Oncologists seek to optimize a transformed landscape in melanoma treatment
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The past decade has ushered in major transformations in the prevention, diagnosis and treatment of melanoma.
Increased public awareness of sun protection measures, the advent of immune checkpoint inhibitors, and the use of treatments that target specific mutations have led to substantial declines in melanoma mortality.
Source: Atrium Health.
“The care of melanoma is wildly different than it was many years ago, particularly high-risk melanoma,” Richard L. White Jr., MD, FACS, chief of surgical oncology and professor of surgery in the department of surgery at Levine Cancer Institute at Atrium Health, said in an interview with HemOnc Today. “It’s changed for the better. The paradigms of melanoma care have shifted dramatically in the last 5 years.”
The 2011 FDA approvals of vemurafenib (Zelboraf, Genentech) for BRAF V600E-mutated unresectable or metastatic melanoma and the anti-CTLA-4 agent ipilimumab (Yervoy, Bristol-Myers Squibb) for metastatic melanoma were the first of several targeted therapies and immunotherapies for this patient population.
Today, researchers are focused on synergizing the benefits of these therapies through combination regimens and discovering biomarkers to best tailor their use.
HemOnc Today spoke with clinical investigators about the dramatic changes in melanoma treatment and outcomes over the last decade, why biomarkers play an important role in determining optimal treatments, how changes in the treatment landscape are impacting neoadjuvant treatment and surgical standards, and how greater public awareness of melanoma has reaped dividends.
‘Boost’ the benefits
Targeted therapies and immunotherapies have significantly improved survival for patients with advanced melanoma.
According to the American Cancer Society, these treatment advances led to a 7% yearly decline in the melanoma death rate among adults aged younger than 50 years from 2013 to 2017, with a corresponding 5.7% yearly decline among older adults. The 5-year survival rate for all stages of melanoma combined is 92%.
Patients who harbor a BRAF mutation — which includes about half of the melanoma population — can receive treatment with BRAF and MEK inhibitors such as dabrafenib (Tafinlar, Novartis) plus trametinib (Mekinist, Novartis), vemurafenib plus cobimetinib (Cotellic, Genentech), and encorafenib (Braftovi, Array Biopharma) plus binimetinib (Mektovi, Array Biopharma).
The combination of BRAF and MEK inhibition is associated with an approximately 65% response rate and a 5-year OS rate of 34%, according to Asim Amin, MD, PhD, melanoma oncologist at Levine Cancer Institute at Atrium Health.
OS and PFS curves for targeted therapies are “immediately divergent,” according to Omid Hamid, MD, chief of translational research/immuno-oncology at The Angeles Clinic & Research Institute, co-director of the cutaneous malignancy program at Cedars-Sinai Cancer Center and a HemOnc Today Editorial Board Member.
“Due to concerns regarding the long-term durability of targeted therapy response, we have hypothesized that by adding immunotherapy, we would achieve more durable long-term benefit and the tail of the curve,” Hamid said in an interview. “We would boost the long-term benefits of targeted therapy through immunotherapy.”
Karl Lewis, MD, professor of medicine-medical oncology at University of Colorado School of Medicine, acknowledged that BRAF-directed therapies demonstrated rapid and meaningful responses with survival improvements.
“However, the biggest impact on survival has likely come from the use of immunotherapy,” he told HemOnc Today. “Monoclonal antibodies against CTLA-4 and PD-1, either alone or in combination, have resulted in long-term survival for a subset of patients with melanoma.”
Amin said treatment with ipilimumab has yielded a 10-year survival rate of about 20%.
“Subsequent discovery of the anti-PD-1 antibodies nivolumab [Opdivo, Bristol-Myers Squibb] and pembrolizumab [Keytruda, Merck] have revolutionized care for advanced melanoma,” Amin told HemOnc Today. “Patients who were treated with the combination of ipilimumab and nivolumab have shown that the median survival has not yet been reached at 5 years; 52% of the patients are alive and doing well.”
CheckMate 067 was a key immunotherapy trial in the melanoma space, although questions remain. This trial demonstrated that the combination of nivolumab plus ipilimumab, as well as nivolumab monotherapy, conferred significantly longer OS vs. ipilimumab monotherapy among previously untreated patients with advanced melanoma.
“CheckMate 067 was designed to compare the combination of nivolumab-ipilimumab and single-agent nivolumab vs. ipilimumab. It was not designed to compare ipilimumab and nivolumab vs. nivolumab, despite the fact that is what we all do,” Ryan J. Sullivan, MD, assistant professor of medicine at Harvard Medical School and assistant professor of hematology/oncology at Massachusetts General Hospital, told HemOnc Today. “We have to make that caveat, because we don’t have the statistical vigor to compare those cohorts for the primary endpoints.”
Still, the advances in melanoma treatment have led the way for advances in other cancers. It cannot be overlooked that the first approvals of a PD-1 inhibitor and combination checkpoint inhibition were for melanoma, Hamid said.
“Not only have we worked to improve the outcomes for patients with melanoma, but these drugs that have been approved initially in melanoma have gone further and have become a paradigm shift for patients with other solid tumors,” he said. “Approvals of these drugs in renal and lung cancer, among other solid tumors, are leading toward significant benefit for those patients.”
‘In the calculus’ of treatment decisions
Given the potential of targeted therapy and immunotherapy as single-agent treatments, researchers have focused increasingly on finding the ideal combination of the two approaches.
“We have one type of treatment that delivers an immediate benefit, and another that can induce durable response,” White said. “The question is, how do we marry these two so that the patient gets the greatest possible benefit?”
Hamid discussed a study that involved a combination of dual targeted therapy with BRAF and MEK inhibition, along with immunotherapy.
The double-blind, randomized, placebo-controlled, phase 3 IMspire150 study evaluated the addition of atezolizumab (Tecentriq, Genentech), a PD-L1 monoclonal antibody, to cobimetinib plus vemurafenib for patients with treatment-naive, unresectable, locally advanced or metastatic melanoma harboring a BRAF V600 mutation.
According to results presented at this year’s virtual American Association for Cancer Research Annual Meeting, the atezolizumab combination was associated with prolonged PFS (15.1 months vs. 10.6 months; HR = 0.78; 95% CI, 0.63-0.97). These data served as the basis for the combination’s FDA approval last month.
Another key trial of an immunotherapy-targeted therapy combination is COMBI-i. This ongoing trial is evaluating the anti-PD-1 antibody spartalizumab (PDR001, Novartis) combined with dabrafenib plus trametinib.
Results of the study, presented at last year’s ASCO Annual Meeting, showed an objective response rate of 75%, with a 33% complete response rate, among 36 patients with unresectable or metastatic BRAF V600-mutant melanoma. Median duration of response, PFS and OS had not been reached at median follow-up of 15.2 months. The combination also showed a manageable safety profile, and a phase 3 study is ongoing.
The results of the IMspire150 and COMBI-i studies will be important in determining the future of targeted treatment/immunotherapy combinations, according to Sullivan.
“Both of those trials are comparing the combination against BRAF-targeted therapy alone, but most of the time when we’re selecting front-line therapy for patients, we’re talking about combined immune checkpoint inhibitor therapy vs. single-agent PD-1 inhibitor therapy,” he said. “We’re not actually talking about BRAF-targeted therapy vs. immunotherapy, a decision for which all of our biases tend to favor immunotherapy, with good reason.”
Sullivan said BRAF mutation status is not necessarily a criterion for treating a patient with combination therapy.
“The presence of the BRAF mutation is another factor that may help select combination vs. single-agent immunotherapy, but it is not the only one,” he said. “I don’t exclude the combination because patients don’t have a BRAF mutation, and I don’t always treat patients with the combination because they have the mutation. However, it is in the calculus of trying to figure out the right therapy for a patient.”
Predicting recurrence with biomarkers
With all of these newly available treatments, a key objective for clinicians has been to determine which patients are more likely to relapse and, thus, need more aggressive treatment.
A focus on biomarkers has been pivotal in making this determination and in customizing cancer treatments.
“Liquid biopsies,” blood-based assays that test for biomarkers, are rapidly gaining popularity for their noninvasive approach and have demonstrated efficacy in predicting relapse of late-stage melanoma.
In a study conducted at The University of Texas MD Anderson Cancer Center, Lucci and colleagues evaluated baseline circulating tumor cells (CTCs) in patients with stage III melanoma with the goal of comparing RFS between patients found to have one or more CTCs vs. those with no CTCs.
The researchers identified CTCs in 90 of 234 patients and found that the presence of CTCs was significantly associated with poorer RFS at 6 months (HR = 3.62, 95% CI, 1.78-7.36) and 54 months (HR = 1.69, 95% CI, 1.13-2.54).
The results show the potential of liquid biopsies to help clinicians identify patients most likely to benefit from adjuvant systemic therapy, according to the researchers, sparing lower-risk patients from the toxic effects of treatment.
Hamid cited another study, conducted at the Melanoma Institute of Australia, in which Lee and colleagues evaluated presurgical circulating tumor DNA (ctDNA) in 174 patients with stage III melanoma undergoing complete lymph node dissection.
Detectable ctDNA appeared significantly associated with worse melanoma-specific survival in a multivariable analysis (HR = 1.85; 95% CI, 1.02-3.35).
“Looking at those patients post-resection in the stage III setting, those whose mutations were not detectable had a better long-term outcome than those where the mutation existed,” Hamid told HemOnc Today. “This is pointing toward monitoring ctDNA as an indicator for relapse or response, or subclinical progression.”
However, melanoma CTCs have been difficult to find, with detection rates varying from 40% to 87%. Thus, Aya-Bonilla and colleagues sought to develop a new technique for detecting CTCs that combines three assays.
An evaluation of the new method, published this year in British Journal of Cancer, showed a detection rate of 72%, which was a “significantly and consistently higher result” than was achieved with any of the individual tests, according to the researchers.
Beyond CTCs, researchers are looking at T-cell fraction (TCFr), an emerging biomarker that has been effective in predicting melanoma progression.
In a retrospective study published in Nature Cancer, researchers found that TCFr — the proportion of cells in a melanoma lesion that are T cells — was a robust and independent predictor of progression.
“This is a simple, elegant test. It’s qualitative rather than subjective, and it may be able to add value to predictions about disease progression,” study researcher Thomas Kupper, MD, chair of dermatology at Brigham and Women’s Hospital, said in a press release. “In the future, such a test could help us tailor treatment; patients with high TCFr may further benefit from checkpoint inhibitor therapy, [whereas patients with low TCFr] may need additional intervention.”
Reconsidering neoadjuvant therapy
Upfront surgical intervention followed by possible adjuvant treatment has long been the standard of care for stage III melanoma. Neoadjuvant treatment was uncommon because chemotherapy failed to show much clinical activity for the disease.
However, survival for this group has remained subpar, with only 30% to 50% of patients with stage IIIB and stage IIIC disease alive at 5 years. Given the high response rates observed with BRAF/MEK inhibition, researchers have sought to evaluate whether moving the combination to the neoadjuvant setting could improve outcomes for this population.
“The first line of therapy in all of melanoma, for generations, was just surgery, surgery, surgery,” White told HemOnc Today. “It is dramatically different now, and one of the things we are seriously debating is whether we should change the order of interventions.”
In a randomized phase 2 study published in 2018 in The Lancet Oncology, Amaria and colleagues evaluated whether neoadjuvant and adjuvant treatment with dabrafenib and trametinib would prolong EFS vs. standard of care among patients with surgically resectable stage III melanoma.
“When a patient presents with bulky disease, with lymph nodes heavily involved, it’s going to take a big surgery to try to get it out,” White said. “Why not give the patient some of these medications to start with, to see if we can get a response?”
Researchers randomly assigned 21 adults in a 2:1 ratio to receive 8 weeks of presurgical dabrafenib and trametinib followed by resection plus up to 44 weeks of adjuvant combination therapy (n = 14) or upfront surgery with the possibility of adjuvant therapy (n = 7).
Results showed 71% of the patients who received neoadjuvant/adjuvant treatment were alive without disease progression at median follow-up of 18.6 months compared with none of the patients who received standard of care. Median EFS was 19.7 months with neoadjuvant treatment vs. 2.9 months for the control group (HR = 0.016; 95% CI, 0.00012-0.14).
White said the potential to reduce the volume of disease through neoadjuvant therapy may play an important role in making surgical resection more manageable.
“From my point of view as a surgeon, it’s certainly a whole lot easier to operate on a small volume of disease than a large volume of disease,” he said.
Shifting surgical standards
Another changing paradigm in melanoma treatment is the shift away from completion lymphadenectomy among patients with melanoma and positive lymph nodes.
MSLT-2, an international, multicenter, randomized phase 3 trial, showed that completion lymphadenectomy conferred no survival benefit for these patients.
“I have the pleasure of working with Mark Faries, MD, who is the head of surgical oncology at The Angeles Clinic & Research Institute, and we are co-directors of the cutaneous malignancy program at Cedars-Sinai,” Hamid told HemOnc Today. “Through his work and the MSLT trial, we found that there is no change in survival with a completion dissection.”
In the trial, Faries and colleagues assessed melanoma-specific survival among patients with sentinel node metastases randomly assigned to immediate completion lymph node dissection or nodal observation with ultrasonography. In the per-protocol analysis of 1,755 patients, the 3-year rate of melanoma-specific survival did not differ between the two groups at median follow-up of 43 months (86 ± 1.3% vs. 86 ± 1.2%).
Patients with stage III melanoma and positive sentinel nodes likely would now have surveillance with imaging and ultrasound of the nodal basin, Hamid said, adding that completion lymphadenectomy would no longer be indicated for these patients.
“This has changed the paradigm of how we take care of our patients,” Hamid said. “It’s changed the aggressiveness of surgical clearance for patients with melanoma.”
Clinicians can monitor these patients and perform surgical procedures if needed upon recurrence, he added, describing the shift away from completion dissection as “the most important surgical informatics over the past year or so.”
Consumer awareness, prevention
Aside from the survival benefits derived from improved treatments and refined surgical approaches, the most notable improvements in the melanoma field stem from catching suspicious lesions early or preventing the disease altogether.
The general population has become much more familiar with the signs of melanoma, and detection guidance, such as the “ABCDE rule,” has empowered the public to do self-checks on their skin.
“Not only are we diagnosing melanoma and skin cancer better due to our outreach, education and surveillance, but we’re also preventing it,” Hamid said. “Encouraging good habits and less sun exposure has made a difference.”
The first melanoma public awareness campaign, “Slip! Slop! Slap!” was introduced by Cancer Council Victoria in Australia and New Zealand in the early 1980s, Lewis said.
“This was in response to climbing melanoma incidence in Australia and the clear association of UV exposure and skin cancer risk,” he said. “Relatively recent cancer data has demonstrated stabilization of incidence, and maybe even a slight decline, in those younger than 45 years, supporting a role for these public health efforts.”
Lewis said the increased emphasis on public awareness efforts in the U.S. also seems to have yielded generation-specific improvements. He cited organizations such as AIM at Melanoma and initiatives such as Melanoma Awareness Month.
“Recent data on melanoma incidence in the U.S. continues to demonstrate an increase of 2% to 3% per year in the older populations,” Lewis said. “Again, this is potentially reflective of melanoma awareness campaigns [geared toward younger populations].”
Paulson and colleagues reviewed incidence of melanoma in the U.S. and observed a 1.8% annual percentage change increase among men and women aged 40 years and older between 2006 and 2015. However, incidence decreased by an annual percentage change of 4.4% among male adolescents, 5.4% among female adolescents, 3.7% among male young adults and 3.6% among female young adults.
Still, not all consumer-facing initiatives are helpful in improving the diagnosis of melanoma. According to a study published this year in The BMJ, smartphone apps designed to serve as early warning systems for melanoma are poorly regulated and often unreliable.
Freeman and colleagues conducted a systematic review of nine diagnostic accuracy studies pertaining to six such apps, reporting that they demonstrated variable and inconsistent accuracy.
The researchers found that the apps have potential to miss potentially fatal skin cancers or may over-investigate false-positive results. Additionally, the studies of these apps were of questionable quality, given that they used photographs taken by experts rather than users of the apps, according to the researchers.
Finally, many of these studies failed to clarify whether lesions categorized as “low risk” by the apps were, in fact, benign.
“I am not aware of any reliable technologies for self-detection,” Amin said. “There are numerous websites with information about how to recognize abnormal skin lesions, including melanoma. Some of these websites are hosted by reputable organizations and cancer centers, whereas others are not. For the uninformed, this can be confusing as to which sites to believe.”
Additionally, some experts believe melanoma is increasingly overdiagnosed, citing stable mortality and metastatic disease rates in the face of dramatic increases in overall occurrence.
“The reason people are having this argument is because the death rate hasn’t changed much, but the diagnosis rate has increased,” he said. “The idea is if all thin melanomas were going to go on to kill people, then finding them when they’re thin and removing them would start to decrease the death rate. So, it seems we are diagnosing some melanomas that were never going to kill people, but we don’t know which ones they are.”
He added that until more is known about which melanomas are potentially fatal, diagnosing them while they are thin remains the best course of action.
“It’s unlikely that a patient will choose not to remove a melanoma under the assumption that it isn’t going to kill them,” he said. “Who’s going to want to take that chance?
References:
Amaria RN, et al. Lancet Oncol. 2018;doi:10.1016/S1470-2045(18)30015-9.
American Cancer Society. Cancer Facts & Figures 2020. Available at: www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2020/cancer-facts-and-figures-2020.pdf. Accessed July 31, 2020.
Aya-Bonilla CA, et al. Br J Cancer. 2020;doi:10.1038/s41416-020-0750-9.
Faries MB, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1613210.
Freeman K, et al. BMJ. 2020;doi:10.1136/bmj.m127.
Lee JH, et al. Ann Oncol. 2019;doi:10.1093/annonc/mdz075.
Long GV, et al. Abstract 9531. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
Lucci A, et al. Clin Cancer Res. 2020;doi:10.1158/1078-0432.CCR-19-2670.
McArthur GA, et al. Abstract CT012. Presented at: AACR Annual Meeting; April 27-28, 2020 (virtual meeting).
Paulson KG, et al. JAMA Dermatol. 2019;doi:10.1001/jamadermatol.2019.3353.
Pruessmann W, et al. Nat Cancer. 2020;doi:10.1038/s43018-019-0019-5.
Wolchok JD, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1709684.
For more information:
Asim Amin, MD, PhD, can be reached at 1021 Morehead Medical Drive, Suite A, Charlotte, NC 28204; email: asim.amin@atriumhealth.org.
Omid Hamid, MD, can be reached at 11800 Wilshire Blvd., Suite 300, Los Angeles, CA 90025; email: ohamid@theangelesclinic.org.; Twitter: @OmidHamidMD.
Karl Lewis, MD, can be reached at 12801 E. 17th Ave., 8122, Aurora, CO 80045; email: karl.lewis@ucdenver.edu.
Ryan J. Sullivan, MD, can be reached at 55 Fruit St., Boston, MA 02114; email: rsullivan7@mgh.harvard.edu.
Richard L. White, Jr., MD, FACS, can be reached at 1021 Morehead Medical Drive, Suite A, Charlotte, NC 28204; email: richard.white@atriumhealth.org.
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