Switching to Immune Checkpoint Inhibitors upon Response to Targeted Therapy; The Road to Long-Term Survival in Advanced Melanoma Patients with Highly Elevated Serum LDH?

Schouwenburg, Maartje G.; Suijkerbuijk, Karijn P M; Koornstra, Rutger H.T.; Jochems, Anouk; Zeijl, Michiel C T van; Eertwegh, Alfons J.M. van den; Haanen, John B.A.G.; Aarts, Maureen J.B.; Akkooi, A.C.J. van; Berkmortel, Franchette W P J van den; Groot, Jan Willem B. de; Hospers, Geke A.P.; Kapiteijn, Ellen; Kruit, Wim; Piersma, Djura; Rijn, Rozemarijn S. van; Tije, Albert J. ten; Vreugdenhil, Gerard; Hoeven, J.J.M. van der; Wouters, Michel W. J. M.

doi:10.3390/cancers11121940

Cited by 33 publications

(24 citation statements)

References 24 publications

(32 reference statements)

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“…The decision tree (CIST) model also showed that ineligible patients with an LDH level of >500 U/L were a prognostic subgroup with poor survival. We previously showed the dismal prognosis in this group of patients and proposed switching to ICI upon response to BRAF(/MEK‐)‐inhibition with LDH normalization as a potential strategy to obtain long‐term survival in these patients 15 . This information supports well‐informed use of systemic therapy in this patient group.…”

Section: Discussionsupporting

confidence: 61%

Real‐world outcomes of advanced melanoma patients not represented in phase III trials

Zeijl

Ismail

Wreede

et al. 2020

Intl Journal of Cancer

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The aim was to provide evidence on systemically treated patients with advanced melanoma not represented in phase III trials to support clinical decision-making. Analysis were performed on advanced melanoma patients diagnosed between 2014 and 2017 in the Netherlands, treated with immune-or targeted therapy, who met ≥1 trial exclusion criteria. These criteria were derived from the KEYNOTE-006 and CHECKMATE-067/-066 phase III trials. Prognostic importance of factors associated with overall survival (OS) was assessed with the Kaplan-Meier method, Cox models, predicted OS probabilities of prognostic subgroups and a conditional inference survival tree (CIST). A nationwide population-based registry was used as data source. Of 2536 systemically treated patients with advanced melanoma, 1004 (40%) patients were ineligible for phase IIII trials. Ineligible patients had a poorer median OS (mOS) compared to eligible patients (8.8 vs 23 months). Eligibility criteria strongly associated with OS in systemically treated ineligible patients were Eastern Cooperative Oncology Group Performance Score (ECOG PS) ≥2, brain metastases (BM) and lactate dehydrogenase (LDH) of >500 U/L. Patients with ECOG PS of ≥2 with or without symptomatic BM had a predicted mOS of 6.5 and 11.3 months and a 3-year survival probability of 9.3% and 23.6%, respectively. The CIST showed the strongest prognostic covariate for survival was LDH, followed by ECOG PS. The prognosis of patients with LDH of >500 U/L is poor, but long-term survival is possible. The prognosis of ineligible patients with advanced melanoma in real-world was very heterogeneous and highly dependent on LDH value, ECOG PS and symptomatic BM.

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Section: Discussionsupporting

confidence: 61%

Real‐world outcomes of advanced melanoma patients not represented in phase III trials

Zeijl

Ismail

Wreede

et al. 2020

Intl Journal of Cancer

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“…Interestingly, also response rates to anti-PD1 are lower in patients with stage IV M1c melanoma compared with lower stages, 30 in patients with higher tumour load 29 and LDH ≥2 × ULN. 31 As we and others have recently shown a correlation between ICI response and toxicity, 32 33 one may hypothesise that immunological responses in these patients are less strong, which might be due to the increased immunosuppressive tumour microenvironment in large volume disease. 34 It is unlikely that the observed association between stage and severe irAEs is explained by immortal time bias, as we adjusted for follow-up time.…”

Section: Discussionmentioning

confidence: 87%

Lower risk of severe checkpoint inhibitor toxicity in more advanced disease

et al. 2020

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BackgroundImmune checkpoint inhibitor (ICI) can cause severe and sometimes fatal immune-related adverse events (irAEs). Since these irAEs mimick immunological disease, a female predominance has been speculated on. Nevertheless, no demographic or tumour-related factors associated with an increased risk of irAEs have been identified until now.MethodsRisk ratios of severe (grade ≥3) irAEs for age, sex, WHO performance status, number of comorbidities, stage of disease, number of metastases and serum lactate dehydrogenases (LDH) were estimated using data from anti-PD1-treated patients with advanced melanoma in the prospective nationwide Dutch Melanoma Treatment Registry.Results111 (11%) out of 819 anti-programmed cell death 1 treated patients experienced severe irAEs. Patients with non-lung visceral metastases (stage IV M1c or higher) less often experienced severe irAEs (11%) compared with patients with only lung and/or lymph node/soft tissue involvement (stage IV M1b or lower; 19%; adjusted risk ratio (RRadj) 0.63; 95% CI 0.41 to 0.94). Patients with LDH of more than two times upper limit of normal had a non-significantly lower risk of developing severe irAEs than those with normal LDH (RRadj 0.65; 95% CI 0.20 to 2.13). None of the other variables were associated with severe irAEs.ConclusionIn patients with melanoma, more advanced disease is associated with a lower rate of severe irAEs. No association with sex was found.

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“…These results from registries can then be confirmed by randomized controlled trials. An example of supporting evidence from DMTR data on advanced melanoma patients treated with first-line targeted therapy with high LDH showed subsequent immunotherapy could lead to long-term survival if normalization of LDH was reached [ 22 ]. This information is easily obtained with the use of a registry including real-world practices.…”

Section: Discussionmentioning

confidence: 99%

Postapproval trials versus patient registries: comparability of advanced melanoma patients with brain metastases

Ismail

Sikkes²,

Wouters

et al. 2020

Melanoma Research

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Postapproval trials and patient registries have their pros and cons in the generation of postapproval data. No direct comparison between clinical outcomes of these data sources currently exists for advanced melanoma patients. We aimed to investigate whether a patient registry can complement or even replace postapproval trials. Postapproval single-arm clinical trial data from the Medicines Evaluation Board and real-world data from the Dutch Melanoma Treatment Registry were used. The study population consisted of advanced melanoma patients with brain metastases treated with targeted therapies (BRAF- or BRAF-MEK inhibitors) in the first line. A Cox hazard regression model and a propensity score matching (PSM) model were used to compare the two patient populations. Compared to patients treated in postapproval trials ( n = 467), real-world patients ( n = 602) had significantly higher age, higher ECOG performance status, more often ≥3 organ involvement and more symptomatic brain metastases. Lactate dehydrogenase levels were similar between both groups. The unadjusted median overall survival (mOS) in postapproval clinical trial patients was 8.7 (95% CI, 8.1–10.4) months compared to 7.2 (95% CI, 6.5–7.7) months ( P < 0.01) in real-world patients. With the Cox hazard regression model, survival was adjusted for prognostic factors, which led to a statistically insignificant difference in mOS for trial and real-world patients of 8.7 (95% CI, 7.9–10.4) months compared to 7.3 (95% CI, 6.3–7.9) months, respectively. The PSM model resulted in 310 matched patients with similar survival ( P = 0.9). Clinical outcomes of both data sources were similar. Registries could be a complementary data source to postapproval clinical trials to establish information on clinical outcomes in specific subpopulations.

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Switching to Immune Checkpoint Inhibitors upon Response to Targeted Therapy; The Road to Long-Term Survival in Advanced Melanoma Patients with Highly Elevated Serum LDH?

Cited by 33 publications

References 24 publications

Real‐world outcomes of advanced melanoma patients not represented in phase III trials

Real‐world outcomes of advanced melanoma patients not represented in phase III trials

Lower risk of severe checkpoint inhibitor toxicity in more advanced disease

Postapproval trials versus patient registries: comparability of advanced melanoma patients with brain metastases

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