I last wrote about melanoma treatment more than 2 years ago, a fairly long time in the evolution of treatments for this type of cancer. Just as a refresher, the current mainstays of drugs to treat melanoma fall into two categories:
- Immune checkpoint inhibitors (ICI), antibody drugs that bind to proteins found on the immune system’s T cells—namely, PD-1 (which is targeted by the drugs pembrolizumab and nivolumab) or CTLA4 (targeted by the drug ipilimumab).
- Targeted drugs for melanomas with mutations in the BRAF gene; these drugs are known as BRAF and MEK inhibitors.
Now, I highlight new developments in melanoma treatment, including overcoming resistance to ICI.
Neoadjuvant (before surgery) treatments for resectable melanoma
Some stage III and (rarely) stage IV melanoma tumors are resectable, meaning they can be removed by surgery. In other types of cancer, neoadjuvant treatment of resectable tumors is known to reduce the risk of recurrence after surgery. It took additional time to explore ICI and targeted drugs in the neoadjuvant setting in melanoma. Now, several clinical trials have addressed the potential of using these drugs to prolong relapse-free survival (RFS) after resection.
A recent analysis of results from six of these trials addressed the rate of pathologic complete response (pCR) after treatment—a term that describes elimination of cancer cells prior to surgery. pCR has already been associated with better RFS in other cancers. In the six trials evaluated, pCR was achieved in 47% of melanoma patients who received targeted drugs (BRAF + MEK inhibitors) and in 33% of patients receiving ICI. However, RFS at two years after surgery was 79% for patients who received BRAF/MEK inhibitors and 96% (with no deaths!) for patients who received ICI.
Overall, these data strongly support the use of neoadjuvant treatment in melanoma, and there are now nearly 20 ongoing trials testing this strategy.
Adjuvant (after surgery) treatments
The U.S. Food and Drug Administration (FDA) first approved ipilimumab (anti-CTLA4) and later pembrolizumab and nivolumab (anti-PD-1) as adjuvant (post-surgery) treatment for stage III melanoma. Adjuvant anti-PD-1 drugs have a higher efficacy in preventing recurrence, which essentially means that ipilimumab is no longer used in this setting.
Pembrolizumab prolongs RFS after surgery, but it has little effect on overall survival time, according to recent trial results. Adjuvant nivolumab has also been linked to improvement in RFS. Overall survival data are pending.
Adjuvant immunotherapy is now moving ahead in trials for patients with stage IIB/C melanoma that are usually treated with surgery only. So far, 3-year overall survival has been reported to be 82.7% for stage II patients who received adjuvant immunotherapy versus 71.6% for those who did not. These data were based on the analysis of historical data from the National Cancer Institute database, and did not specify which checkpoint drugs (anti-CTLA4 or anti-PD-1) were given to the stage II patients.
New treatments for metastatic melanoma
It certainly seems that the rate of new drug approvals in metastatic melanoma has slowed. Between 2011 and 2015, the FDA issued ten approvals, but it issued only one each in 2018 (the combination of encorafenib and binimetinib) and 2020 (the combination of vemurafenib and cobimetinib with atezolizumab), both for BRAF-mutant cancers. The latter did not gain widespread use because of its very limited effects on response rate, alongside significant side effects.
The search for new immune checkpoint proteins to target in melanoma (and other cancers) continues, but so far has yet to produce truly convincing results. The only promising target to emerge recently is LAG3, yet another inhibitory protein found on T cells.
In a clinical trial, first-line treatment with the anti-LAG3 drug relatlimab given in combination with nivolumab produced a progression-free survival time of 10.1 months versus 4.6 months for nivolumab alone. Survival data are not yet mature, but one year after treatment started, 47.7 % of patients receiving the combination had no disease progression, compared to 36% receiving nivolumab only. However, more results will be needed to confirm this benefit, and to convince everyone that this is better than the combination of nivolumab with ipilimumab approved in 2015.
Treatments for patients with resistance to anti-PD-1 drugs
Resistance to anti-PD-1 immune checkpoint drugs is seen in about two thirds of melanoma patients, who either do not respond to them at all, or develop resistance over time. Researchers are exploring a number of approaches to potentially restore sensitivity to anti-PD-1 drugs.
A recent clinical trial tested the anti-CTLA4 drug ipilimumab alone or in combination with anti-PD-1 drugs for people with anti-PD-1-resistant melanoma, producing promising results: the combination had better activity (a 31% overall response rate [ORR] versus 13% for ipilimumab alone), and longer duration of response (20.4 months versus 8.8 months).
Trials testing two different targeted drugs (both of a type known as kinase inhibitors) in combination with anti-PD-1 drugs have reported some preliminary results: lenvatinib produced a 21% ORR and sitravatinib a 24% ORR), but the duration of responses was not impressive (4.2 and 6.7 months, respectively).
CMP-001 is a drug that is injected directly into accessible tumors, and it restored sensitivity to anti-PD-1 in 23.5% of patients in a clinical trial. Another intratumorally injectable drug, PSVRIPO, produced responses in 33% of treated patients. The duration of these responses is not yet clear.
Taking a different direction, other researchers are focused on the gut microbiome, which is now known to shape immune functions, including responses to ICI. In hopes to remake the gut microbiome to support ICI drugs, two small trials explored fecal microbiome transplants (FMT) in patients who had no response to anti-PD-1 drugs. The stool donors were melanoma patients who had either complete or a good partial response to treatment with ICI previously. 6 of 15 patients in one trial, and 3 out of 10 in the other developed good responses to anti-PD-1 treatment after FMT, including some complete responses.
The final treatment approach I’ll highlight for melanoma that is resistant to immune and targeted drug treatment is, however, not new. It involves isolation of a patient’s T cells directly from their tumors; these cells are known as tumor-infiltrating lymphocytes or TILs. The TILs are expanded (multiplied to produce larger amounts) in a lab facility and reinfused into the patient, who, prior to the infusion, had been receiving harsh chemotherapy. IL2, a strong activator of T cells, is also given to the patient. The latest trials with TILs dubbed LN-144, or lifileucil, reported encouraging results: ORR was 36% (historically it was around 20% with TILs in melanoma), and the duration of response was not reached at 33 months. However, the manufacturing process for lifileucil needs to be streamlined, which has recently further delayed application for FDA approval.
The list of treatments mentioned above is not complete, but hopefully presents an understanding of the breadth of efforts in melanoma, which is no longer a universally fatal cancer.
If you or a loved one have advanced melanoma, and you want to know if any of these treatments are a good fit, I encourage you to request free, personalized help from Cancer Commons.
OncLive: Promising results for PSVRIPO
OncLive: Results for CMP-001
OncLive: Results for lenvatinib
BeiGene: Results for sitravatinib
The Scientist: Fecal transplants for melanoma