Neoadjuvant Immunotherapy Represents an Improved Option for Resectable Melanoma

The survival benefit displayed with the administration of pembrolizumab (Keytruda) prior to and after resection in the phase 2 SWOG S1801 trial (NCT03698019) showed that the addition of immunotherapy prior to surgery represents a practice-changing option for patients with high-risk melanoma, according to Anna Pavlick, DO, MBA, who added that data also continue to point to immunotherapy as the optimal frontline treatment for those in the metastatic setting.

“[It is important] to think of immunotherapy first and know that immunotherapy is going to provide patients with the highest chance of long-term, durable responses. When you have a patient who presents with bulky but resectable disease, think about giving them [neoadjuvant] immunotherapy before taking them to the operating room. Immunotherapy prior to surgery is really going to change their outcome,” Pavlick explained in an interview with OncLive® following a State of the Science Summit™ on melanoma, which she chaired.

In the interview, Pavlick discussed key updates from clinical trials that continue to shape the treatment of patients with melanoma, the role of immunotherapy in the frontline setting, and the importance of toxicity management and patient support. Pavlick is a professor of medicine in the Division of Hematology and Medical Oncology, and the director of the Cutaneous Oncology Program at Weill Cornell Medicine in New York, New York.

OncLive^®: What key recent updates have emerged from clinical trials in the melanoma space?

Pavlick: I discussed 3 trials that covered the newest information out there. The first was the 6.5-year follow-up on the phase 3 CheckMate-067 trial [NCT01844505], which evaluated ipilimumab [Yervoy] plus nivolumab [Opdivo] vs ipilimumab [alone] vs nivolumab [alone]. Now, 6.5 years later, this trial demonstrated that the tail of the [progression-free survival] curve remains flat [for patients treated with the combination], which demonstrates that at least 50% of patients who remained disease free at 3 years continued to remain disease free 6.5 years later. That is very encouraging for our patients.

The next trial that we looked at was the SWOG S1801 trial, looking at 3 doses of pembrolizumab before surgery for patients with resectable disease, followed by resection, followed by 15 cycles of adjuvant pembrolizumab, compared with patients who went [right to resection] and then got 18 cycles of pembrolizumab. This study demonstrated that there clearly is a survival benefit to receiving neoadjuvant immunotherapy prior to resection. The other added advantage to that study was that we were able to look at the effect of immunotherapy on the tumors when they were harvested or resected. We saw that patients who had close to complete response [CR] or CR are the patients who did exceedingly well and were long-term survivors.

This is a treatment-changing paradigm for us because we would normally take resectable patients, resect them, and then give them preventive therapy. Now we need to think about giving patients immunotherapy before we send them to surgery, and then following up and giving them continued therapy. What is going to be a question for the next trial is if we give patients up-front immunotherapy, and then [undergo resection], if they’ve already had a CR, do they need any further [adjuvant] therapy? None of us know that answer.

Finally, we discussed the phase 3 DREAMseq trial [NCT02224781], which was an important trial that looked at all patients with metastatic disease who also had a BRAF mutation. There has been a long controversy about giving BRAF[-targeted therapy] as first-line therapy or immunotherapy as first-line therapy. [DREAMseq] was a large, randomized trial where half of the patients with BRAF-mutated metastatic disease received immunotherapy with ipilimumab and nivolumab [as frontline therapy] vs dabrafenib [Tafinlar] and trametinib [Mekinist]. At the time of progression, patients could then cross over [to the other arm]. [If they received] BRAF and MEK inhibitors [first], they would then go on to immunotherapy. If patients got immunotherapy, they would then go on to get BRAF and MEK inhibitors. What we saw favored giving immunotherapy first. Patients had a much higher chance of crossing over to second-line therapy if they got immunotherapy first.

It really was an interesting survival curve because we saw that in the first 3 months, the survival curve was in favor of patients who got BRAF and MEK inhibitors. When thinking about the mechanism of action of targeted therapy, it works very quickly. It’s like flipping on a light switch. If you block the target, the tumor stops growing. Those patients had the benefit. However, that curve dropped off very quickly because those were the patients who developed resistant disease and progressed on [targeted] therapies. Unfortunately, many patients that did progress after targeted therapy progressed too rapidly to go on to get immunotherapy.

In the immunotherapy group, there was a dip in the first 3 months because the immunotherapy is working to wake up a patient’s immune system and get it revved up. That takes anywhere from 8 to 12 weeks. Suddenly, the curves crossed, and the immunotherapy remained elevated and statistically higher than the BRAF/MEK inhibitor group. Like the other immunotherapy curves that we see, the curve now remains flat. There clearly is a benefit to giving immunotherapy first, [irrespective of] a patient’s mutational status.

What can be done to address the needs of patients who may not respond to immunotherapy?

I was teased at one point when immunotherapy came out, with people saying, “What are you going to do in 5 years when you have nothing to do?” I could only hope that would be my problem, that we were able to cure melanoma. We've moved the needle dramatically with respect to melanoma survival, but not everybody survives. What we need to do is focus on identifying patients who are going to benefit and identifying patients who may not have any response to immunotherapy. Because why waste their time? If you can find a biomarker that says this patient is not going to respond to immunotherapy or this patient may have a short-lived response, [we could] take that information and figure out how to improve on that.

We also have a large unmet need for patients who have brain metastases. We are very fortunate to have focused radiation therapy and radiosurgery for them. Although immunotherapy has made a large dent in improving survival [for patients with brain metastases], it is not 100% [effective]. How can we improve their outcomes?

Then there are the rare tumors, including mucosal melanoma, acral melanoma, and uveal melanoma. We’re making small strides there, but we need to focus a lot of our efforts in catching those diseases up to speed to where we are with cutaneous melanoma.

Barbara Ting-Wen Ma, MD, MS, of Weill Cornell Medicine, discussed BRAF-targeted agents in the melanoma treatment landscape. How have these agents evolved, and would there be a situation where a combination of BRAF and MEK inhibitors could be used over immunotherapy in the frontline?

There are multiple generations of BRAF and MEK combinations, the newest being encorafenib [Braftovi] and binimetinib [Mektovi], which looks like it may provide a longer duration of response than the prior BRAF and MEK combinations that we had. Moreover, there was a follow-up on the dabrafenib and trametinib brain metastases data, demonstrating that these are good drugs to get into the brain to control the disease there.

The bottom line is that these drugs should be looked at as a parachute. If a patient has a BRAF mutation, they’re going to get immunotherapy first. However, if immunotherapy doesn’t do what we had hoped, we have the parachute where we can give them BRAF and MEK inhibitors to control their disease.

Keeping that in mind, we must look at the patient clinically. If you have a patient that’s deteriorating in front of your eyes, that’s a patient that doesn’t have the 8 to 12 weeks to wait for immunotherapy to kick in. Although we know that there is an immunotherapy benefit in the first line, depending upon your clinical assessment of the patient, you may need to give the patient targeted therapies first because they work so quickly, and you can get the patient’s disease under control. It really is a clinical judgment.

Caressa Valdueza, NP, of Weill Cornell Medicine, discussed toxicity management for patients with melanoma. Why is it important to raise awareness of what toxicities can occur on treatment?

[Dr Valdueza emphasized] the importance of education and reporting [of toxicities]. We’ve worked with immunotherapy now for many years, so many of us are fully aware of what those toxicities are and know how to manage them. However, we need to educate patients and families about how important it is to report when they’re having a toxicity so we can intervene early. Early intervention will allow easier management of the patient and most likely allow for them to continue therapy smoothly.

Many times, patients are afraid to report their toxicities for fear that they won’t get their next treatment. This is correct [if toxicities aren’t reported]. If a patient comes into the office with a rash, they will not be going to get the next treatment. However, if a patient calls and we manage it, by the next cycle of treatment, that toxicity will be controlled or resolved, and we can continue.

It is important to raise awareness of what those toxicities are, educating patients and family members, and giving family members permission to call when the patient says not to. They could save their life, especially when it comes to diarrhea.

Kathleen Madden, FNP, MSN, AOCNP, of NYU Cancer Institute, discussed health literacy, patient education, and the patient support network. How can these support systems benefit patients with melanoma?

This discussion was informative and made you think. It made you think about how to talk to patients, how to present data so that patients are receptive, understand it, and can ask pertinent questions. It also made you think of home education. What can we give to patients to make their lives easier? Patients have just been diagnosed with cancer and they’re overwhelmed. Now, suddenly, they are somebody who goes from having no medicines to now having 10 or 20 pill bottles in front of them. [We can give] them medication sheets and show them how to keep an accurate calendar of when they take their medicine. On medication sheets, patients can check off if they took their pill.

Education [involves] making people feel comfortable with approaching their care providers, asking questions, and providing an environment that’s safe for them. [Education also involves] providing information about the medicines that you’re giving patients and how they work. The more patients that understand their disease, what medicines they’re taking, and how [those medicines] work, the more likely you’re going to have patient compliance.

Is there ongoing research in melanoma being conducted at Weill Cornell Medicine that you would like to highlight?

There are many new and exciting studies that are out there. Melanomas have multiple mutations, with BRAF being most common, but there is a large portion of patients who also have NRAS mutations. We do not have any effective targeted therapy for those patients with NRAS mutations because many patients with NRAS mutations may not have the vigorous immunotherapy response that other patients have. They will respond, but many of them will progress at some point in time.

Within the next month, we will be opening a trial specifically for NRAS-mutated patients. It’s an oral medicine they take once a day. Hopefully that will be able to push the needle a little further for those patients.

We’re also doing an adjuvant study specifically for patients with stage II melanoma, looking to evaluate the addition of a second medication. We now know that high-risk patients with stage IIB and IIC melanoma may benefit from single-agent anti–PD-1 therapy. We’ll be doing a trial that’s going to compare single-agent PD-1 vs PD-1 inhibition with another checkpoint inhibitor [targeting] TIGIT.

Finally, we’re opening some tumor-infiltrating lymphocyte trials. Those are cellular therapy trials where we harvest some of the patient’s tumor, then take out the T cells that essentially infiltrate the tumor, expand those T cells outside the patient’s body, and then bring the patients into the hospital. It is like a mini bone marrow transplant. We get rid of the patient’s own lymphocytes and then give them back all these fighter lymphocytes to see if we can improve their disease status. That trial is for patients who have stage IV disease.