CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: August 29, 2022
Expiration: August 28, 2023
Hussein Tawbi, MD, PhD:
TRICOTEL was a study of the atezolizumab, vemurafenib, and cobimetinib triplet in patients with central nervous system metastases.19 The triplet is approved by the FDA in the first-line setting for patients with metastatic melanoma but was never studied in patients with active untreated brain metastases.
The current analysis focuses on cohort 2, which included patients with BRAFV600-mutant disease. Cohort 1, which included patients with BRAFV600 wild-type disease, was stopped early because atezolizumab and cobimetinib did not have an impact in the phase III setting.20
The baseline characteristics for patients enrolled on cohort 2 are what you would expect for individuals with BRAFV600-mutant disease.19
Hussein Tawbi, MD, PhD:
The intracranial response rate with the triplet was 42% by independent radiology review and 51% by investigator review.19
Hussein Tawbi, MD, PhD:
The benefit from the triplet was most relevant in patients who were symptomatic and/or receiving steroids.19 On this study, 24 patients were in that category, and the intracranial response was 58% by investigator assessment and 46% by independent review.
Hussein Tawbi, MD, PhD:
Of most importance, median PFS and median DoR were best in that subpopulation.19 This highlights that, for patients receiving steroids at the time of treatment initiation, a regimen in which you administer 4 weeks of a BRAF inhibitor and MEK inhibitor before adding in immunotherapy helps get some patients off steroids and potentially leads to brain benefits.
Hussein Tawbi, MD, PhD:
However, this was a very toxic regimen considering that 70% of patients had grade 3/4 toxicity.19 However, as with other triplets, most patients managed to stay on the 3-drug combination, albeit with dose reductions and interruptions.
Allison Betof Warner, MD, PhD:
My takeaway from TRICOTEL is certainly the toxicity associated with this triplet. Cobimetinib plus atezolizumab is a difficult combination to tolerate, and tolerability is even more difficult with the triplet. I had hoped that the DoR would be significantly longer. Certainly, that was the goal behind adding a PD-1 inhibitor to a targeted therapy. I do not think we saw that in this trial. For patients receiving high doses of steroids, many of us already were giving targeted therapy as a sort of bridge to immunotherapy. I am not sure the TRICOTEL data argue that we should administer triplet therapy up front vs administering targeted therapy followed by ipilimumab plus nivolumab for patients with central nervous system metastases.
There was a lot of enthusiasm 2+ years ago for giving triplet therapy, and we really were waiting for this study to read out to see whether that approach would pan out. Overall, I think there may be individual cases where triplet therapy is important, and it is important to have the safety data. However, overall, I do not think this is the best approach for most patients.
Allison Betof Warner, MD, PhD:
CheckMate 067 is the definitive study that established the benefit of ipilimumab plus nivolumab in metastatic melanoma.21,22 Within the trial, the 3 arms—ipilimumab plus nivolumab, nivolumab monotherapy, and ipilimumab monotherapy—provide good insight into the benefit of each agent alone and in combination. It is important to note that the study was powered to compare nivolumab/ipilimumab vs ipilimumab; it was not powered to compare nivolumab/ipilimumab vs nivolumab.
Data from this trial have continually been reported over the years. At ASCO 2022, the investigators presented data through 7.5 years of follow-up.23
As a reminder, OS was a coprimary endpoint.
Allison Betof Warner, MD, PhD:
The 7.5-year update showed that the OS benefit seen previously with nivolumab plus ipilimumab remains durable.23 After 6.5 years of follow-up, median OS was reported to be 72.1 months with nivolumab plus ipilimumab.22 There was really no new signal at the 7.5-year follow up.23 Median OS was still 72.1 months.
Allison Betof Warner, MD, PhD:
A key secondary endpoint, melanoma-specific survival, looked quite favorable for the nivolumab/ipilimumab arm at a median 11.5 months and, again, is confirmatory of what we have seen in the past.22,23
Hussein Tawbi, MD, PhD:
I would remind everyone that the median age for patients in this study was in the 60s. Now that we are out 7-8 years from the start of the study, patients are dying of other causes. It is noteworthy that the 5-year melanoma-specific survival rate is 57%. You can literally take that to mean that this is the number of patients we cure of melanoma; these individuals will die of other things.
Allison Betof Warner, MD, PhD:
The ORR really is unchanged from previous data. The only notable finding from the 7.5-year analysis is that we had previously not yet reached the median DoR, and we now have those data for the nivolumab arm.23 The median DoR still has not been reached for the combination arm.
Allison Betof Warner, MD, PhD:
Among those patients who remain alive and who are still being followed, only 19% originally assigned to receive nivolumab plus ipilimumab have gone on to receive subsequent systemic therapy.23 Remarkably, 77% remain treatment free.
Allison Betof Warner, MD, PhD:
Perhaps a big update is that 4 patients died of melanoma progression.23 There were no other treatment-related deaths due to late AEs, which is as expected but reassuring. I think, to your earlier point, Dr Tawbi, that many patients are dying of other causes.
There was a health-related quality-of-life assessment, which was stable. There were no late changes, as one would expect 7.5 years out from therapy.
Allison Betof Warner, MD, PhD:
Overall, the 7.5-year results confirm what we have seen in terms of the long-term durability of an OS benefit from nivolumab plus ipilimumab and maintained quality of life.23 One important takeaway from both the 6.5-year and 7.5-year analyses is the treatment-free intervals.22,23 We need to think long and hard when we are selecting an appropriate regimen for a patient. That has been an undervalued endpoint, but for patients it is an important milestone to be off treatment—not only psychologically, but also in terms of quality of life. It was nice to see those data over longer follow-up and, I think, one of the important findings from this year.
Hussein Tawbi, MD, PhD:
The pivotal phase II/III RELATIVITY-047 trial previously demonstrated that nivolumab plus relatlimab significantly improved PFS compared with nivolumab alone in patients with previously untreated metastatic or unresectable melanoma, leading to approval of this new immunotherapy combination.24,25 At ASCO, the RELATIVITY-047 co-investigators and I reported exploratory data from key subgroups to provide more insight into the benefit of nivolumab plus relatlimab across different subpopulations.26
As a reminder, the primary endpoint of this trial was PFS according to blinded independent central review.
Hussein Tawbi, MD, PhD:
Patient baseline characteristics were relatively well balanced between the 2 treatment groups, and the study population was very representative of the population with first-line metastatic melanoma.26
I will highlight that approximately 40% of patients in the study had M1c/M1d disease, with a slight preponderance in the relatlimab/nivolumab arm. The other interesting thing to note is that approximately 18% to 19% of patients had acral or mucosal melanoma, which is an impressive rate for a phase III trial.
Hussein Tawbi, MD, PhD:
Consistent with previously reported data, PFS, OS, and ORR all favored the relatlimab/nivolumab arm vs the nivolumab arm based on a median of 19.3 months of follow-up.24-26
Hussein Tawbi, MD, PhD:
When looking at the subgroup analyses according to LAG-3 positivity and PD-L1 positivity, patients with PD-L1–positive disease (ie, ≥1% PD-L1 expression) had a similar PFS benefit with relatlimab/nivolumab vs nivolumab alone.26 However, the ORRs were quite different, with a 53% response rate with relatlimab/nivolumab vs a 45% response rate with nivolumab alone. This was a univariate analysis. Accounting for other factors such as positive LAG-3 status (ie, ≥1% LAG-3 expression), the response rate with relatlimab/nivolumab rose to 55% compared with 44% for nivolumab alone for patients positive for both PD-L1 and LAG-3 expression. Patients who were PD-L1 negative and LAG-3 positive still had a 14% improvement in ORR vs nivolumab alone with the combination.
Hussein Tawbi, MD, PhD:
We also looked at important characteristics such as age.26 Patients older than 75 years still had an impressive improvement in ORR with relatlimab/nivolumab vs nivolumab. Also, acral melanoma was particularly relevant, with an increase in ORR of approximately 18% with relatlimab/nivolumab vs nivolumab alone. Mucosal melanoma ended up having approximately the same ORR between arms, with a slight improvement with relatlimab/nivolumab.
Presence of a BRAF mutation did not significantly impact any efficacy outcomes. The degree of improvement with relatlimab/nivolumab was consistent whether patients had BRAF-mutant or BRAF wild-type disease.
Hussein Tawbi, MD, PhD:
When we examined higher tumor burden and higher LDH, patients did worse, in general, if they had either of these factors.26 However, the benefit derived from relatlimab/nivolumab vs nivolumab was fairly consistent across all of those subgroups. For example, patients with high tumor burden had a 10% improvement in response rate with relatlimab/nivolumab vs nivolumab despite generally lower response rates across the 2 arms.
Hussein Tawbi, MD, PhD:
There were no new safety signals.26 Grade 3/4 treatment-related AEs occurred in 21% of patients who received relatlimab/nivolumab vs 11% of patients who received nivolumab.
Hussein Tawbi, MD, PhD:
In conclusion, the important aspect of these data is that there is no specific subgroup in which you would use nivolumab over the combination. The combination seemed to have a consistent efficacy benefit across all subgroups.
Allison Betof Warner, MD, PhD:
The only important thing to add is that I am not sure that the subgroups are large enough for patients with mucosal or acral melanoma to provide reliable data. We are likely not going to perform dedicated studies in those patient populations, but it is difficult to draw conclusions from small subgroups in RELATIVITY-047. I think we will need to see the real-world data in these patients now that nivolumab plus relatlimab is approved.
Allison Betof Warner, MD, PhD:
AMBER is a phase I dose-escalation study evaluating dostarlimab, an anti–PD-1 antibody, in combination with cobolimab, an anti–TIM-3 antibody.27 TIM-3 has been a target of great interest over the past few years because it activates immune cells and imparts antitumor activity in combination with anti–PD-1 agents.28
The primary aim of part 1C of AMBER was to determine the recommended phase II dose of the combination in patients with advanced melanoma, which was determined to be cobolimab 300 mg and dostarlimab 500 mg every 3 weeks.27 The primary aim of part 1E was to test efficacy of the combination in an expanded cohort of patients.
Allison Betof Warner, MD, PhD:
Patient baseline characteristics were as expected for a phase I trial.27 Very few patients had mucosal or uveal melanoma, referring again to these small subgroups. A few patients had received previous treatment with a BRAF inhibitor and MEK inhibitor, and some had received previous interferon.
Allison Betof Warner, MD, PhD:
Regarding treatment-related AEs, the important signal that emerged from these cohorts was that of pneumonitis.27 Seven of 277 patients—or 2.5%—developed pneumonitis, which is certainly higher than what we have seen reported previously for a PD-1 inhibitor alone. Granted, the incidence of grade ≥3 pneumonitis was only 1.1%, but this is important to note about this combination.
Allison Betof Warner, MD, PhD:
Patients who received the recommended phase II dose of cobolimab 300 mg and dostarlimab 500 mg every 3 weeks attained an ORR of 57%—all PRs—and a DCR of 71%.27 The ORR across all cobolimab/dostarlimab doses was 43%.
Hussein Tawbi, MD, PhD:
I find the 43% response rate with cobolimab/dostarlimab to be eerily similar to the 43% response rate with nivolumab/relatlimab.24 It will be interesting to see how this novel immunotherapy combination performs in additional analyses.
Allison Betof Warner, MD, PhD:
These data support an early, promising, preliminary signal of efficacy with cobolimab and dostarlimab. We will certainly need confirmatory studies, and I think the safety data do support doing confirmatory studies with this combination.
Hussein Tawbi, MD, PhD:
Researchers had previously presented data in patients with acral melanoma where the combination of a PD-1 inhibitor and a VEGF inhibitor showed interesting and impressive activity, leading to a phase III trial.29 In the hopes of increasing the response among these patients, who are otherwise not responsive to immunotherapy alone, the same group studied the combination of a PD-1 inhibitor, a VEGFR2 inhibitor, and temozolomide based on impressive preclinical results.30
This study was a phase II trial of camrelizumab, apatinib, and temozolomide conducted in patients with acral melanoma.30 The study was designed to show an improvement in ORR with the triplet, assuming a historical control ORR of 16% with pembrolizumab in Chinese patients with advanced/metastatic melanoma.31
Hussein Tawbi, MD, PhD:
The study enrolled 50 patients.30 NRAS mutations were found in 18% of the patients, 62% had no mutation, and 20% had an unknown mutational status. There was a large median tumor burden of 40 mm.
Hussein Tawbi, MD, PhD:
The response rate was impressive at 66.7%; most of those are PRs.30 Of importance, DCR was almost 92%, and median DoR was 17.5 months. These are really impressive results in a population that is very hard to treat.
Allison Betof Warner, MD, PhD:
That is an important point to emphasize. These are really quite impressive responses with this triplet when thinking about the response rate to anti–PD-1 monotherapy or even ipilimumab plus nivolumab, which at this point is the most potent combination we have for acral melanoma.
Hussein Tawbi, MD, PhD:
Ipilimumab/nivolumab yields a response in approximately 20% to 25% of patients with acral melanoma. I just showed you that nivolumab/relatlimab produces a response in 30% of patients with acral melanoma based on updated RELATIVITY-047 data.26 I completely agree that a 67% response rate is just incredible for this population.
Hussein Tawbi, MD, PhD:
The toxicity was notable.30 The triplet includes chemotherapy and a VEGFR inhibitor, so it is not surprising that 62% of patients had grade 3/4 AEs.
Allison Betof Warner, MD, PhD:
I was quite impressed that only 1 patient discontinued treatment with a difficult regimen.
Hussein Tawbi, MD, PhD:
Absolutely.
Hussein Tawbi, MD, PhD:
Immune-related AEs were generally transient and manageable.30 Hepatobiliary AEs were the most common grade 3/4 immune-related events.
Hussein Tawbi, MD, PhD:
In conclusion, I think this is a really impressive study. I appreciate that this group is moving on to a randomized, controlled trial to evaluate the triplet in untreated advanced acral melanoma, because this is only a single-arm study.
Allison Betof Warner, MD, PhD:
Tebentafusp is an agent that has gained lots of attention for its activity and OS benefit in advanced uveal melanoma, for which it is now approved.32 It is a bispecific agent targeting gp100 and CD3—basically redirecting T-cells to gp100-positive melanocytic cells. It is important to know that tebentafusp can be used only in patients who are HLA-A*02:01 positive, so that is an important screening assessment for these patients.
Based on preclinical data suggesting that anti–PD-1 treatment increases the activity of bispecifics with a T-cell receptor and effector function in PD-L1–positive tumors,33 the current study was designed to evaluate various tebentafusp combinations—including tebentafusp plus durvalumab, tebentafusp plus durvalumab and tremelimumab, tebentafusp plus tremelimumab, and tebentafusp alone—in patients with advanced cutaneous melanoma.34
Baseline characteristics were as expected for this patient population.
Allison Betof Warner, MD, PhD:
The safety signal across the various arms was quite similar to what we have seen with immunotherapy in uveal melanoma, including an increased incidence of rash, elevated lipase, and lymphopenia.34 Still, very few patients discontinued treatment, as we have seen in the past. There were no deaths.
Allison Betof Warner, MD, PhD:
Compared with a benchmark 1-year OS rate of 55%,35-38 both tebentafusp/durvalumab and tebentafusp/durvalumab/tremelimumab compared favorably, yielding rates of 73% and 78%, respectively.34 Moreover, these 1-year OS rates were fairly consistent regardless of when prior anti–PD-1/PD-L1 therapy was received and the response to such treatment, except for a slightly lower response rate among patients with primary refractory disease.
Hussein Tawbi, MD, PhD:
The fact that tebentafusp worked in uveal melanoma is impressive, especially considering that all of the patients assessed for efficacy had previously received a PD-1/PD-L1 inhibitor; gp100 is primarily a shared melanoma antigen, and it is a very appropriate target for cutaneous melanoma, so I think that is why this study is really interesting.
Allison Betof Warner, MD, PhD:
It also was interesting that the addition of a CTLA-4 inhibitor did not really change the efficacy outcomes but certainly did change the toxicity profile. I think going forward, tebentafusp plus a PD-1 inhibitor is probably the treatment of choice here.
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