Real-world analysis of BRAF inhibitors in patients with solid tumors positive for BRAF V600E mutation: A retrospective observational study : Cancer Research, Statistics, and Treatment

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Real-world analysis of BRAF inhibitors in patients with solid tumors positive for BRAF V600E mutation: A retrospective observational study

Peelay, Zoya; Patil, Vijay M.; Menon, Nandini; Noronha, Vanita; Parekh, Deevyashali; Chinthala, Sravan Kumar; Shah, Minit; Pathak, Shruti; Nawale, Kavita; Prabhash, Kumar

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Cancer Research, Statistics, and Treatment: Jul–Sep 2022 - Volume 5 - Issue 3 - p 581-584
doi: 10.4103/crst.crst_184_22
  • Open

Molecularly targeted systemic therapies have led to improved outcomes in patients with cancer. Driver mutations have been discovered and studied in multiple cancers, and appropriate targeted therapies for these driver mutations have led to improvements in outcomes and quality of life, with fewer adverse effects. B-type Raf proto-oncogene (BRAF) is an example of a driver mutation.[1]

BRAF inhibitors include vemurafenib, dabrafenib,[2] and encorafenib. In addition to their molecular targeted activity, BRAF inhibitors have immunomodulatory effects in the tumor microenvironment, leading to increased tumor recognition by the immune system, and anti-tumor T-cell responses.[345] Until recently, none of these inhibitors were available in India. It has been frequently observed that the data seen in the clinical trial setting are not replicated in the real-world setting. Hence, we wanted to observe and understand through this analysis whether there is any real-world benefit from the use of BRAF inhibitors in patients with solid tumors with the BRAF V600E mutation.

This retrospective observational study was performed between January 1, 2018, and December 31, 2020, in the department of Medical Oncology at the Tata Memorial Hospital, Mumbai, India, an oncology-only tertiary care center. Given the retrospective observational nature of the study, and the use of only de-identified data, institutional ethics committee approval was not sought.

The study was conducted according to the ethical principles outlined in the Declaration of Helsinki. All patients with head-and-neck cancers, gliomas, or lung cancers who are diagnosed with the BRAF V600E mutation were identified from the molecular oncology database. Patients from this database were selected for inclusion in our study if they were 18 years or older, had been diagnosed with any solid tumor including head-and-neck and lung cancer, and glioma, and had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–3.

We accessed the patients’ case files and the hospital’s electronic medical records. We collected the data regarding baseline demographics, mutation status, primary site and stage of malignancy, and previous treatment details. Additionally, we recorded details on whether the patient received a BRAF inhibitor. If the patient had received a BRAF inhibitor, we recorded which drug was used, the adverse events, response rate, date of progression, and date of death. In patients whose date of death was not available, the date of last follow-up was recorded.

Descriptive statistics were performed. Continuous variables were expressed in terms of the median with range and non-continuous variables (ordinal and nominal) were expressed in terms of percentages. Kaplan–Meier analysis was done for time-to-event analysis.[6] The mean value with its 95% CIs was estimated. As the sample size was small, we did not perform a univariate or multivariate analysis.

We included 17 patients in this analysis, of which nine (52.9%) were able to receive BRAF-targeted therapies. The patients’ baseline characteristics and the treatment received are provided in Table 1.

Table 1:
Table depicting baseline characteristics of all patients

The accessibility to BRAF inhibitors was 52.9% (95% CI, 31–73.7). The BRAF inhibitor was administered in the first line in one patient (5.9%), second line in two patients (11.8%), and third line or beyond in six patients (35.3%). The median number of lines of chemotherapy received in the patients who did not receive a BRAF inhibitor was 2 (IQR, 1–2).

At the time of data censoring, 13 out of 17 patients (76.5%) had died. There was not a single response (complete response [CR] or partial response [PR]) as per the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in patients receiving BRAF inhibitors. The median overall survival (OS) among the nine patients who received BRAF inhibitors was 7.63 months (95% CI, 3.23–16.03), median progression-free survival (PFS) was 6.77 months (95% CI 1.53–16.03), and the one-year progression-free survival (PFS) was 32.4% (95% CI 10.8%–56.6%). The one-year OS and PFS are shown in Figure 1.

Figure 1:
Panel A shows overall survival in months over 1 year. Panel B shows progression-free survival in months over 1 year

This, to our knowledge, is the first report about patients with BRAF V600E mutation and the use of BRAF inhibitors from India. Our study suggests that the accessibility to BRAF inhibitors among those tested at our institute was 52.9% (95% CI, 31–73.7). However, this accessibility is probably an exaggeration for this population. Molecular analysis for BRAF is performed at our center at the physician’s discretion and this discretion takes into account the financial status of the patient and the family. If, in the physicians’ judgment, the patient is unlikely to afford a BRAF inhibitor or any other targeted therapy, then the molecular analysis testing would likely not even be suggested. Hence, the accessibility to BRAF inhibitors in our study was a function of the physicians’ judgment regarding the financial status of the patient. The pattern of use of BRAF inhibitors in our dataset was largely in patients with non-small cell lung cancer (NSCLC), glioma, and melanoma. Patients with thyroid cancer had not received BRAF inhibitors. This is likely due to the prognosis and the availability of other therapeutic options. In radioiodine refractory thyroid cancer, lenvatinib[7] and sorafenib[8] are good therapeutic options, and their effectiveness is independent of the BRAF status. At other sites like NSCLC[9] and glioma,[10] however, the impact of BRAF inhibitors on survival is better than that of other therapeutic options. This explains the difference in the use of BRAF inhibitors seen in this study.

The mean OS of 7.63 months in our cohort was lower than the that reported in the literature—for example, 15.9 months reported by Sosman et al.[11] for vemurafenib and 25.9 months reported by Robert et al.[12] for dabrafenib. This is a matter of concern and needs further evaluation.

The highest proportion of our patients received therapy in the third line and beyond. We believe that this could have skewed the data as later lines of treatment usually correlate with greater disease burden and a poorer PS. With increasing lines of therapy, patient compliance also decreases. Identification of BRAF mutation early in the disease course might help change the result, if more robust data become available on the benefit of BRAF inhibitors in earlier lines of treatment. However, we must be wary that data on OS with the early introduction of BRAF inhibitors would look superior to that in later lines of therapy merely because of the lead-time bias, as the OS would be calculated from an earlier time-point due to the administration of the BRAF inhibitor earlier in the disease course.

Our study was limited by the fact that it was retrospective, included heterogeneous tumor sites, and had patients at different treatment phases. These limitations notwithstanding, our data suggest that BRAF inhibitors are difficult to access in India and the clinical outcomes may be inferior to those reported in the seminal studies.[121314151617]

The real-world data suggest that the efficacy of BRAF inhibitors seems to be lower than that seen in the pivotal studies. This in-practice discrepancy in efficacy is surprising and has important management implications. The reasons for this are currently unknown. Further studies into this mismatch in efficacy between theory and practice might prove useful to help understand the reasons behind it and if or what steps could then be undertaken to bridge this gap in efficacy.

As BRAF V600E is a point mutation, cheaper and quicker detection methods besides next-generation sequencing (NGS), like reverse transcription polymerase chain reaction (RT-PCR) could be developed to improve the detection and the affordability of or accessibility to testing in our setting. However, we believe that the major limiting factor to the widespread use of BRAF inhibitors in India is the financial limitation due to the unaffordability of BRAF inhibitors rather than the cost of BRAF detection methods. In a study performed by Mittal et al.[18] on Indian patients with malignant melanoma, out of a total of 93 patients, testing for BRAF was done in only four patients, and three were positive for BRAF V600E mutation. None of these patients could afford therapy with a BRAF inhibitor. This underscores the problem of financial constraints in our population.[1920] This constraint will continue to exist for our patients even with improved detection methods and is something we believe that future research and development will have to work toward.

We used NGS to detect mutated BRAF in our patients. Confounding mutations or other factors may exist which could have led to a decreased response. For example, in the study by Qu et al.,[21] the presence of a concomitant KRAS mutation with a BRAF mutation diminished the response. Further research into this is required.

The ADMIRE study suggested a similar objective response rate (ORR) to BRAF inhibitors in the first, second, or third-line and beyond of therapy, while OS was high in the first- and second-line of treatment, but dropped by the third-line or beyond for BRAF inhibitors in patients with different tumors.[22] Lead-time bias could play a role in this finding but there is reason for optimism about monotherapy or combination targeted therapy used in early lines of treatment for patients with BRAF mutation rather than the current standard of care.

Author contributions

Conception: All authors; Design of the work: VP, KP; Literature search: All authors; Data collection: All authors: Data analysis and interpretation: VP, KP; Statistical analysis: VP, KP; Drafting the article, critical revision, final approval of the version to be published and accountability for all aspects of the work: All.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


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