BRAF mutant PD-L1 positive metastatic musculoskeletal lesions from primary lung adenocarcinoma treated with combination vemurafenib and pembrolizumab: a case report

Abstract

Background

B-Raf mutation positivity, B-Raf mutation positivity occurrence with programmed death ligand 1 overexpression, and musculoskeletal metastasis are singly rare in non-small cell lung cancer, and even rarer is all occurring in one patient.

Case presentation

A Filipino 63-year-old male had B-Raf mutation positive and programmed death ligand 1 overexpressed symptomatic metastatic musculoskeletal lesions from lung adenocarcinoma treated with a BRAF inhibitor, vemurafenib, in combination with an immune checkpoint inhibitor, pembrolizumab. He exhibited significant reduction in pain and burden of musculoskeletal metastatic lesions.

Conclusion

Although a rare occurrence and known to have a poor prognosis, B-Raf mutation positive programmed death ligand 1 overexpressed lung adenocarcinoma presenting with metastatic musculoskeletal lesions can respond favorably to a combination immune checkpoint inhibitor and BRAF inhibitor medication.

Background

The treatment of advanced lung cancers has evolved to include detection of targetable driver mutations where targeted therapy has improved survival outcomes with tolerable side effects. The mutations of BRAF and expression of PD-L1 are among the targets detected [1, 2]. BRAF mutations promote oncogenesis by causing downstream signaling and activation in the cell cycle [3]. The treatment of BRAF-mutated tumors includes a B-RAF inhibitor (BRAFi) alone or in combination with MEK inhibitors (MEKi), as first or subsequent lines of therapy with a documented response rate of 33–63% [1]. PD-L1 positivity has shown increase in tumor proliferation through immunomodulation. Treatment with anti-PD-L1 agents has also demonstrated benefit in response rates and overall survival [4]. The expression of PD-L1 in BRAF-mutated lung cancers is not common, and the prevalence is not fully established [5, 6]. Furthermore, the targeted treatment of these types of tumors relies on either BRAFi or immune checkpoint inhibitor (ICPi) agents [7,8,9], but no data on combination treatment particularly for lung cancer have been reported.

Case presentation

The patient was a Filipino 63-year-old male, with a body surface area (BSA) of 1.89 m²; he had been a cigarette smoker from 1975 to 2018 (1.5 packs a day), an occasional alcoholic drinker, and he had diabetes mellitus controlled with pioglitazone 15 mg a day. His sister has breast cancer in remission.

He presented with persistent progressive severe lower back musculoskeletal pain limiting his ambulation and needing a fentanyl 50 mcg patch every 3 days for pain control, combined with a paracetamol 500 mg tablet every 8 hours; he also had a painful, hard ~5 cm palpable left thigh mass.

His positron emission tomography–computed tomography (PET-CT) scan revealed multifocal musculoskeletal fluorodeoxyglucose (FDG)-avid lesions in paravertebral and gluteal regions, thigh, and extremities; FDG-avid blastic and lytic changes in the axial and appendicular skeleton; and mildly FDG-avid band-like and linear densities from the left hilum to the posterior aspect of the left lower lobe of the lung. No enlarged FDG-avid axillary, mediastinal, or hilar lymph nodes were seen; there was no pleural or pericardial effusion; and the liver was normal with no masses. Magnetic resonance imaging (MRI) of the thigh showed a T1 isointense and T2 hyperintense heterogenous 5.2 × 2.1 × 2.4 cm enhancing solid mass with a hyperintense rim in the left adductor magnus muscle.

His chest CT scan with contrast showed a thick linear opacity in superior segment of left lower lung lobe extending inferiorly to the posterior basal segment, a partly solid nodule measuring 0.4 cm in the anterior segment of right upper lung, and a nodule about 0.49 cm in the right major fissure. There were multiple sclerotic foci in vertebrae C7, T1–T5, T7, T9–11, L1–L5, left 2–3 ribs, both 4–8 ribs, left 10 and 12 ribs, right clavicle, and both scapula. The thyroid had benign nodules.

His whole abdomen CT scan with triple contrast indicated a normal liver/kidneys, unenlarged prostate with minimal parenchymal calcifications, and unenlarged lymph nodes, but multiple sclerotic foci in vertebrae T10–11, L1–5, both ilium, and the left acetabulum.

A CT-guided biopsy (19 May 2022) of the left transverse process of the T2 vertebral body resulted in cytomorphology compatible with adenocarcinoma, metastatic from lung. Immunohistochemistry revealed positive results for TTF-1, Napsin A, CK19, and cytokeratin7, and negative results for cytokeratinin 20, PSA, CDX2, calretinin, HER2neu. Gene fusion analysis by polymerase chain reaction (PCR) showed negative results for Alk, ROS1, RET, MET Exon 14, and NTRK 1/2/3 abnormalities. Mutational analysis by PCR revealed negative EGFR mu (exons 18/19/20/21) and positive BRAF V600 mutation. The PD-L1 tumor proportion score (TPS) was 50–60%. ALP was 211 mmol/L (n = 40–150), while complete blood count (CBC), creatinine, ALT, AST, T3, T4, TSH, and electrocardiogram (ECG) were within normal values.

The patient was started on pembrolizumab 200 mg intravenously every 3 weeks and vemurafenib 960 mg (240 mg tab) orally twice daily (11 July 2022). On his cycle 1 day 3 treatment, he had relief of pain without the need for his fentanyl patch.

He however experienced cough, fever, and insomnia on cycle 1 day 12, and tested positive via real-time (RT)-PCR positive for coronavirus disease 2019 (COVID-19). He also experienced chest heaviness and rashes over face, chest, and upper extremities. Vemurafenib was deferred on cycle 1 day 13. He took molnupiravir 800 mg per orem a day for 5 days. His rashes improved after intake of oral diphenhydramine and dexamethasone. Cycle 2 pembrolizumab-vemurafenib was 6 days delayed.

Post cycle 6 vemurafenib-pembrolizumab, his 24 November 2022 PET CT scan (compared with 12 May 2022) revealed a significant decrease in focal FDG activity and interval resolution of FDG activity in most of the vertebral lesions [highest standardized uptake values (SUV) up to 4.1 in T9 vertebra previously 10.4]; Fig. 1.

Fig. 1

PET-CT scan vertebral lesions (November 2022 versus May 2022)

Further, focal FDG activity in most of previously noted lesions in the extremities, ribs, pelvis, and femurs were no longer seen (Fig. 2).

Fig. 2

PET-CT scan lesions in extremities, ribs, pelvis, and femurs (November 2022 versus May 2022)

There was also decreased FDG activity in the left adductor magnus muscle (SUV 2.8, previously 5.1), Fig. 3.

Fig. 3

PET-CT scan lesions in left adductor magnus muscle (November 2022 versus May 2022)

The post-cycle 12 pembrolizumab-vemurafenib PET-CT scan (13 April 2023) showed:

Thorax Stable consolidation-atelectasis with adjacent fibrosis was observed in the left lower lobe, exhibiting interval increase in PET FDG activity (SUV 4.2, previously 3.4); Fig. 4a.

Fig. 4

a PET-CT scan of thorax, post cycle 12 pembrolizumab-vemurafenib. b PET-CT scan of thorax, post cycle 12 pembrolizumab-vemurafenib

There was slight increase in the size of the previously noted small pre-carinal lymph node, which now measured 0.7 × 1.2 cm (previously re-measured 0.6 × 0.9 cm), and was now PET FDG avid (SUV 15.6, previously 4.2; Fig. 4b).

Musculoskeletal There was no significant change in the previously noted mixed lytic and blastic changes in the osseous structures. The associated minimal paravertebral soft tissue density at the level of vertebrae T10 was also stable. Upon PET-CT scan, there was interval appearance of increased FDG activity in the left scapula (SUV 3.8) and right anterolateral fifth rib (SUV 12.5; Fig. 5a).

Fig. 5

a Musculoskeletal PET-CT scan, post cycle 12 pembrolizumab-vemurafenib. b Musculoskelatal PET-CT scan, post cycle 12 pembrolizumab-vemurafenib. c Musculoskeletal PET-CT scan, post cycle 12 pembrolizumab-vemurafenib. d Right gluteus (SUV 1.8, previously 2.3)

The following bone lesions mostly showed unchanged FDG activity—save for an interval decrease in FDG activity at the right pubis and a slight interval increase in FDG activity at the L1 vertebral body and left ilium—medial aspect of left clavicular head (SUV 3.0, previously 3.6), right anterolateral sixth rib (SUV 2.5, previously 3.1), left posterior second rib (SUV 1.7, previously 2.5), right pubis (SUV 3.1, previously 5.4), left medial femoral condyle (SUV 4.4, previously 5.1), left ilium (SUV up to 3.1, previously up to 2.4), L1 (SUV 3.9, previously 3.6), and L4 (SUV 3.0, previously 3.8) vertebral bodies (Fig. 5b).

The small, calcified nodule in the left semimembranosus muscle was again seen, measuring 1 × 1.3 cm (previously 0.9 × 1.3 cm), with PET-CT scan FDG activity (SUV 2.7, previously 3.3; Fig. 5c).

Stable calcified focus was seen in the left paraspinal muscle at the vertebrae L3 level, measuring 0.9 × 1.3 cm including its minimal FDG activity (SUV 1.6, previously 2.2). Calcifications were again noted in the bilateral vastus intermedius muscle (SUV 1.8, previously 2.7), bilateral erector spinae (SUV 1.1–1.4, previously up to 1.1, right, and up to 1.1–1.5 previously up to 1.5, left), and right gluteus (Fig. 5d).

As of May 2023, patient was without pain, was ambulant, eats well, weighed 76.6 kg, and was well-nourished, and CBC, AST, ALT, and creatinine were within normal values; he is continuing vemurafenib and is off pembrolizumab. He verbalized that he got scared when told of his illness at diagnosis, and he had knowledge of his prognosis suffering pain and not being able to ambulant well; he was grateful when he started feeling no pain upon treatment, and he is now going through his farm work again.

The patient has given his informed consent for his clinical case history including his PET-CT scan/CT scan images to be presented for discussion and publication for scientific purposes.

Discussion

The treatment of metastatic lung cancer with targetable driver mutations in the recent years has led to improved outcomes and more tolerated side effects compared with conventional systemic chemotherapy [1]. Thus, molecular characterization is recommended, and targeted agents are now standard treatment for advanced non-small cell lung cancer (NSCLC) [2, 10]. The National Comprehensive Cancer Network recommends biomarker testing for advanced non-small cell lung cancers including EGFR mutation, ALK, KRAS, ROS1, BRAF, NTRK1/2/3, METex14 skipping, RET, and PD-L1.

Mutations in the mitogen-activated protein kinase (MAPK) pathway cause a signaling cascade that promotes oncogenesis in lung cancer. BRAF is among the three isoforms of the RAF family of serine/threonine protein kinases that is an essential component of this pathway. Activated BRAF signals downstream activation of MEK and ERK, kinases that ultimately lead to gene transcription and cell cycle progression [3]. Though commonly found in melanomas, mutations in BRAF have also been identified in lung cancer, albeit at lower percentage [3]. BRAF mutations are detected in approximately 2–3% of NSCLC with adenocarcinoma histology. The most identified variant of this mutation in NSCLC is BRAF V600E, accounting for around 50% of BRAF-mutated lung cancers [11]. BRAF mutations in NSCLC are more frequent in females. Smoking risk in these mutations is still not fully established, with some studies suggesting the V600E subtype to be more common in those without smoking history [12]. Studies report that those who harbor the V600E subtype have demonstrated shorter progression-free survival, disease-free survival, and overall survival when treated with platinum-based chemotherapy [13, 14].

BRAF-mutated lung cancers are treated with BRAFi with or without MEKi, and this strategy has been recommended as first or subsequent lines of treatment of these tumors, specifically for those with the V600E mutation [11]. Targeted treatment for these tumors includes single-agent vemurafenib, single-agent dabrafenib, and combination dabrafenib and trametinib with documented overall response rates of 42%, 33%, and 63%, respectively [1].

Programmed death 1 (PD-1), a member of the CD28 family, is a key immune checkpoint receptor expressing on the surface of the activated T-, B-, and NK-cells and plays a crucial role in tumor immune escape [15]. PD-L1, the main ligand of PD-1, is upregulated in different types of tumors, including NSCLC [16]. PD-L1 delivers negative costimulatory signals and binds PD-1 to reduce cellular immune responses by inducing T-cell apoptosis or exhaustion. PD-L1 immunopositivity in NSCLC has conferred improved survival when treated with PD-1 or PD-L1 (immune checkpoint) inhibitors alone or combined with chemotherapy [5, 17]. Anti-PD-L1 immunotherapy has been approved as first-line or further-line options for advanced lung adenocarcinoma. The prevalence of PD-L1 expressors varies from 13% to 70% [5]. The concomitant expression of PD-L1 along with a driver mutation is even less, and driver mutations have been postulated to impede the efficacy of anti-PD1/PD-L1 drugs [18].

NSCLC adenocarcinoma with BRAF mutation and PD-L1 overexpression

There are conflicting data on the prevalence of BRAF -mutant lung cancers with PD-L1 expression. Pandey et al. [5] evaluated the frequency of PD-L1 expression in lung cancers with targetable mutations. PD-L1 expression in EGFR-mutation-positive (EGFRmu+) tumors had the highest frequency (37.93%) followed by KRAS-mutation-positive (KRASmu+) tumors (20.68%); there were no BRAF V600E mutations, and subsequently no data on BRAF V600E, and PD-L1 co-expression was identified. Li et al. [6] evaluated the presence of PD-L1 expression with respect to driver mutations in 1370 cases of NSCLC in China. Ten (0.7%) of these cases harbored the BRAF mutation, and seven of these BRAF-mutated cases had a PD-L1 tumor proportion score (TPS) expression of at least ≥ 1%.

Dudnik et al. [7, 8] identified 39 patients with B-Raf-mutated (BRAFmu) NSCLC. Of these tumors, 29 were evaluated for PD-L1 expression, where 42% had high (≥ 50%) expressor status and 32% had intermediate (1–49%) expressor status for BRAF V600E mutants (Group A), while 50% and 10% had high and intermediate expressor status for non-BRAF V600E mutants (Group B), respectively. Those who received ICPi including pembrolizumab, atezolizumab, and nivolumab obtained an overall response rate of 25% and 33% and progression-free survival (PFS) of 3.7 months and 4.1 months [95% confidence interval (CI) 0.1–19.6] in Groups A and B, respectively.

Mazieres et al. [9] evaluated 551 patients with advanced NSCLC and found 43 of them to harbor BRAF mutation. Out of the 43 patients with BRAF mutation, 9 expressed PD-L1 with a median percentage of cells expressing PD-L1 of 50. Patients with BRAF mutation who received ICPi had a median overall response rate of 13.6 months and median PFS of 3.1 months. The PFS was significantly higher in smokers for BRAFmu patients, while median PFS was numerically shorter in the V600E subgroups (1.8 months versus 4.1 months).

Combining immunotherapy with targeted therapy has demonstrated benefit in emerging preclinical and clinical trials for the treatment of malignant melanoma. Targeting the MAPK pathway with the use of BRAFi and MEKi has demonstrated synergy by improving anti-tumor immunity in the tumor microenvironment of mouse models. Furthermore, preclinical data demonstrated significant tumor volume reduction in combination BRAFi and MEKi as compared with targeted treatment alone. A phase 1b study of the combination of vemurafenib, cobimetinib, and atezolizumab in metastatic melanoma noted an unconfirmed objective response rate (ORR) of 85.3%. KEYNOTE-022, a randomized phase 2 trial, reported that patients with metastatic melanoma who received concurrent dabrafenib and trametinib with pembrolizumab versus placebo had longer PFS in the treatment arm compared with placebo (16.0 months versus 10.3 months). Other trials have preliminary data reporting that the combination of BRAFi with or without MEKi plus ICPi in advanced melanoma has side effects that led to discontinuation of such combinations [19].

Use of ICPi has shown benefit in the treatment of BRAFmu PD-L1 expressor metastatic NSCLC mostly in the second-line setting after a BRAFi. However, ICPi benefit in combination with BRAFi has not been fully established in the first-line setting for advanced NSCLC.

The administration of an ICPi and a BRAFi combination drug in the case of this 63-year-old Filipino patient with lung adenocarcinoma with metastatic musculoskeletal lesions demonstrated that favorable clinical response in terms of symptom control with tolerated adverse effects can be achieved.

Predominantly metastatic musculoskeletal lesions from primary lung adenocarcinoma

The most typical localization of metastases from a primary lung cancer are the liver, brain, lung, bone, and adrenal glands. In the cases of disseminated disease, muscle metastasis are rarely observed [20,21,22,23,24]. The real incidence rate of muscle metastasis is unknown, but it is believed from a series of autopsies to be around 0.8% [20]. Pain was the most frequent symptom (83%); a mass was palpable in 78% of cases; the 5-year survival time was 11.5% with a median survival of 6 months, suggesting an aggressive disease in the presence of skeletal muscle metastasis [22].

There are several theories explaining muscle resistance of metastatic disease; none of them can explain the full mechanism but perhaps a combination of them can [22]. The most important hypotheses are mechanical (muscle contraction, high tissue pressure [23], and extremely variable blood flow [25]), metabolic (pH, lactic acid production [26], and toxic free radical oxygen [23]), or immunologic (cellular and humoral immunity and hypersensitivity reaction [23]). Although skeletal muscles have a rich vasculature, the flow is extremely variable, especially under the influence of beta-adrenergic receptors. During exercise, the capillaries dilate, and the amount of blood they contain may be increased up to 800 times that in the resting state. Irrespective of blood flow, skeletal muscle tissue may be a poor milieu for tumors, and this may be related to lactic acid metabolism [23].

The patient with NSCLC in this report has three features contributing to poor prognosis—PDL1 overexpression [27], a rare BRAF mutation [13, 14], and rare musculoskeletal metastasis [22]—hopefully his favorable response to his first-line pembrolizumab and vemurafenib treatment will continue to work for him over the long term.

Conclusion

Although a rare occurrence and written off as having a poor prognosis, BRAFmu+ PDL-1 overexpressed lung adenocarcinoma presenting with metastatic painful musculoskeletal lesions can respond favorably to a combination ICPi and BRAFi medication.