High serum LDH and liver metastases are the dominant predictors of primary cancer resistance to anti-PD(L)1 immunotherapy

Dercle, Laurent; Roblin, Elvire; Bigorgne, Amélie; Champiat, Stéphane; Taihi, Lokmane; Plaian, Athèna; Hans, Sophie; Lakiss, Sara; Tsélikas, Lambros; Rouanne, Mathieu; Deutsch, Éric; Schwartz, Lawrence H.; Gönen, Mithat; Flynn, Jessica; Massard, Christophe; Soria, Jean‐Charles; Robert, Caroline; Marabelle, Aurélien

doi:10.1016/j.ejca.2022.08.034

Cited by 20 publications

(10 citation statements)

References 44 publications

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“…Our analysis suggests comparable median OS in patients treated with anti-PD(L)1 and longer in patients receiving doublet anti-CTLA4/PD-1 (11.7 and 16.0 months respectively), although inferior with anti-CTLA4 therapy (8.0 months). Additionally, the meta-analysis by Khoja et al reported a 12-month OS rate of 43% (95% CI [40][41][42][43][44][45][46][47] which is greater than our results for anti-CTLA4 therapy (35%), comparable to anti-PD(L)1 (49%), but inferior to combined anti-CTLA4/ anti-PD1 (60%).…”

Section: Discussioncontrasting

confidence: 87%

“…Although liver metastases are themselves a dominant predictor for ICI failure in cancer therapy [45], hepatic disease in mUM is particularly resistant to immunotherapy. In a genomic and transcriptomic study of liver metastases from cutaneous and uveal melanoma by Hoefsmit et al , significantly lower tumour mutational burden (TMB) and PD-L1 expression was observed in mUM samples [46].…”

Section: Discussionmentioning

confidence: 99%

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Efficacy of immune checkpoint inhibition in metastatic uveal melanoma: a systematic review and meta-analysis

Pham,

On,

Ardolino

et al. 2023

Melanoma Research

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Metastatic uveal melanoma (mUM) has historically been associated with short survival and limited effective treatments. Immune checkpoint inhibitors (ICIs) have been trialed in mUM; however, robust conclusions regarding their efficacy are difficult to draw given small study sizes and heterogeneous patient populations. Five databases were searched using a combination of ‘ICI’ and ‘mUM’ headings, and data on patient demographics, objective response rate (ORR), overall survival (OS) and progression-free survival (PFS) were extracted. Pooled ORR was calculated using a random effects model and the inverse variance method. Available Kaplan–Meier OS and PFS curves were used to construct summary OS and PFS plots, from which median values were derived. Pooled ORR was 9.2% overall (95% CI 7.2–11.8) [4.1% for anti-CTLA4 (95% CI 2.1–7.7), 7.1% for anti-PD(L)1 (95% CI 4.5–10.9) and 13.5% for anti-CTLA4 plus anti-PD1 (95% CI 10.0–18.0)]. Median OS was 11.5 months overall (95% CI 9.5–13.8) [8.0 months for anti-CTLA4 (95% CI 5.5–9.9), 11.7 months for anti-PD(L)1 (95% CI 9.0–14.0) and 16.0 months for ipilimumab plus anti-PD1 (95% CI 11.5–17.7) (P <0.001)]. Median PFS was 3.0 months overall (95% CI 2.9–3.1). ICIs have limited efficacy in mUM and a recommendation for their use must consider the balance of benefit and risk for individual patients if no other options are available. Further biomarker profiling studies may be helpful in assessing which patients will benefit from ICIs, in particular the addition of ipilimumab to anti-PD1 therapy.

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Section: Discussioncontrasting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Efficacy of immune checkpoint inhibition in metastatic uveal melanoma: a systematic review and meta-analysis

Pham,

On,

Ardolino

et al. 2023

Melanoma Research

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“… 11 This is an interesting point indicating that MMRd/MSI tumors might have a singular biology compared to other tumors, including microsatellite stability CRC tumors where liver metastases have been associated to immunotherapy resistance. 24 , 25 We also found no difference in ICI sensitivity based on whether MMR deficiency was sporadic or hereditary. However, due to the retrospective nature of the study, not all patients had available information on germline mutations.…”

Section: Discussionmentioning

confidence: 50%

Efficacy of immunotherapy in mismatch repair-deficient advanced colorectal cancer in routine clinical practice. An AGEO study

et al. 2023

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“…61 Randomized trials comparing neoadjuvant regimens and testing the utility of these and other biomarkers would identify the optimal approach. Factors associated with response to immunotherapy in the advanced setting, including serum lactate dehydrogenase, 59,[62][63][64] should also be explored.…”

Section: Next Steps and Future Directions Including Patient Selection...mentioning

confidence: 99%

Neoadjuvant Checkpoint Immunotherapy and Melanoma: The Time Is Now

Long

Menzies

Scolyer

2023

JCO

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The role of neoadjuvant therapy is undergoing an historic shift in oncology. The emergence of potent immunostimulatory anticancer agents has transformed neoadjuvant therapy from a useful tool in minimizing surgical morbidity to a life-saving treatment with curative promise, led by research in the field of melanoma. Health practitioners have witnessed remarkable improvements in melanoma survival outcomes over the past decade, beginning with checkpoint immunotherapies and BRAF-targeted therapies in the advanced setting that were successfully adopted into the postsurgical adjuvant setting for high-risk resectable disease. Despite substantial reductions in postsurgical recurrence, high-risk resectable melanoma has remained a life-altering and potentially fatal disease. In recent years, data from preclinical models and early-phase clinical trials have pointed to the potential for greater clinical efficacy when checkpoint inhibitors are administered in the neoadjuvant rather than adjuvant setting. Early feasibility studies showed impressive pathologic response rates to neoadjuvant immunotherapy, which were associated with recurrence-free survival rates of over 90%. Recently, the randomized phase II SWOG S1801 trial (ClinicalTrials.gov identifier: NCT03698019 ) reported a 42% reduction in 2-year event-free survival risk with neoadjuvant versus adjuvant pembrolizumab in resectable stage IIIB-D/IV melanoma (72% v 49%; hazard ratio, 0.58; P = .004), establishing neoadjuvant single-agent immunotherapy as a new standard of care. A randomized phase III trial of neoadjuvant immunotherapy in resectable stage IIIB-D melanoma, NADINA (ClinicalTrials.gov identifier: NCT04949113 ), is ongoing, as are feasibility studies in high-risk stage II disease. With a swathe of clinical, quality-of-life, and economic benefits, neoadjuvant immunotherapy has the potential to redefine the contemporary management of resectable tumors.

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High serum LDH and liver metastases are the dominant predictors of primary cancer resistance to anti-PD(L)1 immunotherapy

Cited by 20 publications

References 44 publications

Efficacy of immune checkpoint inhibition in metastatic uveal melanoma: a systematic review and meta-analysis

Efficacy of immune checkpoint inhibition in metastatic uveal melanoma: a systematic review and meta-analysis

Efficacy of immunotherapy in mismatch repair-deficient advanced colorectal cancer in routine clinical practice. An AGEO study

Neoadjuvant Checkpoint Immunotherapy and Melanoma: The Time Is Now

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