Patterns of failure after immunotherapy with checkpoint inhibitors predict durable progression-free survival after local therapy for metastatic melanoma

Klemen, Nicholas D.; Wang, Melinda; Feingold, Paul L.; Cooper, Kenneth W.; Pavri, Sabrina; Han, Dale; Detterbeck, Frank C.; Boffa, Daniel J.; Khan, Sajid; Olino, Kelly; Clune, James; Ariyan, Stephan; Salem, Ronald R.; Weiss, Sarah A.; Kluger, Harriet M.; Sznol, Mario; Cha, Charles

doi:10.1186/s40425-019-0672-3

Cited by 69 publications

(53 citation statements)

References 29 publications

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“…We recently reported on our experience with 52 patients who were treated with local therapy for oligoprogression after CPI, 15 of whom had sun-shielded primary melanomas (and are included in the present study). 34 Some of these highly selected patients have been disease-free for years after apparently curative resections of immunorefractory metastases. Retrospective data cannot prove local therapy improved the survival of those patients, and patients with indolent biology have more opportunities to be treated with local therapy.…”

Section: Open Accessmentioning

confidence: 99%

Survival after checkpoint inhibitors for metastatic acral, mucosal and uveal melanoma

Klemen

Wang

Rubinstein

et al. 2020

J Immunother Cancer

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BackgroundCheckpoint inhibitors (CPIs) are thought to be effective against cutaneous melanoma in part because of the large burden of somatic mutations (neoantigens) generated from exposure to ultraviolet radiation. However, rare melanoma subtypes arising from acral skin, mucosal surfaces, and the uveal tract are largely sun-shielded. Genomic studies show these sun-shielded melanomas have a paucity of neoantigens and unique biology; they are thought to be largely resistant to immunotherapy. It has not been definitively shown that CPI improves survival in metastatic sun-shielded melanoma.MethodsWe reviewed a single institutional experience using antibodies against CTLA-4, PD-1 and/or PD-L1 to treat patients with metastatic melanoma. Primary tumor histology was categorized as cutaneous, unknown, acral, mucosal, or uveal. We studied demographic data, treatment characteristics, and overall survival (OS) after CPI.ResultsWe treated 428 patients with metastatic melanoma from 2007 to 2019. Primary tumors were cutaneous in 283 (66%), unknown in 55 (13%), acral in 22 (5%), mucosal in 38 (9%), and uveal in 30 (7%). Patients with metastatic disease from cutaneous primary tumors had median OS after CPI of 45 months compared with 17 months for acral (p=0.047), 18 months for mucosal (p=0.003), and 12 months for uveal (p<0.001). For all patients with sun-shielded melanoma (n=90), first treatment with anti-PD-1 or anti-PD-L1 was followed by a median OS of 9 months compared with 18 months after anti-CTLA-4 (p=0.010) and 20 months after combination therapy (p=0.003). There were 21 patients who achieved actual 3-year survival; 20 received both anti-CTLA-4 and anti-PD-1, either sequentially or in combination. Over 80% of 3-year survivors with progressive disease were treated with local therapy after CPI.ConclusionsLong survival in patients with metastatic melanoma from acral, mucosal, and uveal primary tumors was associated with receipt of both anti-CTLA-4 and anti-PD-1 antibodies. Complete responses were rare, and local therapy was frequently employed to control disease progression. While sun-shielded melanomas exhibit worse outcomes after CPI than cutaneous melanomas, with an aggressive multidisciplinary approach, 5-year survival is still possible for 25%–32% of these patients.

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Section: Open Accessmentioning

confidence: 99%

Survival after checkpoint inhibitors for metastatic acral, mucosal and uveal melanoma

Klemen

Wang

Rubinstein

et al. 2020

J Immunother Cancer

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“…Currently, only one study has explored the management of oligometastatic progression in metastatic melanoma, and the literature is comprised of a few individual case reports on patients with a mixed response. 13,14 Therefore, we conducted a single center retrospective study on patients with metastatic melanoma treated with first-line anti-CTLA-4 and/or anti-PD-1 therapy who developed a mixed response, defined as simultaneous tumor regression and progression, in order to identify clinicopathological characteristics, define high-risk subgroups, and assess subsequent management and outcomes.…”

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confidence: 99%

Mixed Response to Immunotherapy in Patients with Metastatic Melanoma

et al. 2020

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Background. Immunotherapy has improved overall survival in metastatic melanoma. Response to therapy can be difficult to evaluate as the traditionally used RECIST 1.1 criteria do not capture heterogeneous responses. Here we describe the clinical characterization of melanoma patients with a clinically defined mixed response to immunotherapy. Methods. This was a single institution, retrospective analysis of stage IV melanoma patients who received firstline anti-CTLA-4, anti-PD1, or combination anti-CTLA-4/ anti-PD1. Therapy response was assessed via clinical definitions, which consisted of cross-sectional imaging combined with clinical exam. Course of disease, clinicopathological characteristics, and management in patients with a mixed clinical response were analyzed. Results. In 292 patients (anti-CTLA4 = 63; anti-PD1 = 148, anti-CTLA4/anti-PD1 = 81), 103 were responders (35%), 64 mixed responders (22%), and 125 patients had progressive disease (43%). Of patients with a mixed response, 56% eventually had response to therapy (mixed response followed by response, MR-R), while 31% progressed on therapy (MR-NR). MR-NR patients had higher median LDH (p \ 0.01), 3 or more organ sites with metastases (p \ 0.01), and more frequently had M1d disease (p \ 0.01). Mixed responders who underwent surgery (n = 20) had a significantly longer mean OS compared to patients who did not undergo surgery (6.9 years, 95% CI 6.2-7.6 vs. 6.0 years, 95% CI 4.6-7.3, p = 0.02). Discussion. Mixed response to immunotherapy in metastatic melanoma was not uncommon in our cohort (22%). Clinical characteristics associated with progression of disease after initial mixed response included higher LDH, brain metastases, and C 3 organ sites with metastases. Surgical treatment for highly selected patients with a mixed response was associated with improved outcomes.

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“…Therefore, we could not distinguish oligoprogression from multiple progressive lesions. Klemen et al studied patients resected to NED or non-progressive residual disease (NPRD) after progression following immunotherapy and showed a substantial 5-year disease-specific survival of 60% and no significant differences between survival in NED and NPRD patients [29]. They stratified patients for patterns of failure and patients with progression in established tumors had a significant better PFS than patients with new metastases (3-year PFS of 70% versus 6%, p = 0.001).…”

Section: Discussionmentioning

confidence: 99%

Surgery for Unresectable Stage IIIC and IV Melanoma in the Era of New Systemic Therapy

Blankenstein

Aarts

Berkmortel

et al. 2020

Cancers

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Opportunities for surgical treatment in metastatic melanoma patients have re-emerged due to the development of novel systemic therapeutics over the past decade. The aim of this study is to present data on outcomes of surgery in patients with unresectable stage IIIC and IV melanoma, who have previously been treated with immunotherapy or targeted therapy. Data was extracted from the Dutch Melanoma Treatment Registry (DMTR) on 154 patients obtaining disease control to systemic therapy and undergoing subsequent surgery. Disease control was defined as a complete response (CR), which was seen in 3.2% of patients; a partial response (PR), seen in 46.1% of patients; or stable disease (SD), seen in 44.2% of patients. At a median follow-up of 10.0 months (interquartile range 4–22) after surgery, the median overall survival (OS) had not been reached in our cohort and median progression-free survival (PFS) was 9.0 months (95% CI 6.3–11.7). A CR or PR at first follow-up after surgery was associated with both a better OS and PFS compared to stable or progressive disease (p < 0.001). We conclude that selected patients can benefit from surgery after achieving disease control with systemic therapy.

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Patterns of failure after immunotherapy with checkpoint inhibitors predict durable progression-free survival after local therapy for metastatic melanoma

Cited by 69 publications

References 29 publications

Survival after checkpoint inhibitors for metastatic acral, mucosal and uveal melanoma

Survival after checkpoint inhibitors for metastatic acral, mucosal and uveal melanoma

Mixed Response to Immunotherapy in Patients with Metastatic Melanoma

Surgery for Unresectable Stage IIIC and IV Melanoma in the Era of New Systemic Therapy

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