Clinical Benefit From a Combination of Brigatinib and Camrelizumab in Sarcomatoid Transformation of ALK-Rearranged Squamous Cell Lung Cancer Resistant to Crizotinib

A 27-year-old nonsmoking Chinese man was referred to the hospital owing to chest pain in May 2015. He had a diagnosis of stage IV lung squamous cell carcinoma (SCC), (cT2aN3M1b). Computed tomography displayed a 3-cm dense mass in the left superior lung (Fig. 1A, baseline), and immunohistochemistry (IHC) staining of the tumor biopsy reported positive for pulmonary SCC marker p40 (Fig. 1B, baseline).

Figure 1.

Computed tomography (CT) images (A), and pathologic and immunohistochemical stains of patient tumor sampled (B) during treatment course. Tumors are indicated by red arrows. CT scan revealed a dense mass in the left superior lung during baseline, progressive disease (PD) after first-line chemotherapy, crizotinib partial response, crizotinib PD, brigatinib PD, camrelizumab plus apatinib treatment partial response, camrelizumab plus apatinib treatment PD, and lorlatinib PD.

First-line chemotherapy, with a combination of docetaxel and nedaplatin, was given to the patient in May 2015, and a stable state of the disease was achieved after four cycles of treatment. In September 2015, an anaplastic lymphoma kinase (ALK) rearrangement was detected by IHC and was confirmed by fluorescent in situ hybridization in a tumor sample from the patient (Fig. 1B). Subsequently, crizotinib was administered at a dosage of 250 mg twice a day, according to the National Comprehensive Cancer Network guideline, and a partial response was achieved after 1 month. After 22 months, a new lesion in the lower left lung was observed (Fig. 1A, progressive disease after crizotinib). IHC analysis of the puncture biopsy identified spindle cell structure with positive expression of vimentin and ALK but negative expression of p40 (Fig. 1B), indicating that the tumor had transformed from SCC to sarcomatoid carcinoma. Then, a third-line therapy with a second-generation ALK inhibitor brigatinib was given at a dosage of 90 mg once a day and the patient achieved a progression-free survival (PFS) of 12 months. After the patient had progressed, an EML4-ALK fusion (EML4: exon6 ∼ ALK: exon20) was revealed by comprehensive genomic profiling with a panel of 425 cancer-relevant genes. No additional canonical ALK mutation was identified. Meanwhile, a BRCA2 frameshift mutation (c.4808dupA) was identified with a tumor mutational burden of 13.8 mutations per megabase. Anti–PD-1 antibody camrelizumab combined with apatinib, an antiangiogenesis tyrosine kinase inhibitor (TKI), was administered in September 2018 and achieved partial response after 2 months of treatment. However, the tumor relapsed after 7 months. Lorlatinib, a third-generation ALK inhibitor, was subsequently administered, but the disease rapidly developed after 1 month, and eventually, the patient died in September 2019.

Discussion

ALK rearrangement, accounting for 5% to 6% of NSCLC, is usually observed in adenocarcinoma but rarely reported in SCC.^1,2 Transformation to sarcomatoid carcinoma as a potential, acquired resistance mechanism to crizotinib has been reported in ALK-rearranged lung adenocarcinoma and could be interpreted as a kind of epithelial-mesenchymal transition, which is known to cause acquired resistance to EGFR TKI.³

Here, we reported a rare case of lung SCC with ALK rearrangement, which was later identified to be EML4-ALK by next-generation sequencing. We present this case with potential, crizotinib-resistant morphologic transformation to sarcomatoid carcinoma, which is the first one identified in lung SCC. The positive expression of vimentin might indicate the possibility of epithelial-mesenchymal transition development. Further studies are warranted to clarify this resistance mechanism of crizotinib. Subsequent brigatinib treatment revealed sustained disease control and achieved a PFS of 12 months.

It has been implicated that patients with BRCA-mutated tumors might display increased susceptibility to immunotherapy owing to accumulation of DNA damage and increased tumor mutational burden.⁴ This patient with SCC with a BRCA gene mutation achieved a PFS of 7 months under the treatment of camrelizumab and apatinib, suggesting that a patient with ALK-rearranged SCC with BRCA mutation may still benefit from immunotherapy after developing resistance to multiple ALK TKIs.