistance to TKIs in this subset of patients, our patient was given gefitinib + ceritinib, as targeting only one of the actionable drivers would have eventually led to therapeutic resistance mediated by the second driver mutation. However, an important concern with dual ALK and EGFR inhibition is the associated toxicity. Hence, close monitoring for adverse events was recommended in our case.
In our case, post 15 months of treatment with ceritinib + gefitinib, the patient discontinued the use of ceritinib (due to logistic issues), and a follow-up CT imaging revealed two new nodular opacities in the left lower lobe. These were suspected to have appeared either due to therapeutic resistance or stoppage of ceritinib. Given the fact there was a decrease in the nodular opacities post restarting ceritinib and that the patient's latest CT scan suggested stable disease, it appears that she has not yet developed therapeutic resistance. Moreover, the treatment was tolerated well by our patient.
Even though the frequency of concomitant ALK and EGFR alterations is increasing, at present, their incidence is not high enough to generate robust level 1 evidence to help inform the best course of treatment. Nevertheless, several studies suggest that ALK-TKIs could be more effective than EGFR-TKIs in the earlier lines in patients with concomitant ALK and EGFR alterations. To the best of our knowledge, ours is the first study to report on the concomitant use of ALK- and EGFR-TKIs in a patient with NSCLC harboring both ALK and EGFR alterations. We believe that larger prospective studies are required to help determine the potential single-agent, combination, and sequential treatment options for this subset of patients.
It is essential to perform simultaneous molecular testing for multiple genetic alterations, so that concomitant alterations may be identified, thereby enabling the choice of appropriate treatment regimens in the earlier lines.
The authors certify that the patient has given her consent for her clinical images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published, and due efforts will be made to conceal the identity.
Financial support and sponsorship
Conflicts of interest
Unrelated to the current study, Dr Kumar Prabhash has received research funding from Dr. Reddy's Laboratories Inc., Fresenius Kabi India Pvt. Ltd, Alkem Laboratories, Natco Pharma Ltd, BDR Pharmaceuticals Intl Pvt. Ltd, and Roche Holding AG. (All research grants paid to the institution.)
Unrelated to the current study, Dr Vanita Noronha has received research funding from Amgen, Sanofi India Ltd, Dr. Reddy's Laboratories Inc., Intas Pharmaceuticals, and Astra Zeneca Pharma India Ltd. (All research grants paid to the institution.)
All other authors have no competing interests.
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