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Published in final edited form as: Pigment Cell Melanoma Res. 2019 Sep 12;33(1):86–95. doi: 10.1111/pcmr.12813

Neoadjuvant BRAF-targeted therapy in regionally advanced and oligometastatic melanoma

Zeynep Eroglu 1,*,#, Jennifer Eatrides 1,#, Syeda Mahrukh Hussnain Naqvi 2, Youngchul Kim 2, Jeani Rich 1, Nalan Akgul Babacan 1, Andrew S Brohl 1, Joseph Markowitz 1, Amod Sarnaik 1, Jonathan Zager 1, Nikhil I Khushalani 1, Vernon K Sondak 1, Jane Messina 1
PMCID: PMC6928428  NIHMSID: NIHMS1042782  PMID: 31329344

Abstract

Background:

Current management of locoregional and oligometastatic melanoma is typically with surgery; however, some patients are unable to undergo resection due to location/size of their tumors and/or the anticipated morbidity of the surgery. While there are currently no established guidelines for neoadjuvant therapy in melanoma, neoadjuvant BRAF-targeted therapy may make resection more feasible.

Methods:

A retrospective analysis was conducted of 23 patients with BRAFV600-mutant, stage III/IV melanoma treated with BRAF-targeted therapy prior to surgery, with no adjuvant treatment. Surgical specimens, preoperative imaging and clinical outcomes were evaluated.

Results:

Ten of 23 patients (44%) attained a pathologic complete response (pCR), with no correlation between RECIST-response based on preoperative imaging and pathologic response. After a median of 43 months follow-up, only 1 patient (10%) with a pCR recurred; while 8 of 13 (62%) patients without a pCR recurred. Patients with a pCR had significantly improved relapse-free (RFS) and overall survival (OS) compared to patients with residual tumor.

Conclusion:

Neoadjuvant BRAF-targeted therapy is associated with a high pCR rate in patients with stage III-IV melanoma, which may correlate with improved RFS and OS.

Keywords: BRAF-targeted therapy, melanoma, neoadjuvant therapy

Introduction:

The current standard of care treatment of stage III melanoma involves surgical management followed by a discussion of observation versus postoperative adjuvant therapy. A similar strategy is now widely used in oligometastatic disease. While many patients with stage III and a select few patients with stage IV disease are able to undergo curative surgery, there may be significant morbidity associated with some surgeries, and others are considered unresectable or ‘borderline resectable’ due to the size and/or location of their tumors. Neoadjuvant (preoperative) therapy combines the potential benefits of standard postoperative adjuvant therapy (i.e., improved relapse-free survival [RFS] and possibly overall survival [OS] as well) with the ability to make surgery easier when tumors respond and the opportunity to assess the therapeutic efficacy of the treatment based on pathologic assessment of the resected tumor. In patients with stage IV disease, some patients may also receive upfront systemic therapy with surgery only utilized if they do not have an upfront response to therapy without disease progression elsewhere. Although neoadjuvant therapy has a well-established role in other cancer types such as breast, esophageal and rectal cancer, there are no established guidelines for neoadjuvant therapy in melanoma. Several phase II studies evaluated neoadjuvant chemotherapy, biochemotherapy, high-dose interferon or ipilimumab in patients with stage III melanoma, which were associated with either low response rates and/or high toxicity in unresectable metastatic disease. (Buzaid et al., 1998; Gibbs et al., 2002; Kounalakis et al., 2012; Koyanagi et al., 2005; Lewis et al., 2006; Moschos et al., 2006; Serrone et al., 2000; Tarhini et al., 2014)

More promising results have been noted with BRAF inhibition. About 45–50% of patients with melanoma harbor a BRAF mutation, and phase III trials comparing combined BRAF/MEK inhibitors to BRAF inhibitors alone in advanced unresectable melanoma have shown a clear benefit of dual inhibition with median progression-free survival of 11–14.9 months vs 7.2–8.8 months and objective (RECIST) response rates of 64–70% vs 50–53%.(Ascierto et al., 2016; Dummer et al., 2018; Long et al., 2015; Robert et al., 2015) BRAF/MEK-inhibitor therapy is also approved in the adjuvant setting after a study that showed dramatic improvement in RFS in stage III melanoma after complete lymphadenectomy with a year of adjuvant dabrafenib + trametinib.(Long et al., 2017) The rapid response kinetics, low rate of immediate disease progression without any clinical benefit and the overall favorable toxicity profile of BRAF inhibitors, especially combined with MEK inhibitors, make them ideal candidates for investigation in the neoadjuvant setting for regionally advanced or oligometastatic melanoma. Several case reports have shown significant tumor pathologic responses (50–98%) with neoadjuvant BRAF inhibition (duration ranging from 4 weeks to 10 months); four cases showed pathologic complete response (pCR), one showed near pCR with almost complete regression, with only one case that showed a persistent neoplastic nodule.(Fadaki et al., 2012; Kaidar-Person et al., 2014; Koers et al., 2013; Melnik et al., 2013; Rastrelli et al., 2014; Seremet et al., 2015) Two retrospective analyses of neoadjuvant BRAF-targeted therapy for unresectable stage III melanoma have also shown promising results, including clinical response enabling R0 resection in 12 of 13 patients following 6–8 weeks of BRAF-targeted therapy, with pCR in 31% of patients, and 2 of 6 patients with a pCR in another study after 6 months of neoadjuvant therapy.(Sloot et al., 2016; Zippel et al., 2017). Most recently, a randomized phase II trial comparing neoadjuvant/adjuvant dabrafenib+trametinib to surgery with the option of postoperative adjuvant immunotherapy was stopped early, after only 21 patients were accrued, when a planned interim analysis showed dramatically better relapse-free survival for the neoadjuvant arm.(Amaria et al., 2018) After 8 weeks of neoadjuvant dabrafenib and trametinib, 11 of 13 (85%) patients achieved an objective radiographic response (2 complete and 9 partial responses), and no patients progressed. Seven (58%) of 12 patients in the neoadjuvant arm who underwent surgery achieved pCR.

Regardless, several issues remain in question, including the optimal duration of neoadjuvant BRAF inhibition prior to surgery, role of adjuvant therapy, whether imaging response correlates with pathologic response, whether pathologic response correlates with RFS and OS, and if responses can inform postoperative treatment decisions. Hence, a retrospective review of patients with resectable or borderline resectable/unresectable stage III or oligometastatic melanoma treated with neoadjuvant BRAF inhibition followed by resection was carried out to better characterize pathologic patterns of response and their correlation with clinical benefit.

Methods:

After Institutional Review Board approval, a retrospective review was conducted for patients with BRAFV600-mutant melanoma who received neoadjuvant BRAF targeted therapy prior to resection at Moffitt Cancer Center from 2011 to 2017. Patients either had resectable or borderline resectable/unresectable disease, such as bulky adenopathy that was surgically resectable but could potentially compromise neurovascular structures at resection. All patients underwent CT imaging both at baseline before initiation of BRAF-targeted therapy and prior to surgery; best response was assessed using RECIST 1.1 criteria. RFS and OS were calculated from the date of initial BRAF-targeted therapy and from date of surgery.

The resected specimens were analyzed for pathologic response and evaluated for distinctive patterns of response. Pathologic complete response was defined as no viable tumor cells observed. Pathologic major PR/near CR, pathologic partial response (pPR) and pathologic non-response (≥50% viable tumor) were also graded according to recently established guidelines.(Tetzlaff et al., 2018) Histologic response patterns were categorized into four groups: (i) necrotic, (ii) fibrotic/melanotic, (iii) hyalinized, and (iv) mixed patterns. Lymph nodes from dissection specimens were examined either in toto or with a single representative section from larger (>4mm) lymph nodes and evaluated with hematoxylin and eosin (H&E) staining. Immunohistochemical (IHC) staining for Melan-A or Sox-10 was utilized where the presence of tumor was difficult to evaluate on H&E, and to facilitate detection of detect minimal viable tumor in a background of necrosis or fibrosis. All stains were evaluated in conjunction with H&E to exclude false-positive staining of necrotic tumor or melanin-containing macrophages. Available pre-treatment tumor samples were also analyzed for expression of phosphorylated ERK (pERK) via IHC.

The Kaplan-Meier method and Greenwood’s formula were used for the estimation of survival probabilities (RFS and OS) and the corresponding 95% confidence intervals (CIs). Comparisons between groups were done with the log-rank test. Response outcomes were summarized using frequency and proportions. Statistical analyses were performed using SAS 9.4. All tests were two-sided; P values ≤0.05 were considered statistically significant.

Results:

Patient Characteristics

During the study timeframe, a total of 297 patients with melanoma had received BRAF-targeted therapy at Moffitt Cancer Center, not including patients on clinical trials. Of these, a total of 23 patients met the inclusion criteria. There were no patients identified who were treated with neoadjuvant intent but who could not proceed to surgery. All patients underwent surgery, regardless of imaging response to neoadjuvant BRAF-targeted therapy. Most patients had stage IIIC (n=10) or M1a (n=12) disease (AJCC v7). (Table 1 and 2). Twenty-two patients had melanoma with a BRAF V600E mutations; 1 with a BRAF V600K mutation. Patients received neoadjuvant BRAF-targeted therapy for a median duration of 6.6 months and did not receive adjuvant treatment afterwards (Figure 1). Eight patients received BRAF inhibitor alone (vemurafenib or dabrafenib) and fifteen received combined BRAF/MEK inhibition: vemurafenib + cobimetinib (n=2), dabrafenib + trametinib (n=12), or encorafenib + binimetinib (n=1).

Table 1:

Patient Demographics

Characteristic N= 23 %
Median age (range) 50.5 years (33–74) n/a
Gender = male 16 70%
Stage at the start of therapy
 – IIIC 10 43%
 – M1a 12 52%
 – M1c 1 4%
BRAF V600E 22 96%
BRAFV600K 1 4%
Elevated LDH prior to surgery 3 13%
Not available 5 21%
Median duration of neoadjuvant treatment (range) 6.6 months (0.3–18.4)
Median duration of follow-up (range) 43 (10–95 months)
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Table 2.

Treatment and outcomes for patients

Pt # Disease involvement at start of BRAF Stage at start of neoadjuvant therapy BRAF inhibitor therapy Duration of neoadjuvant therapy (months) Best Response by RECIST criteria Pathology findings/interpretation Pathologic Response
1 Axilla/chest wall M1a/IV V 4.0 PR Hyalinized CR
2 Axilla N3/IIIC V 8.8 PR Mixed (necrotic/hyalinized)/TR CR
3 Groin/pelvic wall M1a/IV D+T 1.2 PR Mixed (necrotic, fibrotic/hyalinized) CR
4 Axilla N3/IIIC V 6.4 PR Mixed (necrotic/hyalized)/TR Major PR/near CR
5 Groin/pelvis M1a/IV D+T 1.4 PR Viable disease with no necrosis/RD non-response
6 Axilla N3/IIIC D 4.6 PR Necrosis based on report/RD non-response
7 Thigh/groin/pelvis M1a/IV V 5.0 PR Mixed (necrotic/fibrotic) CR
8 Axilla/neck N1/IIIC E+B 6.6 PR Mixed (necrotic/hyalinized) PR
9 Thigh/groin IIIC D+T 3.3 SD necrotic non-response
10 Axilla/neck N2/IIIC V 14.0 PR Mixed (necrotic and fibrotic/melanotic and hyalinized) PR
11 Pelvis IV D+T 8.2 PR Hyalinized CR
12 Axilla/arm IIIC V 18.4 PR Mixed (necrotic and hyalinized) CR
13 Axilla/neck IIIC D+T 6.2 PR Fibrotic/melanotic Major PR/near CR
14 Pelvis IV D+T 8.5 PR Hyalinized Major PR/near CR
15 Axilla/thyroid M1a/IV D+T 7.5 PR Hyalinized CR
16 Neck M1a/IV D+T 4.6 SD Mixed (necrotic and fibrotic/melanotic) CR
17 Groin/thigh M1a/IV D+T 8.4 PR No necrosis/RD non-response
18 Groin/back M1c/IV D+T 10.6 PR No necrosis(maturation)/TR non-response
19 Bilateral axilla, thigh M1a/IV V 8.6 PR Necrotic PR
20 Axilla/subcut. M1a/IV D+T 9.3 PR Mixed (necrotic and fibrotic/melanotic) CR
21 Axilla IIIC V+C 0.3 PR Hyalinized Major PR/near CR
22 Axilla/chest wall M1a/IV V+C 1.4 SD Mixed (necrotic in soft tissue, no response in nodes) non-response
23 Groin/pelvis IIIC D+T 7.0 PR Mixed (necrotic and fibrotic/melanotic) CR
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V = vemurafenib, V + C = vemurafenib+cobimetinib, D + T = dabrafenib+trametinib, E + B = encorafenib+binimetinib. CR, complete response; PR, partial response.

Figure 1:

Figure 1:

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Swimmer plot with overall survival of all patients after start of BRAF-targeted therapy, grouped by pathologic and RECIST response.

Patient outcomes

Median follow-up was 43 months (range 10–95) from start of targeted therapy. Using CT imaging done after conclusion of neoadjuvant therapy and prior to surgery, the radiographic response rate (RECIST 1.1 criteria, complete or partial response) was 87%; 20 patients had partial responses (PR) and 3 patients had stable disease (SD). Patients were not restarted on BRAF-targeted therapy post-operatively unless they experienced eventual relapse of their melanoma. Nine of 23 patients (39%) developed relapse post-surgery; three of them (33%) developed CNS metastases. Four of the 9 patients who relapsed were restarted on BRAF/MEK targeted therapy. Two patients eventually progressed and died after repeated targeted therapy (after duration of 3 months and 2 months); one patient had partial response at last follow up (6 months) but was then lost to follow up, and one continues to have complete response and still remains on BRAF/MEK targeted therapy 2.5 years after time of relapse.

Histopathologic evaluation and outcomes

In the 23 cases, histologic evaluation of specimens showed necrosis in 4 (17%), fibrosis/melanosis in 1 (4%), hyalinization in 6 (26%), and a mixture of these features in 10 (43%), while no necrosis, hyalinization or fibrosis was seen in the other 2 cases (9%, Figure 2). Pathologic CR, defined as complete absence of viable tumor, was seen in surgical specimens of 10 patients (44%). Six of the pCR cases showed hyalinization, while the remaining showed mixed patterns.

Figure 2:

Figure 2:

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Histologic patterns of response in resected melanoma specimens. H&E stains show the following patterns: (A) necrotic, (B) fibrotic/melanotic, (C) hyalinized, (D) mixed necrotic/melanotic.

Residual viable tumor (non-pCR) was present in 13 patients; eight of these patients (62%) had disease relapse. In contrast, only 1 of the 10 patients who obtained a pCR has relapsed (10%, p=0.04). In further breakdown of the non-pCR patients, 2 of the 4 with major PR/near CR relapsed, while 1 of the 3 partial pathologic response, and 3 of the 6 pathologic non-response patients relapsed. Of note, radiologic tumor response per RECIST did not correlate with pathologic response or RFS (Figure 1,3). Nine of the 20 patients with PR by RECIST actually had a pCR on their surgical pathology, while another with stable disease per RECIST had a pCR (Figure 4). In 8 patients who had pre-treatment tumor tissue available, there was no evident association between pretreatment level of pERK expression and likelihood of pCR or RFS.

Figure 3:

Figure 3:

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Relapse-free survival (RFS) based on radiographic response. There was no statistical significance between response by imaging and relapse-free survival. RECIST response category: partial response (red), stable disease (green).

Figure 4:

Figure 4:

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Patient treated with 6 months of neoadjuvant dabrafenib and trametinib. CT imaging at end of neoadjuvant treatment shows stable disease, while surgical tumor specimen showed a pathologic complete response.

There was a statistically significant difference in RFS based on pathologic response, whether measured from the start of BRAF-targeted therapy or from the time of surgery (Figure 5). Median RFS has not yet been reached in the pCR group, while it was 10.5 months (95% CI 5.7–56.6) from date of surgery and 24.3 months (12 – 65.4) from start of BRAF-targeted therapy in the non-pCR group. Median RFS was 65.4 [24.3 – not reached] and 56.6 [10.2 – not reached] months for all 23 patients, from start of therapy or date of surgery respectively. There was also improved overall survival with a pCR, as all these patients are still alive, while five of the patients who did not obtain a pCR have died (p=0.01, Figure 6). There was no statistically significant difference in RFS discernable based on whether patients received single agent vs combination BRAF-targeted therapy.

Figure 5:

Figure 5:

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Relapse-free survival based on pathology response: RFS of patients treated with neoadjuvant BRAF-targeted therapy from start of BRAF inhibition (A) and from time of surgery (B). Patients with pCR (blue) had improved RFS compared to those with non-pCR (red).

Figure 6:

Figure 6:

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Overall survival based on pathology response for patients treated with neoadjuvant BRAF-targeted therapy.

Discussion:

There is currently significant interest in neoadjuvant systemic therapy in patients with borderline resectable or unresectable stage III or oligometastatic stage IV melanoma, but many questions remain unanswered. A trial from MD Anderson randomized patients to 8 weeks of neoadjuvant + 44 weeks of adjuvant dabrafenib+trametinib compared to surgery followed by standard of care treatment.(Amaria et al.) With a median follow-up of 18.6 months, 10 of 14 patients receiving neoadjuvant treatment were alive without relapse while all seven of those on the standard of care arm relapsed, and neoadjuvant treatment was associated with statistically significantly improved distant metastasis-free survival, with a median RFS of 19.7 months. In the NeoCombi trial from Melanoma Institute Australia, 35 patients with clinically resectable stage III melanoma were treated with 12 weeks of neoadjuvant followed by 40 weeks of adjuvant dabrafenib+trametinib. (Long et al., 2019) With a median follow-up of 27 months, 15 of 35 patients had not relapsed, with a median RFS of 23.3 months.

Of course there are important differences between those clinical trials and this retrospective analysis, including the variable lengths of the neoadjuvant regimens, the use of postoperative adjuvant therapy, and the exclusion of patients with unresectable melanoma from the prospective trials. Nevertheless, some similarities emerge: in the neoadjuvant arm of the MD Anderson trial, 3 of the 4 patients who relapsed recurred in the brain, while 8 of 20 recurrences in the Australia study were also in the brain; 33% of patients who relapsed in our analysis also recurred with CNS metastases. This has raised the question of whether the brain is a sanctuary site or whether neoadjuvant BRAF-targeted therapy in some way predisposes to development of brain metastases.(Ascierto and Eggermont) Also similar to a pooled analysis from MD Anderson and Australia trials, radiologic response assessed prior to surgery in this analysis did not always correlate with whether patients obtained a pCR at surgery.(Menzies et al., 2017) In the MD Anderson trial, 3 of 5 patients with viable residual tumor had a relapse of their melanoma compared with only 1 of the 7 patients who obtained a pCR. In our analysis, the pCR rate was 43% and only 1 of 10 pCR patients have relapsed. In the Australia trial, while 17 of 35 patients (49%) achieved pCR, 8 of 17 (47%) with a pCR had disease relapse, while 12/18 (66%) with a non-pCR relapsed. In a pooled analysis of these two studies, 22% of the 24 patients with a pCR relapsed by 2 years. (Menzies et al., 2019)

There are numerous outstanding questions in consideration of neoadjuvant BRAF-targeted therapy, including the optimal length of treatment. While the MD Anderson trial used 8 weeks and the Australian study 12 weeks of neoadjuvant dabrafenib+trametinib, both employed adjuvant therapy to complete a year of treatment. One of the limitations of our analysis besides its retrospective nature is the different lengths of neoadjuvant treatment patients received, although our preferred approach has been to give six months of neoadjuvant treatment prior to surgery with no adjuvant therapy. Nevertheless, with a median follow-up of 43 months, to our knowledge this is the longest duration of follow-up of patients treated with neoadjuvant BRAF-targeted therapy. Our data also suggest that obtaining a true pCR is important with neoadjuvant BRAF-targeted therapy, as patients with a pathologic major PR/near CR were similarly likely to relapse as those without a pathologic response, although sample sizes are small. However, the benefit of achieving a complete pathologic response with neoadjuvant BRAF-targeted therapy and its correlation with RFS and OS still needs to be validated in larger clinical trials.

For patients with resectable or borderline/potentially resectable disease at presentation, neoadjuvant treatment also has to be considered in the context of data from adjuvant dabrafenib+trametinib in patients with stage III melanoma (Long et al., 2017), as it is not yet known how neoadjuvant vs adjuvant-only therapies compare in long-term relapse-free and overall survival. Furthermore, in our analysis, despite not receiving any adjuvant treatment, nearly all the patients who obtained a pCR after surgery had no disease relapse, raising the question of whether adjuvant treatment to finish a year of BRAF-targeted therapy is necessary in patients with a pCR. Questions also remain about how neoadjuvant and adjuvant anti-PD-1±anti-CLTA-4 therapies fit into the treatment paradigm for BRAF-mutant melanoma. Two small studies that evaluated neoadjuvant ipilimumab 3 mg/kg + nivolumab 1 mg/kg have shown pCR rates in 3 of 10 and 5 of 11 patients respectively, although grade 3/4 toxicity rates of up to 90% were observed (Amaria et al., 2018; Blank et al., 2018); ipilimumab at 1mg/kg with nivolumab 3mg/kg appears to be a less toxic regimen, while maintaining a similar pCR rate (Rozeman et al., 2019) Several studies are currently evaluating neoadjuvant triple-combinations of BRAF/MEK-inhibitors with immununotherapies (, ).

In summary, achieving a pathologic complete response to neoadjuvant BRAF-targeted therapy may correlate with improved patient outcomes including improved relapse-free and overall survival, although this will need to be validated in prospective trials with longer follow-up. Until then, neoadjuvant BRAF-MEK inhibition represents a viable strategy for patients presenting with BRAF-mutant melanoma with borderline resectable or unresectable stage III and selected patients with oligometastatic stage IV disease.

Significance:

This is an analysis of neoadjuvant BRAF-targeted therapy in patients with resectable or borderline resectable/unresectable melanoma treated for a median of 6 months prior to surgery, with no subsequent adjuvant treatment. These 23 patients have a median follow-up of over 3.5 years, which to our knowledge represents the longest follow-up to date for neoadjuvant therapy in melanoma. Only 1 in 10 patients who obtained a pathologic complete response (pCR) had recurrence, and these patients had significantly improved relapse-free and overall survival in comparison to those without a pCR at surgery. These results suggest that pathologic complete response (but not near-complete response or partial response) correlates with both improved relapse-free and overall survival in these patients.

Acknowledgements:

Moffitt Cancer Center NCI Skin SPORE (5P50CA168536) and Moffitt Cancer Center Total Cancer Care Initiative and Collaborative Data Services (P30-CA076292).

Funding:

This work has been supported in part by NCI Skin SPORE P50CA168536–01A1 and the Tissue Core Facility (P30-CA076292) at the H. Lee Moffitt Cancer Center & Research Institute.

Disclosures:

ZE received research funding from Novartis and was on an advisory board for Array Biopharma and Regeneron. JZ received research funding from Novartis and on the advisory board for Array Biopharma. VKS has advisory board relationships with Merck, Bristol-Myers Squibb, Regeneron and Novartis and serves on Data Safety Monitoring Boards for Array, Bristol-Myers Squibb, Novartis, Polynoma, and Pfizer. NIK has advisory board relationships with Bristol-Myers Squibb, EMD Serano, HUYA Bioscience International, Genentech, and Regeneron, has stock ownership of Bellicum Pharmaceuticals, Mazor Robotics, and TransEnterix, Inc., and serves on Data Safety Monitoring Boards for AstraZeneca. AS is a consultant/advisory board member for Iovance Biotherapeutics and received research funding from Iovance and Provectus. AB was on an advisory board for Bayer. JM has received institutional funding from Genoptix and Morphogenesis, was on an advisory board for Array and on Data Safety Board for Newlink Genetics.

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