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In season 3, episode 1 of Targeted Talks, Michael A. Postow, MD, a medical oncologist and chief of the Melanoma Service at Memorial Sloan Kettering Cancer Center in New York, New York, discusses available targeted agents for 

-mutant melanoma and ongoing clinical questions about treating the disease.

During the Physician’s Education Resource® 18th Annual International Symposium on Melanoma and Other Cutaneous Malignancies® held in January 2022, Postow spoke to a room of peers about this topic. His talk focused on the past, present, and future of BRAF-directed treatment. During the podcast discussion with host, Nichole Tucker of Targeted Oncology™, the discussion was expanding to dive into topics like; the efficacy of FDA-approve BRAF targeted therapies, the most recent FDA approval and its impact, exploring approved agents in new treatment settings, and other key druggable targets in melanoma.

During the talk, Postow also touches on the main clinical questions that oncologists still have about treating patients with 

-mutant melanoma and what research is aiming to provide answers in the near future.

In season 3, episode 1 of Targeted Talks, Michael A. Postow, MD, discusses available targeted agents for BRAF-mutant melanoma and ongoing clinical questions about treating the disease.

A Look Inside the Toolbox for BRAF-Mutant Metastatic Melanoma

The FDA has planned a regular review of the biologic license application for cosibelimab for the treatment for metastatic or locally advanced cutaneous squamous cell carcinoma.

FDA Considers Approval of Cosibelimab for Advanced Cutaneous Squamous Cell Carcinoma

During a Targeted Oncology™ Case-Based Roundtable™ event, Francis P. Worden, MD, and Ian Maher, MD, discussed treatment approaches for a patient with basal cell carcinoma who was not a candidate for surgical or radiotherapy options. 

Roundtable Discussion: Examining the Challenges of Hedgehog Pathway Inhibitors and Immunotherapy in Basal Cell Carcinoma

Based on findings from a phase 1 study, the FDA has received a biologics license application for cosibelimab for patients with advanced or metastatic cutaneous squamous cell carcinoma.

FDA Approval Sought for Cosibelimab as cSCC Treatment

During a Targeted Oncology case-based roundtable event, Panayiotis S. Savvides, MD, PhD, MPH, discussed with participants their experiences using hedgehog pathway inhibitors and immunotherapy for patients with basal cell carcinoma. 

Roundtable Discussion: Savvides Analyzes Role of Hedgehog Inhibitors and Immunotherapy in BCC

In an interview with Targeted Oncology, Ryan J. Sullivan, MD, discussed the history of tumor infiltrating lymphocyte therapy, how new data may lead to approved agents in the future, and other ways tumor infiltrating lymphocytes may be used in advanced melanoma.

Tumor Infiltrating Lymphocyte Data Signal Promise for New Options to Treat Advanced Melanoma

Ryan Sullivan, MD, associate professor, Medicine, Harvard Medical School and associate professor, Hematology/Oncology, Massachusetts General Hospital, explains how tumor infiltrating lymphocytes (TIL) could impact the melanoma treatment landscape if approved by the FDA.

 Having a therapy that's totally a different type of therapy than what we have available offers a lot of potential. One next step may be combining it with the things we already have. It may be combined with anti PD-1, anti-PD-1 plus anti CTLA4, or anti-PD-1 and LAG3. It may also be explored in earlier lines of therapy or in the refractory space.

 There's some data with other compounds that suggested that combining these types of drugs with a novel immunotherapy could be useful, even if patients had previously been treated with an anti-PD-1-based regimen. I think that's the second thing, that there may be combinations of therapies that currently are being studied, and it potentially could be a next step beyond just having TIL. The other thing is that there are a lot of ways of modifying and manipulating cells. If you’re getting a TIL harvest from a patient, it's entirely possible that there are ways to make those TIL better. You could select for tumor antigen specific T cells. You can select or treat those cells in a way to make them a better TIL. There's data that's been generated from a lot of labs in this space trying to come up with a better way of not necessarily giving TIL, but a better product that they can generate just by doing certain modifications after the TIL is harvested and before patients receive the TIL.

Videos

Ryan Sullivan, MD, explains how tumor infiltrating lymphocytes could impact the melanoma treatment landscape if approved by the FDA.

Potential Impact of Tumor Infiltrating Lymphocytes on Melanoma Treatment

Glenn J. Hanna, MD, director of the Center for Salivary and Rare Head and Neck Cancers, physician at Dana-Farber Cancer Institute, and assistant professor of medicine at Harvard Medical School, discusses the results of a study investigating nivolumab (Opdivo) as treatment for proliferative leukoplakia (PL) leading to oral cancer.

PL is an aggressive precancerous condition that can transform into oral squamous cell carcinoma. The single-arm phase 2 study (NCT03692325) enrolled 33 patients with PL to receive nivolumab every 28 days for up to 4 cycles. The investigators reported a decrease in composite score based on size and degree of dysplasia of at least 40% in 36% of patients. Hanna says that PL lesions are unlikely to regress without treatment.

The investigators also observed continued improvement several months after patients had received their last dose of nivolumab, which is consistent with nivolumab’s use in cancer treatment. This shows it may take longer to be effective, and longer-term treatment may improve outcomes further, according to Hanna.

There was a 78% rate of cancer-free survival at 2 years, which is encouraging given the high risk of PL transforming into cancer. Hanna says they intend to follow patients to see 5-year cancer-free survival as well. The study shows that immunotherapy can play a role in preventing cancer in patients with precancerous oral disease.

 We saw a 36% regression rate or response rate. So this means that upwards of 36% of patients had more than 40% regression in their lesion sizes and/or the degree of dysplasia in those lesions; remember [they had] up to 1 to 3 lesions [biopsied]. So that was exciting to see. Importantly, we would not expect PL lesions to regress spontaneously. Some people would say, “Could that just be the ebbs and flows of the disease?” No, we don't expect these lesions to get better. These are so high risk that they would likely evolve over time into cancer.

 The other thing we noticed was that there were some patients who had clinically visible regression, and we showed clinical photographs in our slides at ESMO [2022 European Society of Medical Oncology Annual Congress], showing that some lesions regressed and that even carried on well beyond exposure to nivolumab. So even after the 4 doses, months and months later, which we can observe in advanced cancer patients with immunotherapy, we saw some improvements in clinical leukoplakia. That means this may take a while to work, and so the question of whether we should be giving more doses comes up.

I think the other thing was the 2-year cancer free survival. It's a short interval. But...many of these patients will develop cancer events. It was approaching 78%. That's pretty strong compared [with] our historical data. We certainly will follow these patients out to the median 5-year mark, but at least for a 2-year time point, it's encouraging that almost 80% of patients have not suffered a cancer event.

Glenn J. Hanna, MD, discusses the results of a study investigating nivolumab  as treatment for proliferative leukoplakia leading to oral cancer.

Nivolumab Reduces Transformation of Precancerous Leukoplakia to Oral Cancer

Valencia D. Thomas, MD, MHCM, professor in the Department of Dermatology, Division of Internal Medicine, MD Anderson Cancer Center, discusses the unmet needs which remain in the non-melanoma skin cancer space.

The most common types of non-melanoma skin cancers include Basal cell carcinoma, Merkel cell carcinoma, and squamous cell carcinoma. While these cancer types have been met with many new developments in the last 10 years, a need remains for more FDA approved drugs for patients with rare tumor types.

In a session at National Comprehensive Cancer Network (NCCN) Annual Meeting 2022, Thomas discussed advanced or aggressive non-melanoma skin cancers that came back after their first treatment as well as those which began in an advanced detection.

While there are various treatment options available for this patient population, including surgical treatments, radiation, and systemic options, Thomas notes that more research needs to focus on treatment which may provide positive opportunities and lead to a cure for these patients.

Although we have come a long way over the last 10 years, the needs we have are to further gather information for the rare tumor type, to have FDA approved medications for some of these rare tumor types, and to further expand the use of immunotherapy to rare tumors.

We use what is currently available to the best of our abilities. As innovative technologies and therapies become more available, we start with what is most common. Then we must move towards what is less common to get the same body of data and information so that we can give the same outcome to aggressive tumors that may not be as common.

Valencia D. Thomas, MD, MHCM, discusses the unmet needs which remain in the non-melanoma skin cancer space.


News

More FDA Approved Treatments are Needed for Non-Melanoma Skin Cancers

Valencia Thomas, MD, MHCM, Department of Dermatology, Division of Internal Medicine, MD Anderson Cancer Center, discusses the future for managing care in patients with non-melanoma skin cancers.

Within the previous years, updates in technology and research have allowed for the development of new therapies to improve the prognosis of patients with non-melanoma skin cancers. For patients with advanced disease, highly aggressive disease, and disease with distant metastases, current viable options include immunotherapy, medications, surgical intervention, radiation, chemotherapy, and more.

Thomas notes that the future is bright for this patient population and might include collaboration between various medical specialties, new and innovative applications of currently existing therapies, improvements in surveillance, and increased education for both patients and providers.

 The future for the management of non-melanoma skin cancers includes close collaboration between different medical specialties so that the best of each specialty is leveraged in the fight against cancer. What we're seeing moving forward are innovative applications of currently existing therapeutics to address cancers that have historically had poor outcomes or cancers that are very difficult to fight, because our detection is limited. The good news about skin cancer is that with skin cancers, we have a shot at having a sign or a symptom that is there, so making sure that we improve our surveillance, making sure we improve the education of both providers and patients. We can help to intervene at an earlier level.

When I look at the future, I look at the wonderful efforts that are made to educate using technology, using social media to help people identify what is abnormal, but then the future allows us the opportunity to really collaborate and speak.

Valencia Thomas, MD, MHCM, MD Anderson Cancer Center, discusses the future for managing care in patients with non-melanoma skin cancers.

Future Directions for the Management of Non-Melanoma Skin Cancers

Valencia Thomas, MD, MHCM, Department of Dermatology, Division of Internal Medicine, MD Anderson Cancer Center, discusses how the management of care for patients with non-melanoma skin cancers has changed over the past decade.

Improvements in technology, research, and therapies have helped improve the prognosis of patients with non-melanoma skin cancers, including advanced disease, highly aggressive disease, and disease with distant metastases.

There are a variety of new and innovative options for patients with advanced stage non-melanoma skin cancers to choose from. Immunotherapy, medications to aid the body’s immune system, surgical intervention, radiation, chemotherapy, targeted therapies are all potential options for use in this patient population.

 The management of non-melanoma skin cancer has evolved over the years because with every year that passes, we integrate innovations in technology, in pharmaceuticals, and in epidemiology where we have more data to help guide our treatment than 10 years ago. Certain tumors that were at an advanced stage had a prognosis that was very grim for advanced disease and disease with distant metastases.

When we look at these highly aggressive advanced stage non-melanoma skin cancers, a lot of the landscape has changed with the advent of immunotherapy. There are many different medications that are now available that aid the body's immune system in detecting and defeating skin cancers. When combined with some of our traditional therapies and our traditional intervention, both surgical and radiation, we can get to an unexpected outcome compared to what we were seeing 10 years ago. Whereas surgery and radiation were sometimes the best option, now we're seeing situations where a little bit of medicine, some of our targeted therapy or chemotherapy options plus or minus radiation, are really changing the landscape.

 We're getting much better at targeting diseases. For example, a subtype of sarcoma, dermatofibrosarcoma protuberans, has a targeted therapy that attacks the mutation that is present in over 90% of the sarcomas, where a growth factor is next to a collagen team, to the cells that make the collagen grow. Only those cells are affected when the medication is given. Instead of having the chemotherapy of yesteryear that made many people sick, we now have chemotherapy and targeted therapy that can target only the tumor and give us wonderful outcomes. That cancer becomes a chronic disease rather than a fatal disease.

Valencia Thomas, MD, MHCM, discusses how the management of care for patients with non-melanoma skin cancers has changed over the past decade.

Evolving Treatment Landscape of Advanced Non-Melanoma Skin Cancers

Valencia Thomas, MD, MHCM, Department of Dermatology, Division of Internal Medicine, MD Anderson Cancer Center, discusses the current landscape regarding non-melanoma skin cancers.

Non-melanoma skin cancers affect millions of individuals each year with some of the most common consisting of Basal cell carcinoma, Merkel cell carcinoma and squamous cell carcinoma, according to Thomas. However, a lot of time and focus is projected on the management of squamous cell carcinoma as it results in high amounts of morbidity.

At the recent National Comprehensive Cancer Network Annual Meeting, Thomas along with other experts ran a session on managing patients with aggressive non-melanoma skin cancers. The session highlighted a variety of the recent innovations in the management of non-melanoma skin cancers as well as common or uncommon tumors as well.

 We focus our session on the advanced or aggressive non melanoma skin cancers that either didn't read the book and stay gone once they were treated the first time, or the ones that started off in an advanced detection. For example, 25-35% of Merkel cell carcinomas are already present in the lymph node at the time of biopsy. Even though some of these cancers are rare or aggressive, we have multiple treatment options, multiple different surgical treatment options, radiation options, and systemic options that either alone or when combined can give patients a wonderful opportunity for cure.

Valencia Thomas, MD, MHCM, discusses the current landscape regarding non-melanoma skin cancers.

Current Options for Treating Non-Melanoma Skin Cancers 

Annelise Wilhite, MD, gynecologic oncology fellow at the University of South Alabama Health explains what current treatment options look like for patients with vulvar/vaginal melanoma.

Treatment options mimic those of cutaneous melanoma due to the rarity of the disease and the lack of specific therapy guidelines for vulvar/vaginal melanoma. Since few patients develop this disease, Wilhite explains that it is difficult to have new clinical trials as the same individuals are always involved.

Finding treatments that work is the main obstacle in this patient population, and further understanding the differences between those 2 diseases is crucial for future developments.

In addition to treatments similar to that of cutaneous melanoma, hematologists who specialize in melanoma are contacted to provide their feedback on a patient’s individual case, and tumors are sent out for molecular profiling.

 The treatment involves surgical resection, and then for metastatic or unresectable disease or locally advanced disease. Typically, chemotherapy or immuno oncology therapy is recommended. As of now, the frontline agents for cutaneous melanoma are PD-1 inhibitors CTLA-4 inhibitors and a combination of BRAF and MEK inhibitors. Full of rational melanoma, the treatment typically involves a multidisciplinary approach. We will often follow the cutaneous melanoma guidelines.

Annelise Wilhite, MD, explains what current treatment options look like for patients with vulvar/vaginal melanoma. 

Treatment Landscape for Vulvar/Vaginal Melanoma

Richard D. Carvajal, MD, director of experimental therapeutics and director of melanoma service at Columbia University Medical Center, discusses the mechanism of action and efficacy of tebentafusp-tebn (Kimmtrak) for patients with uveal melanoma.

Uveal melanoma is a rare disease with few effective treatment options. According to Carvajal, tebentafusp is a bispecific agent that binds to the GP-100 antigen and CD3-positive cells in patients who have human leucocyte antigen (HLA)-A*0201–positive disease, causing T cells to destroy cancer cells.

The phase 2 IMCgp100-202 trial (NCT03070392) randomized 378 previously untreated patients 2:1 to receive tebentafusp or investigator’s choice, which was most commonly pembrolizumab (Keytruda). The median OS for patients in the tebentafusp arm was 21.7 months (95% CI, 18.6-28.6) and 16.0 months (95% CI, 9.7-18.4) for the control arm. The rate of 1-year overall survival (OS) was 73% versus 59% in the control arm with a hazard ratio of 0.51 in the intent-to-treat population (95% CI, 0.37 to 0.71; 

Another phase 2 trial (NCT02570308) showed that tebentafusp also had clinical activity in previously treated patients with metastatic uveal melanoma. Based on the IMCgp100-202 trial, tebentafusp was approved by the FDA in January 2022 for patients with unresectable or metastatic uveal melanoma.

 Tebentafusp is a bispecific agent. [There are] 2 ends. One end is an optimized T-cell receptor, it binds very strongly to something called GP-100, a melanoma-associated antigen. It binds with very, very high affinity in an HLA-restricted fashion, which means that this drug is only going to work in the subset of patients who are HLA-A*0201 positive, [which] makes up about 40% to 50% of Caucasian [patients]. The other end binds to CD3-positive cells.

So what you can think of this drug doing; it hones and binds very tightly to the tumor cell—in this case, uveal melanoma—and then bring in, in a polyclonal fashion, the T cells in that area. And just by bringing the T-cell to the tumor cell in proximity, that’s enough to kill the cancer cell.

 And so there have been 2 trials now. One [was] a trial for patients who had been previously treated with something else for uveal melanoma, and then, really, the pivotal trial was a randomized trial. It randomized patients on a 2:1 ratio to either to tebentafusp or investigator’s choice. The majority of those patients got pembrolizumab [Keytruda].

That randomized trial showed a significant improvement in OS. The median was almost 22 months for patients treated with tebentafusp versus around 16 months for those treated with the investigator choice. The hazard ratio for survival [was] highly statistically significant, a 49% reduction in the risk of death. Absolutely groundbreaking.

Richard D. Carvajal, MD, discusses the mechanism of action and efficacy of tebentafusp-tebn for patients with uveal melanoma.


Tebentafusp Shows Significant OS Benefit in Advanced Uveal Melanoma

Ryan C. DeCoste, MD, QEII Health Sciences Centre, Nova Scotia Health Authority, Halifax, Nova Scotia, Canada, discusses how comprehensive genomic profiling can be used to identify rare subsets of patients with Merkel cell carcinoma.

Merkel cell carcinoma is a relatively rare but highly aggressive skin cancer, according to DeCoste. A previous publication identified a subset of these patients, making up approximately 80% of cases, are associated with a viral oncogenic pathogenesis, which incorporates Merkel cell papilloma virus DNA into precursor cells for subsequent tumorigenesis. However, subsequent to this, a smaller subset was thought not to be associated with this virus and more likely due to UV-induced DNA damage.

Based on these observations, Merkel cell carcinoma can be classified in 1 of 2 categories: virus-positive or virus-negative, and these subsets each have distinct mutational profiles, DeCoste notes.

Ryan C. DeCoste, MD, discusses how comprehensive genomic profiling can be used to identify rare subsets of patients with Merkel cell carcinoma.

Conference News

Using Comprehensive Genomic Profiling to Identify Rare  Subsets of Merkel Cell Carcinoma

Richard D. Carvajal, MD, the director of Experimental Therapeutics and director of Melanoma Service at the Columbia University Medical Center, discusses 2 therapies in clinical trials registering patients with melanoma.

The first drug Carvajal talks about is called IDE196, and the other is called IMCgp100 or tebentafusp. IDE196 is a PKC inhibitor previously named LXS196, and it targets both a conventional and novel forms of PKC. In a previous clinical trial, a cohort of about 30 patients receiving this treatment on a twice daily schedule, the response rate was fairly modest; about a quarter of the patients were doing well after a year or more. He says this is fairly remarkable for this setting. IDE196 is now under evaluation in another clinical trial which will be trying to replicate or exceed these findings (NCT03947385).

IMCgp100 is a bispecific immunotherapy agent which targets TP100 in an HLA-restricted fashion; it also binds to CD3 and brings the CD3 cells in proximity with the tumor cells, according to Carvajal. The phase I trial investigating this drug recruited patients with HLA A2-positive malignant melanoma (NCT01211262). In previous trials, there has been a modest response rate, and over 70% of patients were alive at 1 year. He says compared to past control studies, this was much better.

<< View more resources and information regarding melanoma

Richard D. Carvajal, MD, discusses 2 therapies in clinical trials registering patients with melanoma.

Early Trials in Melanoma Show Better Response After 1 Year

Jason Luke, MD, associate professor of medicine in the Division of Hematology/Oncology and the director of the Cancer Immunotherapeutics Center at the University of Pittsburgh Medical Center Hillman Cancer Center, discussed the role played by the combination of nivolumab plus relatlimab (Opdualag) in patients with advanced melanoma.

The phase 3 RELATIVITY-047 trial (NCT03470922) randomly assigned patients to receive nivolumab plus relatlimab versus nivolumab alone (Opdivo). Relatlimab is an immune checkpoint inhibitor (ICI) that targets LAG-3, as opposed to other immune checkpoint inhibitors that have targeted PD-1/PD-L1 or CTLA-4. Luke says the use of a third immune checkpoint is potentially important beyond its use in patients with melanoma.

The results of the trial showed benefit to progression-free survival for the combination over nivolumab alone, leading to approval by the FDA. Luke said this impacts practice significantly, especially in lower-risk patients who would have otherwise received single-agent nivolumab or pembrolizumab (Keytruda).

For higher-risk patients with features including brain or liver metastases or high lactate dehydrogenase (LDH), Luke says he would use nivolumab plus ipilimumab (Yervoy), but in other patients who have received no prior systemic therapy, he would now give nivolumab plus relatlimab.

 RELATIVITY-047 was a phase 3 clinical trial demonstrating the benefit of combining nivolumab and relatlimab versus nivolumab alone. And this is a seminal clinical trial in oncology beyond just melanoma because this validates the third immune checkpoint to be used in standard-of-care practice. So that's important in melanoma obviously, as we have another treatment option for our patients, but it actually opens the door more broadly in oncology to see combination immunotherapy start to be used in other tumor types as well.

Focusing back on melanoma however, essentially, the way I think about it is that the data really support the use of Opdualag, nivolumab plus relatlimab, in the lower-risk patients who I would have otherwise treated with PD-1 monotherapy, meaning nivolumab or pembrolizumab. So when I see a new patient who is treatment naive, I go through my mind and think about, first, are there high-risk features here that would make me think I still want to give nivolumab plus ipilimumab? Those might be brain [metastases], liver [metastases], high LDH, etc. If the patient does not have those features, then my default is to give Opdualag, with nivolumab plus relatlimab, in most of these general-risk or low-risk patients that present in the treatment-naive setting.

Jason Luke, MD, discussed the role played by the combination of nivolumab plus relatlimab in patients with advanced melanoma. 