Paul Nathan, MBBS, PhD, MRCP, is a consultant medical oncologist at The Mount Vernon Cancer Centre in the United Kingdom.

Dr Nathan on the Mechanism of Action of Roginolisib in Metastatic Uveal Melanoma

"For patients [with uveal melanoma], we struggle to [maintain long-term disease control], and we know that [these] tumors have an immunosuppressed microenvironment. Early data [with roginolisib] show that it appears to change the immune microenvironment in cancers to be more activated and less suppressed."

Paul Nathan, MBBS, PhD, MRCP, a consultant medical oncologist at Mount Vernon Cancer Centre in England, detailed the mechanism of action of roginolisib and discusses the rationale for its ongoing development in metastatic uveal melanoma.

Roginolisib is a novel non-ATP competitive allosteric modulator of PI3Kδ, which is an isoform of the PI3K enzyme. Early data suggest that roginolisib changes the immune microenvironment in cancers, making it more activated and less suppressed. These observations include a reduction in T-regulatory (Treg) cell infiltrate and changes in myeloid-derived suppressor cells.

This mechanism is particularly relevant to research in uveal melanoma, as these tumors are known to have an immunosuppressed microenvironment. Early data involving roginolisib in uveal melanoma suggest an association with the reversal of Treg-to-CD8 ratios. Furthermore, early-phase clinical studies have shown signs of clinical benefit with roginolisib. In the two-part phase 1 DIONE-01 study (NCT04328844), the median overall survival (OS) was 16 months among and he median progression-free survival was 5 months in patients with uveal melanoma across both cohorts (n = 29). Furthermore, roginolisib was well tolerated at the recommended phase 2 dose of 80 mg; no immune-mediated or dose-limiting toxicities were reported and no dose modifications were required. Of note, the agent demonstrated long-term tolerability, with treatment durations extending up to 4.5 years.

Roginolisib is currently being evaluated in the ongoing randomized phase 2 OCULE-01 trial (NCT06717126), Nathan noted. This study is comparing roginolisib against the standard of care for patients who have experienced progression after receiving prior immunotherapy. The trial's primary end point is overall survival, which Nathan described as a robust end point. Sites for the OCULE-01 trial have recently been opened across Europe, he concluded. 

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Paul Nathan, MBBS, PhD, MRCP, describes the mechanism of action of roginolisib and its ongoing evaluation in metastatic uveal melanoma.

Paul Nathan, MBBS, PhD, MRCP, details the rationale for evaluating roginolisib in patients with advanced or metastatic ocular or uveal melanoma.

Dr Nathan on the Rationale for Evaluating Roginolisib in Advanced Ocular or Uveal Melanoma

“Uveal melanoma is an area of huge unmet need. Huge in terms of the amount of need, rather than the number of patients, because it’s a relatively rare disease. For these patients, we struggle to keep them well for a long time.”

Paul Nathan, MBBS, PhD, MRCP, a consultant medical oncologist at The Mount Vernon Cancer Centre, detailed the impetus for evaluating roginolisib for the treatment of patients with advanced or metastatic ocular or uveal melanoma.

The overactivation of thePI3Kδ pathway is caused by a rare inherited condition, which also leads patients to experience immunosuppression, Nathan began. He noted that the pathway appears activated in several tumors, which could be involved in making immune responses to the suppressed tumor. This leads to a balance change in the T regulatory (T

) cells compared with cytotoxic T cells and therefore changes the immune microenvironment and suppresses immune responses, he explained.

Roginolisib is a novel small-molecule inhibitor of PI3Kδ, which is an isoform of the PI3K enzyme, Nathan continued. Preliminary data have demonstrated that it could change the immune microenvironment in cancers to become an activated environment, he asserted. When this occurs, reductions in T

 infiltrate and changes in myeloid suppressor cells were observed, he said.

Furthermore, uveal melanoma is considered a rare form of cancer, which reflects a significant unmet need, particularly with fewer modalities to provide long-term care, Nathan emphasized. However, early data with roginolisib have demonstrated reversals in T

 and CD8 ratios and preliminary signs of clinical benefit among patients on the study, he explained.

Of note, the phase 2 OCULE-01 (NCT06717126) is evaluating the efficacy of roginolisib at 80 mg once daily compared with investigator choice in patients with ocular or uveal melanoma who have previously been treated with at least 1 immunotherapy. Patients included on the study are at least 18 years of age, have advanced or metastatic uveal melanoma or ocular melanoma, have at least 1 suitable lesion for biopsy, at least 1 measurable lesion per RECIST 1.1 criteria, and an ECOG performance status of 0 or 1.

Dr Nathan on the Design of the IMCgp100-202 Trial in Uveal Melanoma

Paul D. Nathan, MBBS, PhD, FRCP, consultant medical oncologist, Mount Vernon Cancer Centre, discusses the design of the phase 3 IMCgp100-202 trial (NCT03070392) of tebentafusp-tebn (Kimmtrak) in patients with previously untreated, HLA-A*02:01–positive metastatic uveal melanoma, highlighting the key enrollment criteria of the randomized, open-label study.

Notably, the IMCgp100-202 study randomly assigned patients with metastatic uveal melanoma to receive tebentafusp vs the investigator's choice of pembrolizumab (Keytruda), ipilimumab (Yervoy) or dacarbazine. This trial produced data that 

Because of the significant clinical demand in uveal melanoma, the control arm was designed as an investigator’s choice arm, indicating the absence of an established standard of care prior to the approval of tebentafusp, Nathan states. In the control arm, patients had the option to receive pembrolizumab, ipilimumab, or dacarbazine chemotherapy, with 82% opting for pembrolizumab, Nathan notes. Patients were randomly assigned in a 2:1 ratio to either tebentafusp or a control agent, he adds.

To be eligible for the trial, patients needed to have HLA-A*02:01–positive disease or an HLA-A*02:01 haplotype. The presence of HLA-A*02:01 is crucial for the drug's mechanism of action because tebentafusp requires HLA to bind to tumor cells, he expands. This study focused on first-line treatment, and patients had to exhibit a good ECOG performance status, Nathan notes. Included were patients with first-line, metastatic uveal melanoma who had measurable, HLA A*02:01–positive disease, he emphasizes. 

The characteristics of the patient population in the study accurately represented the characteristics of real-world patients with metastatic uveal melanoma, he continues. Nathan says that a notable distinction between uveal melanoma and cutaneous melanoma lies in the hepatotropism of uveal melanoma. Most patients with metastatic uveal melanoma enrolled in the trial had hepatic disease, either exclusively in the liver or in combination with extrahepatic sites, he explains. It is essential to highlight that the characteristics of the registrational study's population mirrored the characteristics of patients encountered in clinical settings, with only a small fraction (4%) having solely extrahepatic disease, Nathan shares. The predominant clinical need was in patients with hepatic involvement, he concludes.

Paul D. Nathan, MBBS, PhD, FRCP, discusses the design of the phase 3 IMCgp100-202 trial of tebentafusp-tebn in patients with previously untreated, HLA-A*02:01–positive metastatic uveal melanoma, highlighting the key enrollment criteria of the randomized, open-label study.


Dr Nathan on Updated Survival Outcomes With Tebentafusp in Metastatic Uveal Melanoma

Paul D. Nathan, MBBS, PhD, FRCP, consultant medical oncologist, Mount Vernon Cancer Centre, discusses the 3-year survival data from the phase 3 IMCgp100-202 trial (NCT03070392) of tebentafusp-tebn (Kimmtrak) in patients with previously untreated, HLA-A*02:01–positive metastatic uveal melanoma.

The randomized, open-label IMCgp100-202 study randomly assigned patients with metastatic uveal melanoma to receive tebentafusp vs the investigator's choice of pembrolizumab (Keytruda), ipilimumab (Yervoy) or dacarbazine.

Previously reported data from the primary analysis of the trial, which focused on previously untreated patients, showed that tebentafusp improved OS compared with the investigator's choice of treatment, with a hazard ratio (HR) of 0.51.

Updated data showed that after a minimum follow-up of 36 months, the estimated 3-year OS rate for tebentafusp was 21.6% vs 16.9% in the control arm, Nathan reports. The updated stratified HR was 0.68 in favor or tebentafusp, he adds. Moreover, prolonged survival benefit was consistently observed among patients with poor prognostic factors in the metastatic setting. Tebentafusp also maintained superior 1– and 2-year progression-free survival (PFS) rate vs the control. Notably, a third of tebentafusp responders were still experiencing responses at the 18-month mark. Disease control rates were 46% with tebentafusp and 27% with the investigator's choice of therapy, Nathan states.

Furthermore, the analysis showed that 37% of patients treated with tebentafusp experienced a greater than 50% reduction in circulating tumor DNA (ctDNA) by week 9. These patients experienced longer OS compared with those who did not experience early ctDNA clearance.

Overall, the agent was shown to prolong and maintain OS benefit, confirming its utility as a standard of care in the first line for this population.

Paul D. Nathan, MBBS, PhD, FRCP, discusses the 3-year survival data from the phase 3 IMCgp100-202 trial of tebentafusp-tebn in patients with previously untreated, HLA-A*02:01–positive metastatic uveal melanoma.

Paul D. Nathan, MBBS, PhD, FRCP, consultant medical oncologist, Mount Vernon Cancer Centre, discusses the long-term outcomes with the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) in patients with 

 V600-mutant unresectable or metastatic melanoma.

Five-year follow-up data presented at the 2019 ASCO Annual Meeting showed a progression-free survival rate of 19% and an overall survival rate of 34% with the combination in this patient population. Notably, of the 19% patients who achieved a complete response (CR) to the combination, 49% were progression-free and 71% were alive at 5 years.

 V600 mutations are amenable to BRAF/MEK inhibition, says Nathan. Those who have favorable baseline characteristics and achieve a CR early on in treatment are likely to derive the greatest long-term benefit from the combination, he added. Given these results, molecular testing for BRAF has become integral to practice. Notably, testing can be sent for in the stage III setting and there are also potent BRAF-directed therapies in the adjuvant setting, concludes Nathan.

Paul D. Nathan, MBBS, PhD, FRCP, consultant medical oncologist, Mount Vernon Cancer Centre, discusses the long-term outcomes with the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) in patients with BRAF V600-mutant unresectable or metastatic melanoma.

Dr. Nathan on Long-Term Outcomes With Dabrafenib/Trametinib in BRAF V600-Mutant Melanoma

Paul D. Nathan, MBBS, PhD, FRCP, consultant medical oncologist, Mount Vernon Cancer Centre, discusses the 5-year analysis of the COMBI-d and COMBI-v trials, which look at the long-term effects of dabrafenib (Tafinlar) plus trametinib (Mekinist) in patients with 

 V600—mutant unresectable or metastatic melanoma.

At the 5-year follow-up, the progression-free survival rate was 19% and the overall survival rate was 34%. There is a cohort of patients who do well on the combination long term, according to Nathan. Now, physicians must figure out how to identify who is going to respond well to the combination at the baseline. Physicians have corroborated some earlier data based on a multivariate analysis and a regression tree analysis, looking at baseline characteristics to identify who is likely to do well, according to Nathan.

Physicians found some markers that are associated with durability of response, including whether someone has a normal lactate dehydrogenase, fewer than 3 organ sites involved, and a good performance status. The most powerful marker of durability of response is whether somebody has a complete response (CR) to treatment. However, that is not a baseline marker; rather, it is a marker that is generated while a patient is on treatment. In the trial, 19% of patients had a CR to treatment. In the 5-year outcome for the patients who had a CR, 49% were progression free and 71% were alive at 5 years.

Paul D. Nathan, MBBS, PhD, FRCP, discusses the 5-year analysis of the COMBI-d and COMBI-v trials, which look at the long-term effects of dabrafenib plus trametinib in patients with BRAF V600–mutant unresectable or metastatic melanoma.

Paul D. Nathan, MBBS, PhD, FRCP

Articles

Dr Nathan on the Mechanism of Action of Roginolisib in Metastatic Uveal Melanoma

Dr Nathan on the Rationale for Evaluating Roginolisib in Advanced Ocular or Uveal Melanoma

Dr Nathan on the Design of the IMCgp100-202 Trial in Uveal Melanoma

Dr Nathan on Updated Survival Outcomes With Tebentafusp in Metastatic Uveal Melanoma

Dr. Nathan on Long-Term Outcomes With Dabrafenib/Trametinib in BRAF V600-Mutant Melanoma

Dr. Nathan on 5-Year Survival Outcomes of COMBI-d and COMBI-v Trials in BRAF V600-Mutant Melanoma