Bartosz Chmielowski, MD, discusses the rationale for IGNYTE, the unique mechanism of action of RP1, and how melanoma research is seeking to determine treatments for patients based on their individual resistance mechanisms.
The preliminary efficacy and tolerability observed with vusolimogene oderparepvec (RP1) plus nivolumab (Opdivo) in patients with cutaneous melanoma signal the expansion of the use of oncolytic viruses to manage cancers that are resistant to PD-1 inhibition, according to Bartosz Chmielowski, MD.
The phase 2 IGNYTE trial (NCT03767348) is investigating RP1 with or without nivolumab in patients with advanced or metastatic non-neurologic solid tumors for whom no suitable treatment options exist. Preliminary data showed that, at a median follow-up of 9.96 months, RP1 plus nivolumab demonstrated an overall response rate (ORR) of 36% in 75 patients with melanoma who progressed on prior PD-1 inhibitors, including those with visceral disease and high tumor burden.1
RP2, a derivative of RP1 that expresses additional immune-activating proteins, is also under investigation with nivolumab in a phase 1 trial (NCT04336241) in patients with uveal melanoma.2
“There are several treatment options [for patients with melanoma], depending on what you select in the first line,” Chmielowski said. “However, many patients still have progressive disease, and there’s a need for new drug development.”
In an interview with OncLive®, Chmielowski discussed the rationale for IGNYTE, the unique mechanism of action of RP1, and how melanoma research is seeking to determine treatments for patients based on their individual resistance mechanisms.
Chmielowski is a health and sciences clinical professor of medicine in the Division of Hematology-Oncology at the University of California Los Angeles.
Chmielowski: Melanoma treatment has changed in recent years. PD-1 inhibitor–based therapies are first-line therapies for most patients. Unfortunately, many patients [progress] or never respond to these treatments. The landscape has become complicated because up front, you need to decide between treating patients with a single-agent PD-1 inhibitor or 2 possible combinations: PD-1 and CTLA-4 inhibitors or PD-1 and LAG-3 inhibitors. Up-front decisions are difficult, outside of patients with BRAF mutations, [for whom there is] targeted therapy.
After [up-front therapy], if you started with a single agent, you could try a combination. If you first tried a PD-1 inhibitor alone, [we commonly try] a PD-1 inhibitor plus a CTLA-4 inhibitor, or a PD-1 inhibitor plus a LAG-3 inhibitor. Or, if you haven’t used a BRAF/MEK inhibitor, [and the patient has] BRAF-mutated disease, you can use a BRAF/MEK inhibitor. If you started with 1 combination, you could try to switch to the other combination.
RP1 is a new drug similar to talimogene laherparepvec [T-VEC; Imlygic]. The backbone is a herpes simplex type 1 virus strain selected to kill a broad panel of human cancer cells. However, it has proprietary differences from T-VEC. [The backbone is] modified and enhances tumor specificity, [making RP1 more tolerable] and able to target cancer cells more selectively.
When this modified virus is injected into the tumor, it may proliferate in the tumor cells but not in the normal cells, leading to antigen release and immune system activation within the tumor. This provides an additional costimulatory signal for the immune system to activate and recognize the tumor. It has some granulocyte-macrophage colony-stimulating factor, like T-VEC, but the structure is different and hopefully more active, although they have not been compared with each other.
Immune responses against cancer resemble immune response against infectious agents. It is a multi-step process, including antigen presentation, antigen release, and pick-up by antigen-presenting cells such as dendritic cells or macrophages, which then travel to the lymph nodes where the T cells sit in a T-cell–rich area and monitor for recognizable antigens. The [dendritic] cells present [antigens] with the T cells, which leads to T-cell activation. Then they leave the lymph nodes. Each of these steps needs to occur for the response to take place, and if the tumor tries to evade [these steps], you can intervene.
RP1 may lead to the initial activation and release of antigens in the tumor environment. If these tumors contain PD-L1 on the surface, activated T cells cannot do their job. In IGNYTE, many patients have already [progressed on] PD-1 inhibitors. They may have [progressed] because there was not enough antigen release. For T cells to do their job, they need a PD-L1 blockade.
There are previous data with RP1 in patients who are treatment naïve or have [progressed on] PD-1 therapy. We’re examining patients who [progressed on] PD-1 inhibitors. They must have received at least [8 weeks of PD-1 inhibitors] and have confirmed [progression]. This population is already resistant to PD-1 blockade, so we want to see if adding RP1 can reverse that resistance.
There are different populations in this trial. The most widely available data are with 75 patients with melanoma who [progressed on] PD-1 inhibitors. The target enrollment is 125 patients. Additionally, patients with previously treated lung cancer were included in this trial. [Other groups include] patients with microsatellite instability–high tumors, other patients with previously treated melanoma, and patients with non-melanoma skin cancers who were either naïve to PD-1 inhibitors or previously [progressed on] PD-1 inhibitors.
After therapy with PD-1 inhibitors, our options are limited. Single-agent CTLA-4 inhibitors or LAG-3 inhibitors may give responses of 10% to 15%. [It is our goal] to get a 20% response rate in PD-1 inhibitor–resistant patients. In patients with cuaneous melanoma [who progressed on PD-1 inhibitors], we saw a 20% complete response rate. Another 16% of patients had partial responses. Additionally, 42.7% of patients had progressive disease. This exceeds the threshold for a significant signal in patients previously treated with PD-1 inhibitors.
We previously saw data in 16 patients where the response rate was 37.5%. Enrolling more patients did not lead to a loss of response. We will wait for [data with] the full 125 patients on this trial to confirm that this magnitude of responses is maintained.
The therapy is well tolerated. These patients were preselected. Patients who had significant or dose-limiting toxicities on prior PD-1 inhibitors were not included. If patients had adverse effects [AEs] during their previous treatment, they would not be re-exposed to PD-1 inhibitors. Patients must have tolerated PD-1 inhibitors and [be fit to tolerate] the possible AEs of RP1.
Since this is a live, viral-based therapy, there were often flulike symptoms, such as chills, fever, and fatigue, as well as a mild degree of nausea and diarrhea. Most of the AEs were grade 1 or 2, with few AEs above grade 2. The chills and fever were short lived. On the day of each injection, which was given every 2 weeks for 8 doses, patients might have had chills and fevers, which usually went away.
The trial will continue enrollment and require follow-up to see how durable these responses are. Already, 85% of responses, if they occurred, were ongoing. Sometimes [in other trials], we see a response for a month or 2 and then the disease progresses, so the response is not as clinically meaningful for patients. In IGNYTE, once patients respond, the responses last a long time.
There are still unmet needs in patients whose disease [progresses on] PD-1 inhibitors. Hopefully, this will become a new option. It requires longer follow-up and FDA review to see if the data on 125 patients is sufficient for an approval.
The landscape has become complicated. One [area of ongoing investigation in which] we are waiting for approval is tumor infiltrating lymphocytes [TILs]. This is a novel, active model of therapy. Data show that TIL therapy is better than ipilimumab [Yervoy] in the second line. It would not be for everyone, but it could be an option for many patients.
Other injectable drugs beyond RP1 are in development or in studies, such as vidutolimod [CMP-001]. We previously saw activity [with this agent]. It is now being studied in combination with pembrolizumab [Keytruda] and nivolumab in the neoadjuvant setting. Another injectable drug, BO-112, might be promising.
We are waiting to complete accrual to [a phase 3 trial investigating] the ATR inhibitor ceralasertib [AZD6738] where patients are randomized to durvalumab [Imfinzi] or durvalumab plus ceralasertib. Will we get an additional benefit [with the combination]?
In smaller trials, of interest is the development of MDM2 inhibitors. Early data with alrizomadlin [APG-115] were promising. Will this [efficacy] pan out as we enroll more patients? How will we expand this to more patients? There are multiple directions in which we are trying to go.
One weakness of all our processes is that we don’t have a good way [of knowing] how patient resistance to PD-1 inhibitors [begins]. Is it a primary resistance where they were never meant to respond, or is it a secondary resistance?
Additionally, we see heterogeneous patterns of progression. A tumor in a patient’s adrenal gland may have a different resistance mechanism than a tumor in their bone or lung. However, pharmaceutical companies [provide us with] 1 or 2 drugs to use because we don’t know the exact resistance mechanisms, so we try to use these drugs in all patients with resistance. If we understand resistance mechanisms, we may better tailor our trials. Although we may see responses of 10% to 20%, with [these drugs], when we do a larger trial, these [responses] might be diluted. If we could find out who these responders are, our efforts would be more successful, and we would better select patients for therapies. It’s not easy to find resistance mechanisms.