Long-term Follow-up of Standard-Dose Pembrolizumab Plus Reduced-Dose Ipilimumab in Patients with Advanced Melanoma: KEYNOTE-029 Part 1B

Carlino, Matteo S.; Menzies, Alexander M.; Atkinson, Victoria; Cebon, Jonathan; Jameson, Michael B.; Fitzharris, B.; McNeil, Catriona M.; Hill, Andrew; Ribas, Antoni; Atkins, Michael B.; Thompson, John A.; Hwu, Wen‐Jen; Hodi, F. Stephen; Guminski, Alexander; Kefford, Richard; Wu, Haiyan; Ibrahim, Nageatte; Moreno, Blanca Homet; Long, Georgina V.

doi:10.1158/1078-0432.ccr-20-0177

Cited by 31 publications

(26 citation statements)

References 9 publications

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“…Similar safety results were achieved with low dose ipilimumab and pembrolizumab in the keynote 029 phase 1b trial [ 25 ]. A recent update with a follow up of 3 years also showed a durable response [ 26 ], which was probably similar to the standard-dose regimen; however, this remains to be further evaluated in a randomized fashion.…”

Section: Introductionmentioning

confidence: 97%

Real World Outcomes of Ipilimumab and Nivolumab in Patients with Metastatic Melanoma

Asher

Ben‐Betzalel

Lev-Ari

et al. 2020

Cancers

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Background: Immunotherapy has drastically changed the outlook for melanoma patients over the past decade. Specifically, the dual blockade of immune checkpoints using ipilimumab and nivolumab has shown unprecedented response rates and survival outcomes. This immense achievement, though, is at the cost of toxicity, with 60% of the patients experiencing high-grade adverse events (AEs). Our study aims to report the efficacy and toxicity outcomes of an out-of-trial, real-life population. Methods: Data on metastatic melanoma patients treated with ipilimumab and nivolumab were retrieved from our melanoma database—a single-center prospectively updated, medical-records based oncologic registry. Data included demographics, clinical and pathological information, as well as tumor responses and survival. Associations between patient or treatment characteristics and outcomes were also evaluated. Results: We identified 172 metastatic melanoma patients, of whom 64% were treatment-naïve. The median follow-up was 12 months. The response rates for treatment-naïve and previously-treated patients were 61% and 25%, respectively; median progression-free survival (PFS) were 12.2 and 2.6 months, and median overall survival (OS) were not-reached (NR) and 6.1 months, respectively. The estimated three-year OS for treatment-naïve patients was 58% (95% CI 42–65). At data cutoff, 22% were still on-treatment. Grade 3–4 adverse events (AEs) were reported in 60% of the patients, almost all of whom were exposed to steroid treatments (59%); AEs were fatal in 4 patients, and led to permanent treatment discontinuation in 31%. Factors significantly associated with outcome were cutaneous histology, low lactate dehydrogenase (LDH), low number of metastatic sites, performance status, first line of treatment and number of combinations administered during the induction phase. Conclusions: Despite the profoundly different baseline patient characteristics, the combination of ipilimumab and nivolumab is as effective in the real-world population as it was in clinical trials, including long-term outcomes. In addition to confirming the significance of baseline prognostic factors, our study reveals that the number of combinations effectively administered may also be correlated with good outcome.

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Section: Introductionmentioning

confidence: 97%

Real World Outcomes of Ipilimumab and Nivolumab in Patients with Metastatic Melanoma

Asher

Ben‐Betzalel

Lev-Ari

et al. 2020

Cancers

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“…It would be of interest to assess whether anti-PD1 + anti-CTLA4 with lower dose anti-CTLA4 might represent an alternative option to maximize the therapeutic benefit with less dose-limiting toxicity than standard anti-PD1 + anti-CTLA4 dosing regimens. Indeed, low dose anti-CTLA4 (1 mg/kg) with full dose anti-PD1—either 3 mg/kg or 2 mg/kg has been investigated for the treatment of cutaneous melanoma in Checkmate-511 [ 37 ] or KEYNOTE-029 [ 38 ]. These combination regimens with low dose anti-CTLA4 appear to have similar efficacy to combination ICI with high dose anti-CTLA4 and have been reported to have less serious adverse events than high dose ICI anti-PD1 + anti-CTLA4 and may result in less treatment discontinuation due to toxicity and less requirement for immunosuppressive therapy.…”

Section: Discussionmentioning

confidence: 99%

Development of a Metastatic Uveal Melanoma Prognostic Score (MUMPS) for Use in Patients Receiving Immune Checkpoint Inhibitors

Kelly

Rose

Muniz

et al. 2021

Cancers

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Metastatic uveal melanoma (mUM) is a rare disease. There are limited data on prognostic clinical factors for overall survival (OS) in patients with mUM treated with immune checkpoint inhibitors (ICI). Retrospective and non-randomized prospective studies have reported response rates of 0–17% for anti-PD1/L1 ± anti-CTLA4 ICI in mUM, indicating a potential benefit only in a subset of patients. This study evaluates the characteristics associated with ICI benefit in patients with mUM. We performed a single-center retrospective cohort study of patients with mUM who received anti-PD1/L1 ± anti-CTLA4 ICI between 2014–2019. Clinical and genomic characteristics were collected from a chart review. Treatment response and clinical progression were determined by physician assessment. Multivariable Cox regression models and Kaplan–Meier log-rank tests were used to assess differences in clinical progression-free survival (cPFS) and OS between groups and identify clinical variables associated with ICI outcomes. We identified 71 mUM patients who received 75 lines of ICI therapy. Of these, 54 received anti-PD1/L1 alone, and 21 received anti-PD1/L1 + anti-CTLA4. Patient characteristics were: 53% female, 48% were 65 or older, 72% received one or fewer lines of prior therapy. Within our cohort, 53% of patients had developed metastatic disease <2 years after their initial diagnosis. Bone metastases were present in 12% of patients. The median cPFS was 2.7 months, and the median OS was 10.0 months. In multivariable analyses for both cPFS and OS, the following variables were associated with a good prognosis: ≥2 years from the initial diagnosis to metastatic disease (n = 25), LDH < 1.5 × ULN (n = 45), and absence of bone metastases (n = 66). We developed a Metastatic Uveal Melanoma Prognostic Score (MUMPS). Patients were divided into 3 MUMPS groups based on the number of the above-mentioned prognostic variables: Poor prognosis (0–1), Intermediate prognosis (2) and Good prognosis (3). Good prognosis patients experienced longer cPFS (6.0 months) and OS (34.5 months) than patients with intermediate (2.3 months cPFS, 9.4 months OS) and poor prognosis disease (1.8 months cPFS, 3.9 months OS); p < 0.0001. We developed MUMPS—a prognostic score based on retrospective data that is comprised of 3 readily available clinical variables (time to metastatic diagnosis, presence of bone metastases, and LDH). This MUMPS score has a potential prognostic value. Further validation in independent datasets is warranted to determine the role of this MUMPS score in selecting ICI treatment management for mUM.

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“…It would be of interest to assess whether anti-PD1 + anti-CTLA4 with lower dose anti-CTLA4 might represent an alternative option to maximize the therapeutic benefit with less dose-limiting toxicity than standard anti-PD1 + anti-CTLA4 dosing regimens. Indeed, low dose anti-CTLA4 (1mg/kg) with full dose anti-PD1 -either 3 mg/kg or 2mg/kg has been investigated for the treatment of cutaneous melanoma in Checkmate-511 [37] or KEYNOTE-029 [38]. These combination regimens with low dose anti-CTLA4 appear to have similar efficacy to combination ICI with high dose anti-CTLA4 and have been reported to have less serious adverse events than high dose ICI anti-PD1 + anti-CTLA4, and may result in less treatment discontinuation due to toxicity and less requirement for immunosuppressive therapy.…”

Section: Discussionmentioning

confidence: 99%

Development of a Metastatic Uveal Melanoma Prognostic risk Score (MUMPS) for use in patients receiving immune checkpoint inhibitors

Kelly

Rose

Muniz

et al. 2021

Preprint

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Background: Metastatic uveal melanoma (mUM) is a rare disease for which no systemic therapy has demonstrated overall survival (OS) benefit. There are no robust data on prognostic factors for OS in patients with mUM treated with immune checkpoint inhibitors (ICI). Retrospective and non-randomized prospective studies have reported response rates of 0-37% for anti-PD1/L1 +/-anti-CTLA4 ICI in mUM, indicating a potential benefit only in a subset of patients. This study evaluates the characteristics associated with ICI benefit in patients with mUM. Methods: We performed a single-center retrospective cohort study of patients with mUM who received anti-PD1/L1 +/- anti-CTLA4 ICI between 2014 to 2019. Clinical and genomic characteristics were collected from chart review. Treatment response and clinical progression were determined by physician assessment. Multivariable Cox regression models and Kaplan-Meier log-rank tests were used to assess differences in clinical progression-free survival (cPFS) and OS between groups and to identify clinical variables associated with ICI outcomes. Results: We identified 71 mUM patients who received 75 lines of ICI therapy. Of these, 54 received anti-PD1/L1 alone, and 21 received anti-PD1/L1 + anti-CTLA4. Patient characteristics were: 53% female, 48% were 65 or older, 72% received one or fewer lines of prior therapy. Within our cohort, 53% of patients had developed stage IV disease < 2 years after their initial diagnosis. Bone metastases were present in 12% of patients. For the entire cohort, the median cPFS was 2.7 months and median OS was 10.0 months. In multivariable analyses for both cPFS and OS, the following variables were associated with good prognosis: ≥ 2yrs from initial diagnosis to stage IV (n=25), LDH <1.5xULN (n=45), and absence of bone metastases (n=66). We developed a Metastatic Uveal Melanoma Prognostic risk Score (MUMPS). Patients were divided into 3 MUMPS risk groups based on the number of the above-mentioned prognostic variables: Poor risk (0-1), Intermediate risk (2) and Good risk (3). Good risk patients experienced longer cPFS (6.0 months) and OS (34.5 months) than patients with intermediate (2.3 months cPFS, 9.4 months OS) and poor risk disease (1.8 months cPFS, 3.9 months OS); P<0.0001. Conclusion: We developed a MUMPS risk score, based on retrospective data, that is comprised of 3 readily available clinical variables (time to stage IV diagnosis, presence of bone metastases, and LDH). This MUMPS risk score has potential prognostic value. Further validation in independent datasets is warranted to determine the role of this MUMPS risk score in selecting ICI treatment management for mUM.

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Long-term Follow-up of Standard-Dose Pembrolizumab Plus Reduced-Dose Ipilimumab in Patients with Advanced Melanoma: KEYNOTE-029 Part 1B

Cited by 31 publications

References 9 publications

Real World Outcomes of Ipilimumab and Nivolumab in Patients with Metastatic Melanoma

Real World Outcomes of Ipilimumab and Nivolumab in Patients with Metastatic Melanoma

Development of a Metastatic Uveal Melanoma Prognostic Score (MUMPS) for Use in Patients Receiving Immune Checkpoint Inhibitors

Development of a Metastatic Uveal Melanoma Prognostic risk Score (MUMPS) for use in patients receiving immune checkpoint inhibitors

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