Christian U. Blank, MD, PhD, a medical oncologist in the Division of Immunology at the Netherlands Cancer Institute, discusses the OpACIN and OPACIN-neo trials examining ipilimumab (Yervoy) plus nivolumab (Opdivo) in stage III macroscopic melanoma. 

In the phase 1b OpACIN trial, neoadjuvant ipilimumab plus nivolumab was compared with adjuvant ipilimumab plus nivolumab, while the subsequent OpACIN-neo trial evaluated 3 different dosing schedules of neoadjuvant ipilimumab plus nivolumab.

As the OpACIN study looked at a very small patient population, the OpACIN-neo study was conducted, says Blank. In the OpACIN study, patients were treated using the stage IV schema with 3 mg/kg of ipilimumab and 1 mg/kg of nivolumab; this was a toxic regimen. Therefore, different dosing schemes were evaluated in the OpACIN-neo study.

One scheme was sequential and 1 gave only 2 courses instead of the 4 courses of therapy that were given in the OpACIN study. Additionally, the dosing of ipilimumab was lowered to 1 mg/kg and the dosing of and nivolumab was increased to 3 mg/kg. By doing this, the rate of grade 3/4 toxicities was reduced to 20% while preserving the p

 rate of 77% compared with the 80% observed with the previous dosing; this regimen was found to be equally effective, according to Blank.

Only 1.4% of responders relapsed while 65.2% of non-responders relapsed, adds Blank. As such, at week 6, patients can live their lives freely. Unfortunately, patients who do not respond should undergo have strict follow-up because they have a higher chance of relapse, concludes Blank.

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Christian U. Blank, MD, PhD, discusses the OpACIN and OPACIN-neo trials examining ipilimumab plus nivolumab in stage III macroscopic melanoma.  

Dr. Blank on the OpACIN, OpACIN-neo Trials in Stage III Macroscopic Melanoma

Christian U. Blank, MD, PhD, medical oncologist in the Division of Immunology at the Netherlands Cancer Institute, discusses ongoing research efforts to personalize neoadjuvant therapy in stage III macroscopic melanoma. 

Many ​smaller neoadjuvant studies with similar designs have been conducted in this space, says Blank​. ​However, the next step is to define the responders and non-responders, ​potentially through RNA signature ​assessment.

Ultimately, any differences or overlaps that are found could suggest the best course of treatment for individual patient​s, Blank explains. 

In comparison with other malignancies, melanoma appears to be leading the way in terms of neoadjuvant therapy research, Blank concludes. 

Christian U. Blank, MD, PhD, discusses ongoing research efforts to personalize neoadjuvant therapy in stage III macroscopic melanoma. 

Dr. Blank on Personalizing Neoadjuvant Therapy in Stage III Macroscopic Melanoma  

Christian U. Blank, MD, PhD, a medical oncologist in the Division of Immunology at the Netherlands Cancer Institute, discusses the future of baseline biomarkers in macroscopic stage 3 melanoma.

In the OpACIN trial, investigators compared neoadjuvant ipilimumab (Yervoy) plus nivolumab (Opdivo) with adjuvant ipilimumab plus nivolumab, while the subsequent OpACIN-neo trial evaluated 3 different dosing schedules of neoadjuvant ipilimumab plus nivolumab only. Updated data from the trials were recently presented during the AACR Virtual Meeting II.

For translational analyses from the trial, baseline biomarkers, such as tumor mutational burden (TMB) and interferon gamma expression, were used to predict which patients would have favorable responses to treatment, says Blank. These were found to be independent biomarkers, but if both of these markers were favorable, patients would also have a favorable response, adds Blank. If only 1 of the markers are favorable, either interferon signature high and TMB low or TMB high and interferon signature low, patients still experienced a relatively high response rate. If both biomarkers are low, then patients have a lower response rate; this is a subgroup of patients that will require extended treatment, either with a triplet or alternative treatment to increase response rates, explains Blank.

That effort is being worked on with the phase 1/2 DONIMI trial (NCT04133948), which will examine a neoadjuvant triplet combination versus monotherapy in patients with either low or high interferon signature; this will also examine de-escalated therapy in the patients who have a very high interferon signature.

It is known that a PD-1 inhibitor given by itself can provide a good response, although the percentage of response is low. Therefore, if the optimal patients for this approach can be identified, they also can achieve benefit, says Blank. This is the future of personalized treatment in patients with melanoma: trials examining RNA signature–driven treatments. Through the use of precision medicine, there will be less patients with stage IV disease, concludes Blank.

Christian U. Blank, MD, PhD, discusses the future of baseline biomarkers in macroscopic stage 3 melanoma.

Dr. Blank on Predictive Biomarkers in Macroscopic Stage III Melanoma

Christian U. Blank, MD, PhD, medical oncologist in the Division of Immunology at the Netherlands Cancer Institute, discusses adjuvant versus neoadjuvant approaches in macroscopic stage III melanoma.

The melanoma field has efficacious adjuvant approaches available for use, with targeted therapies, such as trametinib (Mekinist), and immunotherapies, such as pembrolizumab (Keytruda) and nivolumab, says Blank.

The relapse-free survival (RFS) for patients with stage III melanoma in the macroscopic setting is within the range of 60% and 70%, according to Blank. However, the problem is that all these trials within this patient population have excluded patients who experience early relapse. Patients who relapsed following surgery before they began adjuvant therapy at week 12 were excluded from these trials. As such, the RFS in the intention-to-treat population, or event-free survival, is estimated to range from 15% to 25%, according to Blank.

With neoadjuvant therapy, patients have the advantage of starting treatment with immunotherapy when the whole tumor is still present; that means a broader and more intense immune response can be induced compared with if the entire tumor was removed and only the smoldering small tumor cells were present. Those cells are sometimes not particularly immunogenic; thus, a lower immune response would be produced, concludes Blank.

Christian U. Blank, MD, PhD, discusses adjuvant versus neoadjuvant approaches in macroscopic stage III melanoma.

Dr. Blank on Adjuvant Versus Neoadjuvant Approaches in Stage III Melanoma

Christian Blank, MD, PhD, Netherlands Cancer Institute, discusses early findings from the OpACIN trial testing a combination of ipilimumab and nivolumab in the neoadjuvant and adjuvant setting for patients with stage III melanoma. The results were presented at the 2016 Society for Melanoma Research (SMR) Annual Meeting. 

In early findings from the trial, the overall response rate (ORR) was 80% with the combination of nivolumab and ipilimumab. Additionally, 30% of patients treated with the neoadjuvant combination experienced a pathologic complete response (pCR). 

Blank noted that he is interested in following up with these patients to see if they relapse. With the possible successful outcomes down the line, this combination may shift the landscape for how high-risk melanoma is treated.

View more from the 2016 SMR Annual Meeting

Christian Blank, MD, PhD, Netherlands Cancer Institute, discusses some of the early findings from the OpACIN trial testing a combination of ipilimumab and nivolumab in the neoadjuvant and adjuvant setting for patients with stage III melanoma.

Christian Blank, MD, PhD

Articles

Dr. Blank on the OpACIN, OpACIN-neo Trials in Stage III Macroscopic Melanoma

Dr. Blank on Personalizing Neoadjuvant Therapy in Stage III Macroscopic Melanoma

Dr. Blank on Predictive Biomarkers in Macroscopic Stage III Melanoma

Dr. Blank on Adjuvant Versus Neoadjuvant Approaches in Stage III Melanoma

Dr. Christian Blank on Combining Immunotherapy Agents in High-Risk Melanoma