New Developments in Melanoma Treatment

Neoadjuvant (before-surgery) treatments for resectable melanoma

Neoadjuvant treatments are the mainstay in the care of patients with breast, colon, and other cancers, but have not traditionally been used in melanoma. This has changed now, with the publication of a report showing that patients with resectable stage III or IV BRAF-mutant melanoma benefit from treatment with the BRAF/MEK inhibitor drugs dabrafenib and trametinib prior to (and continued after) surgery. The randomized clinical trial that produced these findings was small, but the benefits were so obvious that the researchers had to close the control group—those patients who received a placebo instead of neoadjuvant treatment. 71% of the 14 patients in the trial who received BRAF/MEK inhibitors prior to surgery were disease-free after 18 months, whereas all seven patients in the control group experienced a recurrence. The trial is continuing without the control group: all patients will receive treatment prior to surgery

Adjuvant (after-surgery) treatments

Melanoma patients whose tumors are surgically removed experience a very high rate of recurrence. Until recently, adjuvant treatments to prevent recurrences were limited to the drug interferon alpha-2B and, more recently, ipilimumab (brand name Yervoy), an anti-CTLA-4 immune checkpoint drug approved by the U.S. Food and Drug Administration (FAD) for adjuvant treatment in 2015. Interferon treatment is extremely harsh, with many adverse effects, and is not often used anymore. Yervoy is often associated with autoimmune side effects, which are sometimes quite serious.

Enter nivolumab (Opdivo) the anti-PD-1 checkpoint drug approved by the FDA to treat metastatic melanoma and other cancers. A clinical trial showed that the recurrence-free survival (RFS) rate at 18 months with nivolumab was 66.4% compared to 52.7% for ipilimumab (Yervoy) in patients with resected stage IIIB/C or IV melanoma. This amounts to a 35% reduction in the risk of recurrence or death with the PD-1 inhibitor versus the CTLA-4 inhibitor. Not the least important factor is the much lower rate of side effects seen with nivolumab compared to ipilimumab. Nivolumab is now approved by the FDA as an adjuvant treatment after surgical resection of melanoma.

Pembrolizumab, a competing anti-PD-1 drug, also showed encouraging results in a randomized trial for stage III melanoma. The stakes in this trial were lower, since the control arm received a placebo (not ipilimumab!). Risk reduction was 43%, according to preliminary results of the trial.

For patients with BRAF-mutant stage III melanoma, adjuvant treatment with the BRAF/MEK inhibitors dabrafenib and trametinib was just recently granted a priority review by the FDA, signaling a likely approval soon. Recurrence-free 3-year survival was 58% for the combination versus 39% for placebo.

New treatments for metastatic melanoma

A Knowledge Blog post from last summer described new combination treatments for metastatic melanoma. There have been significant developments since then.

Several trials combined PD-1 blockers (pembrolizumab or nivolumab) with small molecules known as IDO inhibitors. The latter help shut down the activity of immune system cells known as regulatory T cells (T regs), which dampen the immune response triggered by anti-PD-1 drugs. Combination of pembrolizumab with the IDO inhibitor epacadostat increased the rate of responses to pembrolizumab from 32% to 56%. This is very comparable to the response rate seen with the FDA-approved combination of nivolumab and ipilimumab. However, the significant toxicities seen with addition of ipilimumab are not observed when IDO inhibitors are added. Several other competing IDO inhibitors are currently in trials with both pembrolizumab and nivolumab. Importantly, there is also hope that these drug combinations may abolish resistance to PD-1 blockers in previously treated melanoma patients.

Another promising combination has been tested in a small clinical trial of nivolumab with NKTR-214, a specifically modified form of the protein IL-2, which is a strong activator of the immune system. High-dose IL-2 is a drug that has long been approved for metastatic melanoma but is rarely used because of the extremely serious adverse effects. NKTR-214 is a modified (PEGylated) IL-2 that has much reduced side effects, and does not activate inhibitory T regs. Clinical trial results have been released for 11 melanoma patients treated with the combination. Of the patients enrolled, 73% have experienced objective responses, which is obviously much higher than what is seen with nivolumab alone. This trial is now enrolling patients who have or have not already been treated with immune drugs.

Patients who were treated with anti-PD-1 drugs and experience progression may consider enrolling in trials that add relatlimab (an anti-LAG3 immune drug) to nivolumab. In a trial that enrolled heavily pretreated patients who failed on previous treatment with anti-PD-1 drugs, the rate of response was 11.5%, but many more patients (38%) have achieved stable disease. The presence of LAG3 protein (but not PD-L1 protein) in the tumors was predictive of response.

There are other new drugs to watch. TLR9 agonists (activators) have shown early promising results in melanoma. TLR is a group of receptors that are strongly involved in innate immunity. A recent publication showed that intratumoral injection of a TLR9 activator with an antibody to OX40 (a protein on T cells) has extraordinary activity in a mouse cancer model. Trials that combine anti-OX40 and TLR9 agonists are forthcoming. However, two TLR9 agonists, SD-101 and IMO-2125, have shown very promising results in combination with anti-PD-1 or anti-CTLA4 drugs.

The other drug with early promise is ImmunoPulse IL-12 (pIL-12). In combination with pembrolizumab, it induced responses in 43% of patients who had not been previously treated with immune drugs. The important point is that patients in this trial were specifically selected to have a tumor profile that is associated with lack of response to pembrolizumab. pIL-12 is injected into tumors, so this intervention is appropriate for patients who have injectable tumors.

New BRAF/MEK inhibitors for melanoma have emerged: encorafenib and binimetinib produced a 3-year overall survival rate that is twice as high as seen with vemurafenib, a BRAF inhibitor. The comparison is not exactly meaningful because vemurafenib is not used as a single drug in BRAF-mutant melanoma these days, but this phase III trial was initiated back in 2013, prior to the approval of other BRAF/MEK combinations. The new combination may be approved mid-2018.

The triplet combinations for BRAF-mutant melanoma should be mentioned (immune plus targeted drugs). A trial that combined dabrafenib and trametinib with pembrolizumab reported early success, with a confirmed response rate of 67% in 15 patients who received the combination.

IL-12 Therapy Elicits Encouraging Response Rates in Melanoma


“Immunopulse IL-12 monotherapy and in combination with pembrolizumab was associated with encouraging response rates and safety data in patients with melanoma who may not respond to anti-PD-1 therapy, according to a press release.

“The findings were presented at the 9th World Congress of Melanoma — A Joint Meeting with the Society for Melanoma Research. The data include a phase 2 Immunopulse IL-12 (OncoSec) monotherapy study with 51 patients and a phase 2 study of the immunotherapy in combination with pembrolizumab, which included 22 patients.”

Go to full article.

If you’re wondering whether this story applies to your own cancer case or a loved one’s, we invite you to use our ASK Cancer Commons service.

Immune System-Boosting ImmunoPulse to Be Tested in Triple-Negative Breast Cancer Patients in Pilot Study

The gist: A new treatment that has shown promise in other types of cancer will soon be tested in triple negative breast cancer (TNBC) patients. The treatment, called IL-12 ImmunoPulse, delivers instructions for making a protein called IL-12 into a patient’s tumor. The patient’s cells then make IL-12, which boosts the immune system. A small pilot study will take place at Stanford University in California. It will test whether ImmunoPulse has promising effects on the immune system. If it is successful, researchers might try combining the treatment with drugs that are known to be more effective when the immune system is stimulated.

“OncoSec Medical Inc. (OTCQB: ONCS), a company developing DNA-based intratumoral cancer immunotherapies, plans to initiate a pilot study to assess IL-12 ImmunoPulse in patients with Triple Negative Breast Cancer (TNBC). The study will be conducted at Stanford University with Melinda L. Telli, MD, serving as lead investigator.

“This pilot study is designed to assess whether IL-12 ImmunoPulse increases TNBC tumor immunogenicity by driving a pro-inflammatory cascade of events that leads to increases in cytotoxic tumor-infiltrating lymphocytes (TILs). The presence and number of TILs is thought to be a key requirement for promoting the anti-tumor activity of antibodies like anti-PD-1/PD-L1. By driving cytotoxic immune cells into the tumor, IL-12 ImmunoPulse may be an ideal candidate to combine with checkpoint blockade therapies which reported some activity in TNBC.

“Worldwide, TNBC amounts to approximately 200,000 cases each year and accounts for approximately 20 percent of all breast cancer. It is most commonly diagnosed in younger women (less than 40 years) and is characterized by higher relapse rates when compared with estrogen receptor (ER)-positive breast cancers. TNBC is also associated with an increased risk of recurrence, both locally and in distant sites, including the lung and brain. Advanced TNBC remains a significant area of unmet medical need and there is no established standard-of-care. Treatment generally includes chemotherapy, with or without radiation and/or surgery. However, no treatment regimen has clearly demonstrated superiority.”

OncoSec Reports ImmunoPulse May Prolong Survival Based on Analysis of Long-Term Survival Data from Phase I Study in Melanoma

The gist: A new treatment called ImmunoPulse has shown promise for improving the long-term survival of metastatic melanoma patients. ImmunoPulse delivers instructions for making a protein called IL-12 into a patient’s tumor; the patient’s cells then make IL-12, which boosts the immune system to kill cancer cells. It was tested in 24 volunteer patients in a clinical trial in 2007. Now, long-term follow-up data has been analyzed. The researchers found that the median length of time patients lived after treatment was 23.9 months.

“OncoSec Medical Inc. (OTCQB: ONCS), a company developing DNA-based cancer immunotherapies, released long-term survival results from its Phase I study in patients with metastatic melanoma, evaluating a single treatment cycle of intratumoral plasmid IL-12 (pIL-12) injection with electroporation (EP). Dr. Robert Pierce, Chief Scientific Officer at OncoSec, a co-author of the abstract presented these data today at the Melanoma Bridge 2014 conference in Naples, Italy.

“The Phase 1 dose-escalation study, which completed enrollment in February 2007 and was first published in the Journal of Clinical Oncology (Daud et al., 2008), established that a single treatment cycle of intratumoral pIL-12 EP, administered on Days 1, 5 and 8, has an acceptable safety profile and is well-tolerated. Escalating concentrations of pIL-12 were administered in cohorts of three patients. No dose-limiting toxicities, treatment-related serious adverse events, or treatment-related Grade 4 or 5 adverse events were reported. Importantly, the study also demonstrated that local intratumoral pIL-12 EP can induce systemic responses, as evidenced by stable disease or objective regression in non-injected, non-electroporated lesions. Moreover, pIL-12 EP monotherapy was shown to achieve objective responses in this initial Phase 1 trial in patients with metastatic melanoma, with three complete responses (CRs) observed after only one treatment cycle.

“OncoSec collected data from long-term follow-up and determined that the median overall survival for the patients in the Phase 1 study was 23.9 months. In addition, a statistically significant difference (p = 0.0054) was observed when comparing overall survival between patients who had a best overall response of at least stable disease or better (median OS = 49.1 months) versus patients who only had disease progression while on study (median OS = 10.9 months).”

UC San Francisco and OncoSec Medical Collaborate to Evaluate Investigational Combination of ImmunoPulse and Anti-PD-1 Treatment

The gist: Two drug companies are teaming up to see wether two melanoma treatments can work better together than either on its own. The treatments are Keytruda (aka pembrolizumab) and ImmunoPulse. Both drugs use a patient’s own immune system to fight cancer.

“OncoSec Medical Inc. (OTCQB: ONCS), a company developing DNA-based intratumoral cancer immunotherapies, has entered a clinical collaboration with the University of California, San Francisco (UCSF), to evaluate the safety, tolerability and efficacy of the combination of KEYTRUDA® (pembrolizumab), Merck’s anti-PD-1 therapy, and OncoSec’s ImmunoPulse (intratumoral IL-12) in metastatic melanoma.

“Recent data suggest that patients who are PD-L1 positive and have increased tumor-infiltrating lymphocytes (TILs) are more likely to respond to anti-PD-1/PD-L1 mAbs compared to patients who are PD-L1 negative. Therefore, therapies that promote TIL generation and PD-L1 positivity may play an important role in augmenting the clinical efficacy of these agents.

“Interleukin-12 (IL-12) is an inflammatory cytokine believed to be a master regulator of the immune system, promoting up-regulation of both the innate and adaptive immune responses. More specifically, IL-12 stimulates the production of another cytokine, interferon gamma (IFN-), which results in the stimulation of antigen processing and presentation machinery, leading to increased TILs and anti-tumor cytotoxic T-cell (CTL) activity.”

ASCO 2014: Highlights for People Dealing with Melanoma

Every year, new cancer treatment insights are shared at the American Society of Clinical Oncology (ASCO) Annual Meeting. Here are some of the most notable recent developments in melanoma treatment, gleaned from researchers’ presentations at ASCO last month: Continue reading…

OncoSec Medical Presents Positive Phase 2 Interim Data Evaluating ImmunoPulse in Melanoma

“OncoSec Medical Inc. (OTCQB: ONCS), a company developing its ImmunoPulse DNA-based intratumoral cancer immunotherapy, announced interim data from its Phase 2 melanoma study at the American Society of Clinical Oncology’s (ASCO) 50th Annual Meeting in Chicago. The abstract, titled “Systemic anti-tumor effect and clinical response in a Phase 2 trial of intratumoral electroporation of plasmid interleukin-12 in patients with advanced melanoma” (ASCO Abstract #9025), was presented by Adil Daud, M.D., OncoSec’s Chief Clinical Strategist and Principal Investigator of the Phase 2 melanoma study, and selected for discussion during a poster highlights session for melanoma/skin cancers led by Axel Hauschild, M.D., Ph.D.”

Editor’s note: This article describes a promising immunotherapy treatment that boosts a patient’s own immune system to fight melanoma. 

Melanoma: A 2013 ‘Progress Report’

The past year saw some remarkable advances in melanoma clinical research and treatment. This feature explores the most notable melanoma news of 2013: Continue reading…

IL-12 Therapy May Shrink Melanomas Not Directly Treated

An experimental immunotherapy that delivers interleukin-12 (IL-12) directly into a melanoma tumor may also shrink tumors elsewhere in the body. Called ImmunoPulse, the treatment entails injecting a tumor with interleukin-12 DNA and delivering electric shocks to make the tumor cells absorb this DNA. These cells then produce IL-12, boosting the immune response against the tumor. In an ongoing phase II trial of 21 people with melanomas that were treated with ImmunoPulse, tumors shrank in 8 of them (38%) and disappeared for at least 6 months in 2 more of them. Moreover, untreated tumors also shrank in about 60%. The possibility of body-wide effects is encouraging because, in contrast to systemic IL-12 therapy, ImmunoPulse treatments have yet to cause serious side effects.