Overcoming resistance in a BRAF V600E–mutant adenocarcinoma of the lung

Case Report

Overcoming resistance in a BRAF V600E–mutant adenocarcinoma of the lung


T. Schmid, MD*, M. Buess, MD PhD*


doi: http://dx.doi.org/10.3747/co.25.3936


ABSTRACT

We report on a patient with an adenocarcinoma of the lung harbouring a BRAF V600E mutation who benefited from combination therapy with dabrafenib–trametinib after developing resistance to vemurafenib. To our knowledge, our report shows, for the first time, that combination therapy with dabrafenib–trametinib can overcome vemurafenib resistance in a BRAF V600E–mutated adenocarcinoma of the lung.

KEYWORDS: Adenocarcinoma, BRAF, MEK, targeted therapy, acquired resistance, non-small-cell lung cancer, dabrafenib, trametinib

BACKGROUND

BRAF mutations occur in 2%–3% of patients with non-small-cell lung cancer (nsclc), and about 50% of those mutations are BRAF V600E1. That seemingly small frequency still corresponds worldwide to about 20,000 new patients per year with nsclc who could be diagnosed with a BRAF V600E mutation and who would therefore benefit from targeted therapy. The activity of braf inhibitor monotherapy with vemurafenib2 or dabrafenib3 has been shown in case series of lung adenocarcinomas. However, it is well known that resistance to braf inhibitor therapy inevitably develops, frequently after a few months of treatment, resulting in tumour progression. In a phase ii trial, Schreuer et al.4 recently showed that re-challenging melanoma patients with a combination of the braf inhibitor dabrafenib and the mek inhibitor trametinib can overcome that resistance. Here, we report a benefit from treatment with dabrafenib–trametinib in a patient with an adenocarcinoma of the lung harbouring a BRAF V600E mutation that was progressing under treatment with vemurafenib.

CASE PRESENTATION

In September 2012, a 62-year-old man diagnosed with an adenocarcinoma of the lung, including liver and brain metastases, was initially treated with irradiation to the brain followed by 4 cycles of palliative first-line chemotherapy with carboplatin–pemetrexed.

In November 2013, upon progression after first-line chemotherapy, a BRAF V600E mutation was identified, and the patient was treated with the oral braf inhibitor vemurafenib (960 mg twice daily). He showed rapid symptomatic improvement and achieved a partial remission as determined by computed tomography imaging. He tolerated vemurafenib well, with very favourable quality of life, and the tumour remained stable for 16 months. The patient then developed asymptomatic oligometastatic progression in the liver and was treated with microwave ablation. Vemurafenib was continued until January 2017.

Because the tumour had progressed systemically under vemurafenib treatment, with growing liver and lung metastases, the patient was switched to oral dabrafenib (150 mg twice daily) plus oral trametinib (2 mg once daily). During the first 6 months, the patient tolerated the new regimen without any significant toxicities, and after 2 months, the tumour again showed a formal partial remission. A further remission was confirmed after 6 months of combination therapy (Figure 1).

 


 

FIGURE 1 Computed tomography images show the left hilar mass and the liver metastases, which were resistant to vemurafenib, (A,B) before (February 2017), (C,D) at 2 months after (April 2017), and (E,F) at 6 months after (August 2017) initiating treatment with dabrafenib and trametinib.

DISCUSSION AND SUMMARY

In a randomized phase iii trial, a combination of the braf inhibitor dabrafenib and the mek inhibitor trametinib was shown, in melanoma patients, to be superior to vemurafenib monotherapy5. In BRAF V600E–mutant nsclc, a nonrandomized phase ii trial that included patients with progressive disease after platinum-based therapy had recently established that combination regimen. However, patients previously exposed to a braf inhibitor had been excluded from that trial6.

Acquired resistance to braf inhibitor monotherapy in melanoma is frequently a result of BRAF-mutation-independent reactivation of the mapk pathway or activation of alternative survival pathways, rather than to secondary mutations in BRAF that prevent binding of the small-molecule braf inhibitors7. In nsclc, BRAF-mutation-independent activation of the mapk pathway under braf inhibition has also been shown in vitro8. Those findings establish the rationale to add the mek inhibitor trametinib to a braf inhibitor when a lung cancer escapes braf inhibition alone. Considering the difference in the response rates to single-agent braf inhibition for BRAF V600E–mutated metastatic melanoma and colon cancer9, BRAF V600E mutation clearly has a different predictive value in different tumour entities. It therefore cannot be automatically assumed that BRAF V600E–mutated nsclc will necessarily behave the same way as BRAF-mutated metastatic melanoma.

To our knowledge, the present report is the first of a patient with a vemurafenib-resistant adenocarcinoma of the lung who benefited from the dabrafenib–trametinib combination. Our case suggests that resistance to braf inhibitors can be overcome with combination dabrafenib–trametinib therapy not only in melanoma4, but also in nsclc harbouring a BRAF V600E mutation.

Recently, a seemingly similar case of a patient with a BRAF V600E–mutated nsclc who was rescued by combination vemurafenib–trametinib after dabrafenib monotherapy was reported10. However, that patient had to stop dabrafenib because of intolerance, and progression occurred while he was off targeted therapy. He then went on to respond to dual brafmek inhibition with vemurafenib and trametinib. As long as no results from a randomized trial are available, it remains unclear whether, in nsclc, dual blockade should be initiated upfront or only after development of resistance to monotherapy with a braf inhibitor. When attempting to answer such questions in the incurable setting of metastatic nsclc, the focus should be on the aspects of progression-free survival and quality of life. Given the rarity of the disease, randomized clinical trials are difficult to perform, and phase i/ii cohort studies are probably the most reasonable way to improve the evidence for a therapeutic rationale. Currently, an ongoing multicentric open-label phase ib study in BRAF-mutated nsclc is testing the novel oral pan-raf inhibitor LXH254 in combination with the oral erk inhibitor LTT462 (NCT02974725 at http://ClinicalTrials.gov). Another nonrandomized open-label single-arm multicentric phase ii study is planned in Japan to test dabrafenib–trametinib in Japanese patients with BRAF V600E–mutated stage iv nsclc (NCT02672358).

CONFLICT OF INTEREST DISCLOSURES

We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare that we have none.

AUTHOR AFFILIATIONS

*Department of Oncology, St. Claraspital, Basel, Switzerland..

REFERENCES

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Correspondence to: Martin Buess, Department of Oncology, St. Claraspital, Kleinriehenstrasse 30, Basel 4016 Switzerland. E-mail: martin.buess@claraspital.ch

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Current Oncology, VOLUME 25, NUMBER 3, June 2018








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ISSN: 1198-0052 (Print) ISSN: 1718-7729 (Online)