First-line TKI treatment in a patient with advanced NSCLC and major uncommon EGFR mutations
History and presentation
The patient is a 55-year-old female who first sought consultation in absentia through her family members in November 2020. According to her husband, the patient, who lived nearby, was non-ambulatory and too frail to visit the clinic. She had fever, haemoptysis and a bleeding mass in the right thigh, and was in severe pain, which was inadequately managed with NSAIDs.
The patient initially complained of cough with sputum in July 2020, when chest X-ray showed a 4 cm ill-defined nodular opacity in right upper to mid zone, highly suggestive of malignancy.
A PET-CT scan in August 2020 revealed a 4.2 cm irregular mass in the apical segment of the right upper lobe (RUL) of the right lung, which was consistent with a malignant lung tumour. There were signs of pleural effusion, metastatic lymph nodes, and ground-glass opacities in the RUL superior to the tumour mass. A CT-guided biopsy of the lung lesion led to diagnosis of non-small-cell lung cancer (NSCLC). Further molecular studies revealed compound EGFR major uncommon mutations involving exon 18 p.(G719X) and exon 21 p.(L861Q).
The patient was referred to a cardiothoracic surgeon but was deemed to be ineligible for surgery due to the presence of contralateral lung lesions. Upon referral to the clinical oncology department, she was recommended to receive systemic treatment with the second-generation EGFR tyrosine kinase inhibitor (TKI), afatinib, due to the presence of the EGFR major uncommon mutation.1 Unfortunately, the patient refused treatment at that time due to fear of possible adverse effects of systemic treatment.
The patient’s condition deteriorated, and she developed multiple bone and painful subcutaneous lesions all over her body, including a 6 cm right posterior thigh mass with a 4 cm bleeding central ulceration, which made it uncomfortable for her to sit, as well as a 4 cm mass under the scalp. At her initial clinic visit, the patient was on a wheelchair and in pain, and had fever and cough with bloodstained sputum. Her Eastern Cooperative Oncology Group performance status (ECOG PS) was 3.
Treatment and response
Repeat PET-CT on 11 November 2020 showed extensive disseminated disease. (Figure 1A) The patient eventually agreed to start treatment with first-line oral afatinib at 40 mg QD on 14 November 2020.
During her follow-up visit on 26 November 2020, the patient reported feeling much better after 2 weeks of continuous daily treatment with afatinib. Upon examination, she was afebrile, and there were significant reductions in size of the previously reported masses and subcutaneous lesions. For example, the right thigh mass had markedly decreased to 3 cm and was no longer bleeding. The pain associated with the multiple subcutaneous masses was also under control and did not require analgesics.
On 11 December 2020, the ulceration in her right thigh mass further regressed to 1 cm in diameter. Chest X-ray also showed shrinkage of the lung lesions.
In February 2021, a repeat PET-CT scan showed only residual primary lung lesion and mediastinal lymph nodes, with resolution of pleural effusion and the painful mass under the scalp. (Figure 1B) The patient regained her ability to walk unaided.
While receiving afatinib, the patient experienced grade 2 diarrhoea, which was adequately managed with loperamide, and grade 1 facial rash (ie, pustules) and paronychia, which resolved with topical antibiotic creams.
Last seen in March 2021, the patient’s primary lung lesion began bleeding again. She continued to receive oral afatinib at the same dose and was advised to receive palliative radiotherapy. At this time, the patient’s ECOG PS had improved to 1.
The emergence of targeted therapy has revolutionized the treatment of NSCLC.2-4 In particular, the identification of actionable genetic abnormalities has helped personalize treatment and optimize patient outcomes. Of these, EGFR mutations are the most common and are present in up to 20 percent of all lung cancer cases in Europe and North America, and up to 50 percent of Asian patients with NSCLC.2,3
The presence of EGFR mutations helps predict response to EGFR TKIs, which are the current first-line standard of care for patients with advanced EGFR-positive NSCLC.1,5,6 The most common EGFR mutations (ie, exon 19 deletions and exon 21 L858R substitutions, which account for approximately 90 percent of currently targetable mutations in NSCLC) are associated with high sensitivity to TKIs.3 Meanwhile, there is limited evidence regarding the efficacy of EGFR TKIs against uncommon EGFR mutations, which may account for >10 percent of all EGFR mutations and include exon 20 insertions, exon 18 point mutations, such as our patient’s, and complex mutations.2,6
Among the available TKIs, the second-generation irreversible ErbB blocker, afatinib, has the most comprehensive data on efficacy in patients with uncommon EGFR mutations.6,7 A potent and highly selective TKI, afatinib irreversibly blocks tyrosine kinase autophosphorylation to downregulate ErbB signalling.8
Afatinib was originally shown to be active in NSCLC tumours that harboured certain types of uncommon EGFR mutations, particularly, G719X, L861Q, and S768I, in a post hoc analysis of 600 TKI-naïve patients enrolled in the LUX-Lung clinical trials programme, 75 of whom had the uncommon mutations.7
Subsequently, afatinib was confirmed to have clinical activity against major uncommon and compound EGFR mutations in a pooled analysis of clinical outcomes of 693 NSCLC patients who had received afatinib in randomized clinical trials, as part of compassionate use and expanded access programmes, and in phase IIIb trials, noninterventional trials, and case series or studies. Notably, the analysis included 62 and 55 TKI-naïve patients with G719X and L861Q mutations, respectively, both of which were reported in our patient.
In EGFR TKI-naïve patients, the median time to treatment failure and overall response rate (ORR) were 10.8 months and 60.0 percent, respectively, for patients with major uncommon EGFR mutations (G719X, L861Q, and S768I; n=127), 14.7 months and 77.1 percent for patients with compound mutations (n=40), 4.5 months and 65.2 percent for patients with other uncommon mutations (n=34), and 4.2 months and 24.3 percent for patients with some exon 20 insertions (n=77). Among EGFR TKI-naïve patients with time to treatment failure (TTF) data available (n=272), TTF was the longest in cases harbouring compound mutations, particularly if one of them was a major uncommon mutation (median, 16.6 months), like our patient case. These patients also had the highest ORR of 78.3 percent.6
The dramatic improvement of our patient’s symptoms after 2 weeks of initiating treatment is consistent with the reported efficacy of afatinib in patients with NSCLC and uncommon EGFR mutations. The reported adverse reactions were adequately managed with conservative treatment and were consistent with the reported safety profile of afatinib.8