Melanoma Experts Make Sense of ASCO 2020 Data and Advise on Clinical Implications

As new data emerge in the melanoma treatment paradigm, new questions have come to light regarding neoadjuvant/adjuvant strategies, reduced dosing for immunotherapy combinations, and approaches following progression on, or resistance to, PD-1 inhibition.

In a special OncLive video program, The Board, several experts came together to discuss key melanoma data that were presented during the 2020 ASCO Virtual Scientific Program. Omid Hamid, MD, chief of Translational Research and Immunotherapy and director of Melanoma Therapeutics at The Angeles Clinic, led the dynamic discussion, which featured insights from the following panelists:

• Sunandana Chandra, MD, MS: medical oncologist and assistant professor of medicine (hematology and oncology) at Northwestern Feinberg School of Medicine
• Pauline Funchain, MD: director of melanoma and genomics at Cleveland Clinic
• Geoffrey T. Gibney, MD: co-leader of the Melanoma Disease Group at the Lombardi Comprehensive Cancer Center and MedStar Cancer Network, member of the Developmental Therapeutics (Phase I) program, and medical oncologist at MedStar Georgetown Cancer Institute
• Ragini Kudchadkar, MD: medical oncologist, associate professor in the Department of Hematology and Medical Oncology, and medical director of the skin program at Emory University School of Medicine, and chair of the Clinical and Translational Review Committee at Winship Cancer Institute of Emory University
• Jason Luke, MD, FACP: associate professor of medicine in the Division of Hematology/Oncology and the director of the Cancer Immunotherapeutics Center within the Cancer Immunology and Immunotherapy Program at UPMC Hillman Cancer Center
• Evan J. Lipson, MD: associate professor of oncology at Johns Hopkins Kimmel Cancer Center
• Anna C. Pavlick, DO: professor in the Department of Medicine and the Ronald O. Perelman Department of Dermatology at NYU Grossman School of Medicine, director of High Reliability Organization Initiatives at Perlmutter Cancer Center, and co-director of the Melanoma Program at NYU Langone Health
• Tara C. Mitchell, MD: associate professor of medicine at the Abramson Cancer Center of the University of Pennsylvania

As part of the discussion, the panel weighed some of the data presented at the meeting with what is typically done in clinical practice and examined whether certain standard approaches should be reconsidered in light of newer evidence that has come to light.

Neoadjuvant Approaches Generate Interest

“Neoadjuvant approaches seem to be quite promising in melanoma and the question of whether we can use pathologic response as a surrogate outcome marker for survival is actively being evaluated,” said Chandra, who kicked off the discussion on the phase 2 PRADO trial.

In this extension cohort, investigators set out to confirm the high pathologic complete response (pCR) rate and safety of ipilimumab (Yervoy) given at 1 mg/kg in combination with nivolumab (Opdivo) at 3 mg/kg that had been demonstrated in the OpACIN-neo trial (NCT02977052). They also hypothesized that therapeutic lymph node dissection (TLND) could potentially be omitted in a subset of patients who achieved either a pCR or a near-pCR.

“What was interesting about this abstract is that the value of an index lymph node approach was analyzed,” noted Chandra. “Basically, they placed a marker in the largest lymph node before neoadjuvant therapy, and patients underwent evaluation of that index lymph node after neoadjuvant therapy to determine what type of pathologic response they achieved.”

Results showed a pathologic response rate (PRR) of 71% with this approach in a total of 99 patients with stage IIIB/C de novo or recurrent melanoma, with a pCR of 50% and a near-pCR of 11%.¹ Notably, the major pathologic response (MPR) in 91 patients who underwent an index lymph node resection was 61%, which was significantly higher than what is generally observed with single-agent PD-1 inhibitors in the neoadjuvant setting, according to Chandra. Additionally, a TLND was omitted in 60% (n = 59) of patients who achieved an MPR.

“This trial showed that this neoadjuvant ipilimumab/nivolumab regimen actually induced a high PRR and the toxicities were tolerable. TLNDs, which we know are quite morbid, were omitted for quite a number of patients,” said Chandra. “Longer follow-up is needed to see further safety outcomes and relapse-free survival, but it’s certainly promising to be able to reduce significant morbidity in our patients.”

Mitchell added that individualizing care for neoadjuvant treatment is the direction that the field is headed, while Luke noted that although this might be an appropriate approach for some patients, it’s not broadly applicable to everyone. “It is still in the research setting,” he stressed.

Can Reduced Dosing of Nivolumab/Ipilimumab Improve Safety?

The standard treatment approach with nivolumab/ipilimumab is to administer 4 doses of nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg followed by maintenance nivolumab. In a phase 2 trial (NCT03122522), investigators set out to determine if decreasing the dose of the combination would reduce toxicity and achieve either the same outcome or an improved benefit than that of the standard approach in patients with unresectable stage III or IV melanoma with no prior anti–PD-1 or –CTLA-4 treatment in the metastatic setting.

“This study was very interesting in that investigators examined 2 cycles of treatment and waited to see what would happen after 2 cycles,” said Funchain. “The idea was that if they saw any growth, they would continue treatment, but if there was either stable disease or some kind of response, then they would stop after 2 doses of the combination.”

Results showed that 68% of patients experienced tumor shrinkage or no growth at week 6 with 2 or fewer doses of the combination.² Of the 19 patients who experienced tumor growth, none had subsequent response per RECIST criteria.

Investigators concluded that efficacy and toxicities with the combination appear to be driven by the first 2 doses of treatment; however, it is still unclear which patients are at increased likelihood of benefitting from fewer doses.

“The finding that caught everyone's eye was that of the patients who had no response, and then continued to cycle 3 and 4, no additional responses were reported,” noted Funchain. “As such, the temptation is to say that we only need 2 cycles. This is the outcome we all want, right? We want to stop at 2 cycles, not have any additional toxicity.”

Gibney noted that although it looks like fewer doses could potentially be used in these patients, it is still unclear whether patients would have experienced more favorable outcomes if they continued to receive all 4 doses.

“In the data set that was presented, a number of those patients came off of treatment for toxicity reasons, so they would not have continued treatment anyway; that makes it a little difficult to interpret these data,” said Gibney. “It does beg the question of, if you get an interval scan at 6 weeks and you don’t see a positive result, do you keep that patient on the same course, or do you change? Until we have more data, it’s very hard to [know how to] apply this to real-life practice.”

Chandra added that although these data would not change how she currently approaches treatment, it does provide reassurance that if a patient experiences bad toxicity on the combination, it might be appropriate to switch them over to PD-1 monotherapy more quickly rather than continuing the combination approach.

PD-1/CTLA-4 Combo Following Progression on PD-1 Therapy Shows Promise

Data from the largest prospective study (NCT02743819) of low-dose ipilimumab and pembrolizumab (Keytruda) immediately following progression on a PD-1 inhibitor performed to date showed antitumor activity and tolerability in patients with unresectable or metastatic melanoma who had progressed on a PD-1 inhibitor immediately before or within 6 months of adjuvant therapy.

To be eligible for enrollment, patients had to have an ECOG performance status of 0 to 1; patients were able to have received prior treatment with a BRAF inhibitor or have treated central nervous system disease, but those with uveal melanoma were excluded from the analysis. For the trial, patients received intravenous pembrolizumab at 200 mg every 3 weeks and ipilimumab at 1 mg/kg every 3 weeks for 4 doses. The primary end point of the trial was immune-related response per irRECIST, while key secondary end points included safety, progression-free survival (PFS), overall survival (OS), and biomarkers.

Results showed an irRECIST response rate of 27% with the combination, with 5 complete responses reported, along with 14 partial responses; 11 patients achieved stable disease.³ Notably, this response proved to be higher than the 15% seen in historical controls with ipilimumab monotherapy. The median PFS was 5.0 months (95% CI, 2.8-8.3) and the median OS was 24.7 months (95% CI, 15.2–undetermined).

“Pembrolizumab plus low-dose ipilimumab actually showed that there might be some activity in what we traditionally see as noninflamed tumor,” said Chandra. “Patients with non-T cell–inflamed gene expression profile also seemed to benefit from this combination.”

Lipson added that studies such as this one open the door to using low-dose ipilimumab in select patients, although strong data still support the use of the normal dose of 3 mg/kg in patient populations such as those with brain metastases. “Some of the data we are discussing today provides me with some support to use a lower dose,” said Lipson. “Having said that, patients with brain metastases essentially always receive standard-dose ipilimumab.”

Pavlick also pointed out that although her standard approach in practice is to use full dose, she might consider a flip dose for her older patient population. “I have a very large geriatric patient population who present with metastatic disease, but I feel that single-agent PD-1 probably isn’t enough,” noted Pavlick. “That’s when I’ll go to the flip doses as frontline. If I do go with PD-1 and they progress, then I don’t hesitate to add low-dose ipilimumab into that combination.”

Ipilimumab Plus PD-1 Elicits Responses in PD-1–Resistant Melanoma

A pressing question that investigators have been working to answer in the melanoma space is what can be done for patients who become refractory to PD 1 inhibition. “Should all patients receive combination therapy with an anti–PD-1/anti–CTLA-4 regimen, or would it be sufficient to offer patients just ipilimumab monotherapy?” questioned Gibney. “We’ve had many debates on what is the right choice, but we haven’t seen a lot of randomized data to suggest one strategy is better than the other.”

In the retrospective, multicenter study, 355 patients with stage III/IV melanoma received PD-1 monotherapy in the adjuvant or metastatic setting, recurred or progressed on treatment, and then were randomized to receive either ipilimumab monotherapy (n = 162) or ipilimumab plus a PD-1 inhibitor (n = 193). Key end points included response rate, PFS, OS, and safety.

In the cohort of patients with PD-1–resistant metastatic disease, 74% (n = 230) had innate resistance and 26% (n = 81) had acquired resistance. The median time to PD-1 progression was 3 months.⁴ Results showed an objective response rate of 32% with the combination versus 13% with the monotherapy (P = .0021). The duration of response with the combination and monotherapy was 11.6 months and 9.0 months, respectively (P = .0467). Moreover, the median PFS reported with the combination was 2.8 months versus 3.1 months with the monotherapy (HR, 0.67; 95% CI, 0.53-0.85; P = .0005). The median OS was 20.4 months with the combination versus 8.8 months with the monotherapy (HR, 0.51; 95% CI, 0.38-0.67; P <.0001).

“Where does this leave us? I think these are very helpful data, suggesting that patients who progress on anti–PD-1 therapy should receive the combination,” said Gibney. “However, in light of the design of this study, we have to be a little cautious interpreting this. This is particularly helpful when I think about patient management and I do largely offer combination therapy to patients in this situation.”

Kudchadkar added that it’s important to note that it’s not the same in the second-line setting. “Many very well-respected physicians have said, ‘Well, I don't want to deal with the toxicity in the frontline [setting]. I'll use combination in the second-line [setting], because it can salvage many patients.’ I think that point is really important, that the second-line setting is better [for the combination]; it's still not the same as giving it in the frontline setting.”

Funchain noted that what made the abstract so interesting is the challenge of understanding what mechanism makes it such that the combination of CTLA-4/PD-1 following PD-1 failure would be more effective than CTLA-4 alone.

“There’s some combinatorial effect between the 2 of them biologically, but what is that? What kind of resistance happens that you still can’t drop the PD-1 inhibitor?” questioned Funchain. “Is there something that’s not suppressed that PD-1 keeps for some reason and it’s important to maintain that? I don’t have answers for those questions, but that is what intrigued me most about this work.”

References

1. Blank CU, Reijers ILM, Pennington T, et al. First safety and efficacy results of PRADO: a phase II study of personalized response-driven surgery and adjuvant therapy after neoadjuvant ipilimumab (IPI) and nivolumab (NIVO) in resectable stage III melanoma. J Clin Oncol. 2020;38(suppl 15):10002. doi:10.1200/JCO.2020.38.15_suppl.10002
2. Postow MA, Goldman DA, Shoushtari AN, et al. A phase II study to evaluate the need for > two doses of nivolumab + ipilimumab combination (combo) immunotherapy. J Clin Oncol. 2020;38(suppl 15):10003. doi:10.1200/JCO.2020.38.15_suppl.10003
3. Olson D, Luke JJ, Poklepovic AS, et al. Significant antitumor activity for low-dose ipilimumab (IPI) with pembrolizumab (PEMBRO) immediately following progression on PD1 Ab in melanoma (MEL) in a phase II trial. J Clin Oncol. 2020;38(suppl 15):10004. doi:10.1200/JCO.2020.38.15_suppl.10004
4. Da Silva IP, Ahmed T, Lo S, et al. Ipilimumab (IPI) alone or in combination with anti-PD-1 (IPI + PD1) in patients (pts) with metastatic melanoma (MM) resistant to PD1 monotherapy. J Clin Oncol. 2020;38(suppl 15):10005. doi:10.1200/JCO.2020.38.15_suppl.10005