Neoadjuvant and Frontline Studies Guide Malignant Melanoma Treatment

Ryan J. Sullivan, MD

The development of targeted therapies and immune checkpoint inhibitors has changed the management of malignant melanoma, providing safer and more effective treatment options and improving outcomes for many patients with this malignancy. However, the question of how best to use these and other treatments, such as oncolytic viruses, to optimize outcomes remains unanswered.

“I think if we had no other effective agents in the next 10 years, we’d be very busy trying to figure out what to do for our patients. We could probably improve the survival of our patients if we just knew which patients to offer which therapies to,” Ryan J. Sullivan, MD, said during an OncLive Peer Exchange^®.

During the Peer Exchange, 5 melanoma experts discussed findings from several exciting studies presented at the 2019 American Society of Clinical Oncology Annual Meeting that are helping to change the way patients with malignant melanoma are treated. The studies were conducted in the neoadjuvant and frontline settings.

Although the panelists acknowledged that significant work is still needed to determine the optimal use of melanoma therapies, particularly in identifying biomarkers to help guide treatment sequencing, they shared their insights into how currently available data from these studies can be put into practice to better personalize treatments.

Neoadjuvant Therapy Studies

Neoadjuvant therapy, which is adjuvant therapy administered before tumor surgery, is not yet the standard of care in patients with malignant melanoma. However, results from several studies have shown that neoadjuvant therapy has benefits in patients with this malignancy, with some regimens demonstrating greater benefit than others.

REDUCTOR Trial

A major benefit of neoadjuvant therapy is that it may convert an inoperable tumor into an operable one. “[In patients with very advanced disease], we knew that we couldn’t get all the disease out—we’d be leaving microscopic or even macroscopic disease at the margins. The availability of BRAF/MEK inhibitors lets us shrink those tumors down with a high level of reliability,” Vernon K. Sondak, MD, said. He proceeded to discuss the findings of the nonrandomized, prospective, phase II REDUCTOR trial.

REDUCTOR assessed neoadjuvant dabrafenib (Tafinlar), a BRAF inhibitor, and trametinib (Mekinist), a MEK inhibitor, for 8 weeks in patients with unresectable, BRAF-mutated, locally advanced, stage III or oligometastatic stage IV melanoma. Of the 21 patients who received the dual inhibitor regimen, 17 (81%) were able to undergo radical resection and 1 (5%) received microscopic irradical resection. Among patients who underwent resection, 8 relapsed and 10 had no evidence of disease. Recurrence was observed usually within a few months of surgery. Patients with no recurrence experienced a prolonged disease-free interval; the median recurrence-free survival (RFS) was 9 months (range, 3-37).¹

Sondak said it has yet to be determined whether neoadjuvant therapy might also have a role in treating less advanced melanoma, including locally advanced disease and resectable, measurable tumors. He advised clinicians to consider neoadjuvant therapy for any tumor measuring ≥1.5 cm in the lymph nodes. He also emphasized that surgeons should make a melanoma diagnosis with a needle biopsy rather than surgical excision. “Get a needle biopsy. Get a BRAF test. Bring that [information] to the multidisciplinary evaluation so these neoadjuvant approaches have a chance to be used,” he said.

INMC Consortium Pooled Analysis

Another major benefit of neoadjuvant therapy is that it can help distinguish early on between patients who would benefit from use of a certain adjuvant regimen and those who would not, enabling continued use of an efficacious regimen in responders and an earlier switch to another treatment strategy in nonresponders. “Give people a year of adjuvant therapy [postoperatively], and you have no idea whether it did anything— whether they were cured, whether they were resistant. You don’t know until it’s too late. Neoadjuvant therapy gives us a window into what’s happening,” Sondak said.

A pooled analysis by the International Neoadjuvant Melanoma Consortium (INMC) reported that patients who experienced a pathologic complete response (pCR) to neoadjuvant therapy had improved RFS.²

The analysis found neoadjuvant immunotherapy and neoadjuvant targeted therapy to be active regimens in patients with stage III melanoma with nodal metastases, with both treatment approaches associated with a high pCR (Table).² These findings were based on pooled data from 6 modern neoadjuvant systemic therapy trials of antiPD-1—based immunotherapy or BRAF/MEK targeted therapy conducted across institutions participating in the INMC. In all, outcomes were analyzed for 184 patients who received neoadjuvant therapy and then underwent surgery.

“There was a pathologic complete rate of about 40% across the board. This is with a reasonable follow-up of around 15.2 months,” Hussein A. Tawbi, MD, PhD, said, indicating this is the time frame in which most events would be expected to occur.

Table. Neoadjuvant Therapy in Melanoma: Pooled Analysis of 6 INMC Studies²

The RFS rate was 100% among the patients who achieved a pCR with immunotherapy (N = 51) and 78% among those who achieved a pCR with targeted therapy (N = 24). Long-term follow-up is needed to determine whether these results will be maintained. Additionally, randomized clinical trials are needed to determine whether patients who achieve a pCR with neoadjuvant therapy also require adjuvant therapy.²

T-Vec Study

Talimogene laherparepvec (T-VEC; Imlygic) is an oncolytic virus (ie, a weakened form of herpes simplex virus type 1) that is directly injected into tumors. It is approved for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with recurrent melanoma after initial surgery.³ More recently, it has been explored as another neoadjuvant therapy option but has thus far shown a less robust response than what has been observed with neoadjuvant immunotherapy or BRAF/MEK inhibition.⁴

In a phase II study (NCT02211131), patients with high-risk resectable stage IIIB/C-IVM1a melanoma were randomly assigned to neoadjuvant T-VEC administered in 6 doses over 12 weeks plus surgery or up-front surgery alone.

The use of neoadjuvant T-VEC was associated with improvements in rates of histopathologic tumor-free (R0) surgical resections among the 57 patients who received at least 1 dose of T-VEC plus surgical resection compared with the R0 rate among 69 who received surgery alone (56.1% vs 40.6%, respectively; P = .082). In the intention-to-treat population, which comprised all enrolled patients, the 1-year RFS rate was 33.5% among 76 patients randomized to T-VEC plus surgery versus 21.9% in the 74 patients who were assigned surgery alone (HR, 0.73; 80% CI, 0.56-0.93; log-rank P = .048). Additionally, investigators noted a trend for improved overall survival (OS): The 1-year OS was 95.9% in the T-VEC arm compared with 85.5% with surgery alone (HR, 0.47; 80% CI, 0.27-0.82; log-rank P = .076).⁴

Of note, T-VEC was also associated with a reduced number of patients proceeding to surgery. “So 75% of patients who got the T-VEC made it [to surgery], which kind of sounds good until you realize that everyone should have had surgery,” Jason J. Luke, MD, FACP, said. In contrast, 93% of patients randomly assigned to surgery alone received it.⁴ “If we’re going to consider neoadjuvant therapy, I really think we should think about using the active agents that are systemic agents and that we know can be effective,” he said.

Frontline Therapy Studies

In the frontline setting, immunotherapy options for metastatic melanoma include single-agent nivolumab (Opdivo), single-agent pembrolizumab (Keytruda), and combination therapy with ipilimumab (Yervoy) and nivolumab. For patients with BRAF mutations, 3 targeted combination therapies are also available: dabrafenib/trametinib, vemurafenib (Zelboraf)/cobimetinib (Cotellic), and encorafenib (Braftovi)/ binimetinib (Mektovi).

Each of these treatments has been associated with substantial response rates and improvements in OS; however, no head-to-head trials have been conducted comparing immunotherapy with a targeted approach, making treatment selection challenging, especially in patients with BRAF mutations, for whom a plethora of options exist.

Tawbi said he generally favors immunotherapy because it has a more durable response. “In patients who have a low LDH [lactate dehydrogenase level] and low tumor burden, single-agent immunotherapy is a reasonable approach,” he said.

In contrast, Tawbi said he would consider combination immunotherapy in the setting of a high tumor burden, a high LDH level, and, especially, brain metastases. “At our institution, we tend to keep targeted therapy for the second line, although there are no data for BRAF/MEK [inhibition] in the second line after PD-L1 resistance,” he said, adding that he may also favor BRAF/MEK inhibitors in patients with autoimmune disorders to avoid immune-mediated toxicities.

The panelists proceeded to discuss longer-term data for some of the available first-line treatments as well as some novel strategies still under investigation, such as adding immunotherapy to targeted therapy.

Updated Dabrafenib/Trametinib Data

A 5-year analysis of the long-term effects of first-line dabrafenib/trametinib in patients with BRAF V600—mutant unresectable or metastatic melanoma found this treatment to be associated with a durable, long-term benefit in many patients.⁵

“We saw that the progression-free survival [PFS] was around 20%. That means that about one-fifth of the patients never progressed on targeted therapy, and I think that’s important,” Luke said. He also noted that LDH level, which has been used as prognostic biomarker in melanoma for at least 50 years, correlated with patient outcomes, with 40% of patients with a low LDH level being progression free compared with only 10% of those with a high LDH level.

COMBI-i: Adding Spartalizumab to Dabrafenib/Trametinib

Although checkpoint inhibitors and targeted therapies have improved outcomes in patients with BRAF-mutant unresectable or malignant melanoma, many patients progress, which has spurred the search for new and more durable treatment strategies. One such approach under investigation is the addition of an anti—PD-1/PD-L1 agent to BRAF/MEK inhibition.

An analysis of parts 1 (run-in cohort) and 2 (biomarker cohort) of the 3-part COMBI-i trial (NCT02967692) showed that the addition of the anti—PD-1 antibody spartalizumab to dabrafenib/trametinib was associated with a promising and durable objective response rate (ORR); the ORR by local investigator review was 78% (28 of 36 patients), including a complete response rate of 42% (15 of 36 patients).⁶ After a median follow-up of >15 months, the median PFS was 23.7 months (95% CI, 12.0—not estimable).

The triplet had a higher rate of toxicity than what has been observed with dabrafenib/trametinib but was manageable. “When you do some dose interruptions and dose reductions and follow some algorithms that have been developed as part of the study, you can still deliver the 3 drugs together. About 17% of patients discontinued all 3 drugs, but again, that means that the other 83% managed to get them,” Tawbi said.

He noted that thus far the findings suggest the triplet may be more effective in the first line for patients with BRAF mutations compared with dabrafenib/trametinib and that the data are generating excitement among the oncology community about what benefit triplet therapies might demonstrate in phase III trials. The randomized phase III portion (part 3) of COMBI-i is ongoing.

COLUMBUS: OS Update for Encorafenib/Binimetinib Versus Monotherapies

An updated analysis of OS and other endpoints from the COLUMBUS trial (NCT01909453) found encorafenib/binimetinib to be superior to vemurafenib or encorafenib monotherapy (Figure).⁷ “The median overall survival of encorafenib/ binimetinib is about 33 months…with single-agent encorafenib, it’s about 23 months, and with single-agent vemurafenib, it’s about 16 months,” Sullivan said.

Luke also explained that the median PFS with this combination was more favorable than what investigators have observed with dabrafenib/ trametinib and vemurafenib/cobimetinib in other studies. “Whereas around 11 months had been the median progression-free survival for dabrafenib/ trametinib and vemurafenib/cobimetinib, for encorafenib and binimetinib, it was about 14.5 months,” he said.

Tawbi outlined some mechanisms that may explain the improved efficacy and safety of encorafenib/binimetinib versus the other BRAF/MEK combinations. “[With encorafenib] there seems to be a slower dissociation constant, so it seems to stick to its target and hold on to it a little longer, which can be part of the reasons it works better,” he said. He suggested the improved safety may be due to the shorter half-life of binimetinib compared with that of other MEK inhibitors.

Figure. Updated Survival Findings in COLUMBUS Study⁷

“Binimetinib seems to have the shortest half-life of all MEK inhibitors. While other MEK inhibitors have half-lives that take 2 to 3 weeks to get a complete washout, binimetinib has a half-life of just hours, so you can get a washout from the MEK inhibitor within a couple of days,” he said, explaining this also makes it easier to manage MEK-related toxicities. He noted that withholding treatment for a few days or reducing the dose is often sufficient to resolve the MEK-related adverse effects.

CheckMate-067: 4-Year Data on Patient-Reported QOL

CheckMate-067 (NCT01844505) randomly assigned 945 patients with advanced melanoma 1:1:1 to receive nivolumab plus placebo, nivolumab plus ipilimumab, or ipilimumab plus placebo.⁸ One-year data suggested quality of life (QOL) was maintained in patients receiving nivolumab with or without ipilimumab. The new 4-year data suggested patient-reported QOL and symptoms continue to be maintained from baseline in these patients.

“I think the message from this particular trial was pretty clear. Once you get through the initial adverse effects—especially of the ipilimumab/nivolumab combination, which has a lot of them—if you get into a maintenance phase, most of those patients maintain a very reasonable quality of life that’s not dramatically different from what it was before,” Sondak said.

However, he noted that sometimes patients will experience a rare but lingering complication and say they would have selected another treatment had they known about the risk. Subsequently, he emphasized the importance of involving patients in treatment decision making.

“We have 3 different BRAF/MEK inhibitor combinations that have 3 different sets of toxicities, all similar but some unique. We’ve got PD-1, which has relatively low toxicity, and the combination of PD-1 and anti—CTLA-4 that really ramps up the early toxicity. We need to be asking our patients, ‘What’s most important?’ How are you going to weigh and balance the advantages and disadvantages of these regimens?” Sondak concluded.

References

1. Blankenstein SA, Rohaan MW, Klop WMC, et al. Neoadjuvant cytoreductive treatment with BRAF/MEK inhibition of prior unresectable regionally advanced melanoma to allow complete surgical resection: REDUCTOR trial. Poster presented at: 2019 American Society of Clinical Oncology Annual Meeting; May 31June 4, 2019; Chicago, IL. Abstract 9587. meetinglibrary.asco. org/record/176412/abstract.
2. Menzies A, Rozeman EA, Amaria RN, et al. Pathological response and survival with neoadjuvant therapy in melanoma: a pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC). Abstract presented at: 2019 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 9503. meetinglibrary.asco.org/record/173444/abstract.
3. IMLYGIC (talimogene laherparepvec). FDA website. www.fda.gov/ vaccines-blood-biologics/cellular-gene-therapy-products/imlygic-talimogene-laherparepvec. Updated March 1, 2018. Accessed August 27, 2019.
4. Dummer R, Gyorki DE, Hyngstrom JR, et al. One-year (yr) recurrence-free survival (RFS) from a randomized, open label phase II study of neoadjuvant (neo) talimogene laherparepvec (T-VEC) plus surgery (surgx) versus surgx for resectable stage IIIB-IVM1a melanoma (MEL). Poster presented at: 2019 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 9520. meetinglibrary.asco.org/record/174628/abstract.
5. Nathan PD, Robert C, Grob JJ, et al. Five-year analysis on the long-term effects of dabrafenib plus trametinib (D + T) in patients with BRAF V600—mutant unresectable or metastatic melanoma. Abstract presented at: 2019 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 9507. meetinglibrary.asco.org/record/174754/abstract.
6. Long GV, Lebbe C, Atkinson V, et al. The anti—PD-1 antibody spartalizumab (S) in combination with dabrafenib (D) and trametinib (T) in previously untreated patients (pts) with advanced BRAF V600mutant melanoma: updated efficacy and safety from parts 1 and 2 of COMBI-i. Poster presented at: 2019 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 9531. meetinglibrary.asco.org/record/174904/abstract.
7. Liszkay G, Gogas H, Mandalà M, et al. Update on overall survival in COLUMBUS: a randomized phase III trial of encorafenib (ENCO) plus binimetinib (BINI) versus vemurafenib (VEM) or ENCO in patients with BRAF V600—mutant melanoma. Poster presented at: 2019 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 9512. meetinglibrary.asco.org/record/173422/abstract.
8. Schadendorf D, Larkin JMG, Wolchok JD, et al. Patient-reported quality of life (QoL) of advanced melanoma patients in a phase 3 study of nivolumab (NIVO) with or without ipilimumab (IPI) versus IPI: CheckMate 067 4-year data. Poster presented at: 2019 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 9551. meetinglibrary.asco.org/record/176201/abstract.