ADOReg is the largest prospective clinical registry in Germany in the field of dermatological oncology with great added value for all stakeholders in the healthcare system

Moritz R. K. C., Gutzmer R., Zimmer L. et al. (2021) SARS-CoV-2 infections in melanoma patients treated with PD-1 inhibitors: A survey of the German ADOREG melanoma registry. European Journal of Cancer. 2021 Feb; 144:382-385. doi:10.1016/j.ejca.2020.11.015

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699158/

Background:
Skin cancers are known for their strong immunogenicity, which may contribute to a high treatment efficacy of immune checkpoint inhibition (ICI). However, a considerable proportion of patients with skin cancer is immuno-compromised by concomitant diseases. Due to their previous exclusion from clinical trials, the ICI treatment efficacy is poorly investigated in these patients. The present study analyzed the ICI treatment outcome in advanced patients with skin cancer with a concomitant hematological malignancy.

Methods:
This retrospective multicenter study included patients who were treated with ICI for locally advanced or metastatic melanoma (MM), cutaneous squamous cell carcinoma (cSCC), or Merkel cell carcinoma (MCC), and had a previous diagnosis of a hematological malignancy irrespective of disease activity or need of therapy at ICI treatment start. Comparator patient cohorts without concomitant hematological malignancy were extracted from the prospective multicenter skin cancer registry ADOREG. Treatment outcome was measured as best overall response, progression-free (PFS), and overall survival (OS).

Results:
84 patients (MM, n=52; cSCC, n=15; MCC, n=17) with concomitant hematological malignancy were identified at 20 skin cancer centers. The most frequent concomitant hematological malignancies were non-Hodgkin’s lymphoma (n=70), with chronic lymphocytic leukemia (n=32) being the largest entity. While 9 patients received ICI in an adjuvant setting, 75 patients were treated for advanced non-resectable disease (55 anti-PD- 1; 8 anti-PD-L1; 5 anti-CTLA-4; 7 combinations). In the latter 75 patients, best objective response (complete response+partial response) was 28.0%, disease stabilization was 25.3%, and 38.6% showed progressive disease (PD). Subdivided by skin cancer entity, best objective response was 31.1% (MM), 26.7% (cSCC), and 18.8% (MCC). Median PFS was 8.4 months (MM), 4.0 months (cSCC), and 5.7 months (MCC). 1-year OS rates were 78.4% (MM), 65.8% (cSCC), and 47.4% (MCC). Comparison with respective ADOREG patient cohorts without hematological malignancy (n=392) revealed no relevant differences in ICI therapy outcome for MM and MCC, but a significantly reduced PFS for cSCC (p=0.002).

Conclusions:
ICI therapy showed efficacy in advanced patients with skin cancer with a concomitant hematological malignancy. Compared with patients without hematological malignancy, the observed ICI therapy outcome was impaired in cSCC, but not in MM or MCC patients.

Leiter U., Loquai C., Reinhardt L. et al. (2020) Immune checkpoint inhibition therapy for advanced skin cancer in patients with concomitant hematological malignancy: a retrospective multicenter DeCOG study of 84 patients. Journal for ImmunoTherapy of Cancer 2020;8:e000897. doi:10.1136/jitc-2020-000897

https://jitc.bmj.com/content/8/2/e000897

Background:
GNAQ and GNA11 mutant non‐uveal melanoma represent a poorly characterized, rare subgroup of melanoma with a gene mutation profile similar to uveal melanoma.

Objectives:
To characterize these tumours in terms of clinical behaviour and genetic characteristics.

Methods:
Patients with non‐uveal GNAQ/11 mutated melanoma were identified from the prospective multicentre tumour tissue registry ADOREG, Tissue Registry in Melanoma (TRIM) and additional cooperating skin cancer centres. Extensive data on patient, tumour and treatment characteristics were collected retrospectively. Targeted sequencing was used to determine tumour mutational burden. Immunohistochemistry staining was done for PD‐L1 and BAP1. Existing whole‐exome cutaneous and uveal melanoma data was analysed for mutation type and burden.

Results:
We identified 18 patients with metastatic GNAQ/11 mutant non‐uveal melanoma. Tumours had a lower tumour mutational burden and less UV‐signature mutations than cutaneous melanomas. In addition to GNAQ and GNA11 mutations (9 each), 6 SF3B1, 3 EIF1AX and 4 BAP1 mutations were detected. In contrast to uveal melanoma, GNAQ/11 mutant non‐uveal melanomas frequently metastasized lymphatically and concurrent EIF1AX, SF3B1 and BAP1 mutations were not apparently associated with patient prognosis. Objective response to immunotherapy was poor with only one partial response observed in ten treated patients (10%).

Conclusions:
Our findings suggest that GNAQ/11 mutant non‐uveal melanomas are a melanoma subtype distinct both clinically and genetically from cutaneous and uveal melanoma. As they respond poorly to available treatment regimens, novel effective therapeutic approaches for affected patients are urgently needed.

Livingstone E., Zaremba A., Horn S. et al. (2020) GNAQ and GNA11 Mutant Non‐Uveal Melanoma, a Subtype Distinct From Both Cutaneous and Uveal Melanoma. British Journal of Dermatology. DOI:10.1111/bjd.18947

https://onlinelibrary.wiley.com/doi/abs/10.1111/bjd.18947

Background:
Programmed cell death protein 1 (PD-1) checkpoint inhibition has recently advanced to one of the most effective treatment strategies in melanoma. Nevertheless, a considerable proportion of patients show upfront therapy resistance and baseline predictive biomarkers of treatment outcome are scarce. In this study we quantified PD-1 and programmed death-ligand 1 (PD-L1) in baseline sera from melanoma patients in relation to therapy response and survival.

Patients and methods:
Sera taken at therapy baseline from a total of 222 metastatic melanoma patients (two retrospectively selected monocentric discovery cohorts, n ¼ 130; one prospectively collected multicentric validation cohort, n ¼ 92) and from 38 healthy controls were analyzed for PD-1 and PD-L1 concentration by sandwich enzyme-linked immunosorbent assay.

Results:
Melanoma patients showed higher serum concentrations of PD-1 (P ¼ 0.0054) and PD-L1 (P < 0.0001) than healthy controls. Elevated serum PD-1 and PD-L1 levels at treatment baseline were associated with an impaired best overall response (BOR) to anti-PD-1 (P ¼ 0.014, P ¼ 0.041), but not to BRAF inhibition therapy. Baseline PD-1 and PD-L1 serum levels correlated with progression-free (PFS; P ¼ 0.0081, P ¼ 0.053) and overall survival (OS; P ¼ 0.055, P ¼ 0.0062) in patients who received anti-PD-1 therapy, but not in patients treated with BRAF inhibitors. By combining both markers, we obtained a strong discrimination between favorable and poor outcome of antiPD-1 therapy, with elevated baseline serum levels of PD-1 and/or PD-L1 associated with an impaired BOR (P ¼ 0.037), PFS (P ¼ 0.048), and OS (P ¼ 0.0098). This PD-1/PD-L1 combination serum biomarker was confirmed in an independent multicenter validation set of serum samples prospectively collected at baseline of PD-1 inhibition (BOR, P ¼ 0.019; PFS, P ¼ 0.038; OS, P ¼ 0.022). Multivariable Cox regression demonstrated serum PD-1/PD-L1 as an independent predictor of PFS (P ¼ 0.010) and OS (P ¼ 0.003) in patients treated with PD-1 inhibitors.

Conclusion:
Our findings indicate PD-1 and PD-L1 as useful serum biomarkers to predict the outcome of PD-1 inhibition therapy in melanoma patients and to select patients for PD-1-based versus BRAF-based therapy strategies.

Ugurel S., Schadendorf D., Horny K. et al. (2020) Elevated baseline serum PD-1 or PD-L1 predicts poor outcome of PD-1 inhibition therapy in metastatic melanoma. Annals of Oncology. 2020;31(1):144-152. DOI: 10.1016/j.annonc.2019.09.005

https://www.sciencedirect.com/science/article/pii/S0923753419354067

Background:
- Nivolumab monotherapy (NIVO) and nivolumab plus ipilimumab combination therapy (NIVO+IPI) are approved for the treatment of advanced melanoma in first and subsequent lines of therapy. In addition, NIVO is indicated for the adjuvant treatment of melanoma after complete resection. ¹
- Real-world data complement available clinical data on the effectiveness and tolerability of NIVO / NIVO+IPI in a broader patient population.

- NICO (NCT02990611) is an ongoing prospective, multicenter non-interventional study (NIS) in Germany associated to ADOReg.
- NICO collects real-world data from patients treated with NIVO and NIVO+IPI, respectively, diagnosed with advanced/metastatic melanoma as well as from patients with adjuvant NIVO therapy after complete surgical resection.²

Study Design:
Population: In total, 950 adult patients treated according to marketing authorization in Germany, will be enrolled in three cohorts:
- Cohort 1+2 (n=750): patients with advanced melanoma, who start therapy with NIVO+IPI or NIVO
- Cohort 3 (n=200): patients treated with NIVO as adjuvant therapy
- Primary objectives: overall survival (OS) in cohort 1 (NIVO+IPI); relapse-free survival (RFS) in cohort 3 (adjuvant NIVO)
- Secondary objectives include progression free survival (PFS), response rates, safety profile, and quality of life (QoL)

Results:
Cohort 1 & 2: Baseline Characteristics
238 patients in cohort 1 (60.1%) and 159 patients in cohort 2 (70.0%) received NIVO+IPI and NIVO as first line (1L) therapy. Demographic parameters of 1L patients reflect a population similar to that of the pivotal study CheckMate 067 (CM 067)³ in regard to parameters such as age, sex and ECOG performance status.

Cohort 1 & 2: Overall Survival
Overall survival of 1L patients in NICO at 12 months is 70.3% (95% CI 62.8–76.6%) with NIVO+IPI and 72.0% (95% CI 62.4–79.5%) with NIVO. Observed OS in NICO is comparable to that observed in the pivotal CM 067 trial (72.3% and 73.1%, respectively).⁴

Cohort 1 & 2: Adverse Events
More side effects were reported for NIVO+IPI combination therapy (cohort 1) than for NIVO monotherapy (cohort 2). In line with these findings, more treatment discontinuations (66 [16.7%] vs 18 [7.9%]) and more treatment interruptions (117 [29.5%] vs. 28 [12.3%]) due to TrAE of any grade occurred with NIVO+IPI than with NIVO.

In total, 3 grade 5 TrAE occurred with NIVO+IPI; 1 case was due to autoimmune hepatitis and 2 were due to general disorders. With NIVO, 2 grade 5 TrAE occurred; 1 case was due to autoimmune disorder (multi organ failure) and 1 was due to general disorders.

Summary and Conclusion:
Presented data from the current interim analysis of NICO cohort 1 and 2 show 12 months effectiveness data for advanced melanoma patients treated with NIVO+IPI or NIVO in routine care in Germany.

- With the exception of a distinctively higher prevalence of brain metastases and more patients with LDH > ULN in the NICO study, patient characteristics are generally comparable to those of the corresponding pivotal clinical trial CM 067.

- 12-month OS in NICO was comparable to OS observed in the CM 067 trial even though some patient characteristics show less favorable health conditions in NICO.

- Treatments were generally well tolerated based on safety data from 623 patients. Data confirmed the safety profiles for NIVO and NIVO+IPI as determined in clinical trials.

References:
1. Summary of product characteristics OPDIVO® (01/2020) and YERVOY®(01/2020)

2. ClinicalTrials.gov Identifier: NCT02990611; BMS study number: CA209-654
3. Larkin et al. N Engl J Med 2015; 373:23
4. Larkin et al. N Engl J Med 2019; 381:1535

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Schadendorf D., Eigentler T., Mohr P., et al. (2020) NICO: Real world evidence in advanced melanoma; a national prospective non-interventional study of nivolumab monotherapy or in combination with ipilimumab in patients with advanced melanoma and in patients with adjuvant nivolumab therapy. Poster presented at the 34th Annual German Cancer Congress 2020

Einleitung:
- Wirksamkeit und Sicherheit von Nivolumab (NIVO) als Monotherapie oder in Kombination mit Ipilimumab (NIVO + IPI) bei der Behandlung des fortgeschrittenen Melanoms wurden in mehreren zulassungsrelevanten Studien für die dort definierten Patientenkollektive gezeigt. ^1–7
- Die multizentrische, prospektive, mit dem ADOREG assoziierte, nicht-interventionelle Studie NICO (NCT02990611) erhebt Real-World-Daten bei Patienten mit fortgeschrittenem Melanom in Deutschland, bei denen eine Therapie mit NIVO + IPI oder NIVO innerhalb der zugelassenen Indikation durchgeführt wird.^8,9

Studiendesign:
Population: Insgesamt 1050 volljährige Patienten (Kohorte 1 und 2: 750 Patienten, Kohorte 3: 300 Patienten), die eine Behandlung mit NIVO + IPI oder mit NIVO entsprechend der zugelassenen Indikation beginnen, werden in drei Kohorten der Studie eingeschlossen und über fünf Jahre dokumentiert:
- Kohorte 1 (K1): Patienten mit metastasiertem, nicht-resezierbarem Melanom; Behandlung mit NIVO + IPI
- Kohorte 2 (K2): Patienten mit metastasiertem, nicht-resezierbarem Melanom; Behandlung mit NIVO
- Kohorte 3 (K3): Patienten nach kompletter Tumorresektion; adjuvante Behandlung mit NIVO (Daten dieser Kohorte hier nicht vorgestellt)
- Primäre Endpunkte: Gesamtüberleben (OS) in K1; rezidivfreies Überleben (RFS) in K3
- Sekundäre Endpunkte: u. a. OS in K2, progressionsfreies Überleben (PFS), Ansprechraten, Sicherheitsprofil und Lebensqualität (QoL)

Ergebnisse der Kohorten 1 und 2:
Patientencharakteristika

Zum Zeitpunkt der dritten Interimsanalyse (Mai 2020) waren insgesamt 767 Patienten mit metastasiertem, nicht-resezierbarem Melanom in die Studie eingeschlossen, davon 486 in K1 (NIVO + IPI) und 281 in K2 (NIVO). In K1 waren 60,3 % und in K2 63,7 % der Patienten männlich. Die Patienten in K1 waren im Vergleich zur K2 jünger (durchschnittliches Alter 61 versus 69 Jahre); ein größerer Anteil der Patienten in K1 wies bei Studieneinschluss Hirnmetastasen auf (33,5 % versus 18,5 %) und hatte einen erhöhten LDH-Wert (44,4 % versus 39,9 %)

Im Vergleich zu den zulassungsrelevanten Studien wurden in Rahmen von NICO unter anderem mehr Patienten in späteren Behandlungslinien, mehr ältere Patienten und mehr Patienten mit schlechterem ECOG-Performance Status, mit erhöhtem LDH-Wert oder mit Hirnmetastasen behandelt.

Gesamtüberleben (OS) in Kohorte 1 (NIVO + IPI)

Unter Kombinationstherapie mit NIVO + IPI (K1) in der Erstlinie (1 L) lag das Gesamtüberleben (OS) in NICO nach 24 Monaten bei 50,8 % (95 % KI 41,3 — 59,5 %). Das geschätzte mediane Gesamtüberleben (mOS) unter NIVO + IPI in der 1 L lag bei 25,9 Monaten (95 % KI 19,5 — nicht ermittelbar [n. e.]).
In späteren Behandlungslinien (≥ 2 L) unter NIVO + IPI lag das OS nach 24 Monaten in NICO bei 36,7 % (27,6 — 45,8 %). Das geschätzte mOS unter NIVO + IPI in ≥ 2 L lag bei 11,7 Monaten (95 % KI 7,5 — 16,7).

Gesamtüberleben (OS) in Kohorte 2 (NIVO)

Unter Monotherapie mit NIVO (K2) in der Erstlinie (1 L) lag das OS nach 24 Monaten in NICO bei 48,6 % (95 % KI 36,0 — 60,1 %). Das geschätzte mOS unter NIVO in der 1 L lag bei 22,0 Monaten (15,4 — n. e.).
In späteren Behandlungslinien (≥ 2 L) unter NIVO lag das OS nach 24 Monaten in NICO bei 46,0 % (31,1 — 59,8 %). Das geschätzte mOS unter NIVO in ≥ 2 L lag bei 18,3 Monaten (11,1 — n. e.).

Ansprechraten

Unter Kombinationstherapie mit NIVO + IPI (K1) lag die beste Gesamtansprechrate (BORR) in der Erstlinie (1 L) bei 54,2 % und in späteren Behandlungslinien (≥ 2 L) bei 34,7 %.
Unter Monotherapie mit NIVO (K2) lag die BORR in der 1 L bei 48,5 % und in ≥ 2 L bei 40,4 %.

Sicherheit

Unter Kombinationstherapie mit NIVO + IPI (K1) wurden mehr behandlungsbedingte unerwünschte Ereignisse (treatment-related adverse events, TrAEs) Grad 3 und 4 beobachtet als unter Monotherapie mit NIVO (K2). Die insgesamt häufigsten TrAEs Grad 3 und 4 waren Kolitis (7,2 %) und Autoimmunerkrankungen (5,6 %).

In K1 kam es bei 5,1 % der Patienten zu Behandlungsabbrüchen und bei 15,4 % zu Behandlungsunterbrechungen aufgrund TrAEs. In K2 kam es bei 1,4 % zu Behandlungsabbrüchen und bei 7,5 % zu Behandlungsunterbrechungen aufgrund TrAEs.

In K1 wurden insgesamt fünf TrAEs Grad 5 beobachtet (je ein Fall von Autoimmunerkrankung, Störung des Blut- oder Lymphsystems, Kolitis, Neoplasie und Tod sonstiger Ursache). In K2 wurden insgesamt drei TrAEs Grad 5 beobachtet (je ein Fall von Autoimmunerkrankung, Kolitis und Pneumonie).

Zusammenfassung:
- Die Ergebnisse der dritten Interimsanalyse der nicht-interventionellen Studie NICO umfassen aktuelle Real-World-Daten zur Anwendung von Nivolumab in Kombination mit Ipilimumab oder als Nivolumab Monotherapie bei Patienten mit metastasiertem, nicht-resezierbaren Melanom in Deutschland.
- Die Daten zeigen, dass im klinischen Alltag auch ältere Patienten sowie Patienten mit ECOG-Performance Status ≥ 2, mit erhöhtem LDH-Wert und mit Hirnmetastasen behandelt werden.
- Zwischen den Kohorten K1 (NIVO + IPI) und K2 (NIVO) sind Unterschiede in Bezug auf Patientencharakteristika und prognostische Faktoren zu beobachten.
- Das Gesamtüberleben (OS) nach 24 Monaten deutet auf eine gute Wirksamkeit von NIVO + IPI und NIVO auch bei Patienten mit schlechterem Risikoprofil hin, sowohl in der Erstlinie als auch in späteren Behandlungslinien.
- Im Vergleich z. B. zur CheckMate 067-Studie^1,2 wurden in NICO auch Patienten mit ungünstigen prognostischen Faktoren (wie ungünstiger ECOG, erhöhte LDH, oder Hirnmetastasen) eingeschlossen, durch die sich ggf. Unterschiede im klinischen Outcome erklären.
- Die Daten bestätigen die in klinischen Studien gezeigten Sicherheitsprofile von NIVO + IPI und NIVO. Das in der klinischen Routine berichtete Sicherheitsprofil stimmt mit dem in anderen Studien beobachteten Sicherheitsprofil dieser Medikamente überein.

Referenzen:

1. Larkin et al. N Engl J Med 2015;373:23-34
2. Larkin et al. N Engl J Med 2019; 381:1535-46
3. Robert et al. N Engl J Med 2015;372:320-30.
4. Ascierto et al. JAMA Oncol 2018; 5:187
5. Weber et al. Lancet Oncol 2015; 16:375
6. Hodi et al. N Engl J Med 2015; 372:2006-17
7. Hodi et al. Lancet Oncol 2016; 17:1558-68
8. ClinicalTrials.gov Identifier: NCT02990611; BMS study number: CA209-654
9. Aktuelle Fachinformationen OPDIVO® (Nivolumab) und YERVOY® (Ipilimumab)

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Ugurel S., Satzger I., Eigentler T. et al. (2020) Real-World-Daten zur Anwendung von Nivolumab als Monotherapie oder in Kombination mit Ipilimumab in der Behandlung des fortgeschrittenen Melanoms: Zwischenergebnisse der nicht-interventionellen Studie NICO. Poster präsentiert auf dem 30. Deutschen Hautkrebskongress 2020

Background:
Melanoma brain metastases (MBMs) are common among patients with advanced/metastatic disease
- 28.2% of patients have been estimated to have MBMs at diagnosis, and 44% were found to develop MBMs during the course of treatment^1,2
- The prognosis of patients with MBMs has historically been poor, with median overall survival (OS) estimated at 4.7 months in one study and MBMs frequently reported to contribute to death²
- These patients are often excluded from prospective clinical trials because of their poor prognosis
- Comparatively little is known about the effectiveness and tolerability of standard treatment options for metastatic melanoma, such as nivolumab (NIVO) alone or in combination with ipilimumab (NIVO+IPI), in this vulnerable patient population
- NIVO+IPI treatment was associated with an intracranial objective response rate (ORR) of 54% and a median OS that had not been reached (at a follow up of 20.6 months) in one study (CheckMate 204) 3 and a median OS of 32.8 months in another study (ABC trial)⁴
- Treatment with NIVO monotherapy was associated with an intracranial ORR of 20% and a median OS of 26.1 months in the ABC trial⁴
- Real world evidence concerning the use of these agents in the first and later line settings is limited
- The current study evaluated real world treatment patterns, effectiveness, and safety in patients with MBMs treated with NIVO+IPI or NIVO monotherapy

Results:
Patients and treatment patterns:
- A total of 767 patients with advanced melanoma were enrolled, of whom 215 (28%) had MBMs
- Most patients with MBMs were male (64%); 10% had an ECOG performance status (PS) ≥ 2
- Among patients with MBMs, a higher proportion of those treated with NIVO+IPI versus NIVO had received prior
radiotherapy (29% vs 19%) and/or surgery (18% vs 6%)
- Among all patients in the study, approximately 2/3 received NIVO+IPI and 1/3 received NIVO
- In patients with MBMs, approximately 3/4 received NIVO+IPI and 1/4 received NIVO
- A higher proportion of patients aged ≤ 65 years were treated with NIVO+IPI (60%) than with NIVO (34%)
- In contrast, higher proportions of patients aged > 65 or > 75 years received NIVO than NIVO+IPI (65% vs 37% and 37% vs 15%, respectively)

Efficacy:
- In patients with MBMs, ORRs were higher with NIVO+IPI (26%) than with NIVO (15%)
- ORRs were approximately 10 percentage points higher with the combination than with monotherapy,
irrespective of the setting (1L: 30% vs 19%, 2L+: 20% vs 8%)
- Notably, the combination was administered more frequently as 2L+ treatment than was NIVO alone in patients with MBMs
- In the overall population, ORRs with NIVO+IPI versus NIVO were 54% versus 48% in the 1L setting and 35% versus 40% in the 2L+ settings, respectively
- Disease control rates (DCRs) were similar in both treatment groups, reflecting a higher percentage of patients with objective response in the NIVO+IPI group and stable disease (SD) in the NIVO group
- The presence of MBMs was associated with a poor prognosis with both NIVO+IPI and NIVO, which became even worse in patients with MBMs who received 2L+ versus 1L therapy (e.g. median OS with NIVO+IPI: 9.9 vs 23.5 months)
- The number of MBMs appeared to have comparatively little effect on OS in patients treated with NIVO+IPI or NIVO (although numbers of patients were small)
- Among patients with MBMs, those with a BOR of CR or PR derived a high level of OS benefit with both treatments, in contrast to patients with a BOR of SD or PD
- Preliminary results indicated that treatment with NIVO+IPI or NIVO was effective in patients with BRAF mutant and wild type tumors (data not shown), consistent with results reported in clinical trials

Safety:
- Grade 3−4 treatment related adverse events (TRAEs) were reported in 41% of all patients and 27% of patients with MBMs treated with 1L NIVO+IPI
- Grade 3−4 TRAEs were reported in 19% of all patients and 26% of those with MBMs treated with 1L NIVO
- A total of 8 patients died due to TRAEs: 5 in the NIVO+IPI group and 3 in the NIVO group

Conclusion:
- In this real world study, both NIVO+IPI and NIVO provided effective and generally tolerable treatment options for patients with advanced melanoma
- NIVO+IPI was preferred to NIVO as the treatment of choice, particularly among younger patients and those with MBMs
- ORR was approximately 10 percentage points higher in patients with MBMs treated with NIVO+IPI than with NIVO
- Real world patients with MBMs showed OS benefit with NIVO+IPI or NIVO in the 1L as well as in the 2L+ setting
- OS results with 1L NIVO+IPI were comparable to those of the ABC trial, but did not reach the high OS levels observed with the more highly selected patient population in CheckMate 204 (1 year OS: NICO, 59%; ABC, 63%; CheckMate 204, 82%)^3,4
- OS benefit was pronounced in patients with MBMs who achieved a CR or PR, suggesting that achieving a deep response is a particularly important goal
- TRAE incidences in this real word study were largely consistent with prior clinical trials³
- Further analyses are needed to compare the safety profile of patients with MBMs with that of the total population
- Limitations of these results include their descriptive nature, imbalances between the treatment groups, and the immaturity of the current data

References:

1. 1. Cagney DN, et al. Neuro Oncol 2017;19:1511−1521.
2. Davies MA, et al. Cancer 2011;117:1687−1696.
3. Tawbi H, et al. Oral presentation at ASCO 2019; May 31−June 4, 2019; Chicago, IL. Presentation 9501.
4. Long GV, et al. Poster presentation at ESMO 2019; September 27−October 1, 2019; Barcelona, Spain. Presentation 1311O.

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Gutzmer R., Eigentler T., Mohr P. et al. (2020) Nivolumab monotherapy or combination therapy with ipilimumab in advanced melanoma patients with brain metastases: real world evidence from the German non interventional study NICO. Poster presented at the ESMO Virtual Congress 2020

Background:
Patient-reported outcomes regarding health-related quality of life (HRQoL) were assessed as secondary or exploratory outcomes in phase II/III clinical trials with nivolumab plus ipilimumab (NIVO+IPI) combination therapy and nivolumab (NIVO) monotherapy in advanced melanoma; NIVO and NIVO+IPI maintained HRQoL in these trials.^1-4

NICO (NCT02990611)⁵ is a prospective, multicenter, non-interventional study in Germany associated to ADOReg, collecting real-world data on the use of NIVO+IPI or NIVO in patients with advanced melanoma as well as on the use in patients treated with adjuvant NIVO after complete surgical resection.

Objectives:
To describe longitudinal change from baseline in European Organization for Research and Treatment of Care (EORTC) Quality of Life Questionnaire (QLQ-C30) scores in NICO separately for advanced (unresectableor metastatic) melanoma patients treated with NIVO+IPI or NIVO overall and among patients treated as first line therapy (1L) or as a second or later line of therapy (≥ 2L).

Methods:
- HRQoL was assessed at baseline, week 6, month 3/6/9/12 using the European Organization for Research and Treatment of Care (EORTC) QLQ-C30 Questionnaire
- Analyses were performed on all advanced melanoma patients with baseline and ≥ 1 post-baseline assessment
- For an analysis at each visit separately, the mean within-person change from baseline were calculated for each visits; change in scores were tested using the paired t-test (P≤0.05)
- For an analysis taking the complete observation time into account, a mixed effects model for repeated measures (MMRM), with time point as fixed effect, study day as a random effect, time point as a repeated measure and baseline score as a covariate was performed

Results:
Questionnaire completion rate and patient characteristics
- 766 patients with advanced melanoma were treated with NIVO+IPI (487 patients) or NIVO (279 patients)
- EORTC QLC-C30 completion rate at baseline: 86% (656 patients)
- 470 patients with baseline and ≥1 post-baseline assessment were included in HRQoL analysis population
- NIVO+IPI: 298 patients (61%)
- NIVO: 172 patients (62%)
- HRQoL analysis population is similar to all advanced melanoma patients in NICO with some differences in ECOG performance status, LDH level, and presence of brain metastases

Subgroup Analysis - HRQoL in patients with adverse events
- The majority of adverse events occurred during the first 3 months of treatment
- Clinically meaningful transient decline in EORTC QLC-C30 at month 3 for NIVO+IPI population, and maintained HRQolafterwards
- Clinically meaningful improvement at month 12 and overall time period for NIVO population

Subgroup analysis based on response
- In general, stabilization of HRQoL in both patient cohorts
- Clinically meaningful improvement of HRQoL at 12 months for NIVO patients

Conclusion:
- Patients in NICO treated with NIVO+IPI or NIVO for advanced melanoma, maintained HRQoL, and for patients treated with NIVO overall and 1L, statistically significant and clinically meaningful improvement was shown
- Exploratory subgroup analysis have been carried out on patients experiencing adverse events grade 3 and 4 as well as patients with complete or partial response
- The rate of grade 3/4 adverse events was higher in NIVO+IPI patients than NIVO patients, with most events occurring within the first 3 months of treatment
- A clinically meaningful transient decline in HRQoL was observed at month 3 for NIVO+IPI patients who experienced grade 3/4 adverse events
- These data suggest that declines in HRQoL may be related to onset of adverse events, however the overall trend shows maintained HRQoL over time
- In patients with complete or partial response a stabilization of HRQoLwith both, NIVO+IPI and NIVO was observed
- HRQoL observed in this real-world study is in line with published data from clinical trials

References:
1. Long GV, et al. Poster presented at American Society of Clinical Oncology 2015 Annual Meeting; May 29–June 2, 2015; Chicago, IL, USA;
2. Abernethy AP, et al. Poster presented at American Society of Clinical Oncology Annual Meeting (ASCO); May 29–June 2, 2015; Chicago, IL, USA;
3. Schadendorf D, et al. Poster presented at American Society of Clinical Oncology Annual Meeting (ASCO); May 31-June 4, 2019; Chicago, IL, USA. Abstract 9551;
4. Schadendorf D, et al. Europ J Cancer2017;82:80-91;
5. Clinicaltrials.gov; https://clinicaltrials.gov/ct2/show/NCT02990611. EORTC, European Organization for Research and Treatment of Care.

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Mohr P., Eigentler T., Gutzmer R. et al. (2020) Real-world outcomes on health-related quality of life in the non-interventional study NICO in Germany. Presentation at 16th EADO Congress 2020

Background:
- Advanced melanoma, in particular unresectable stage III and stage IV disease, is an aggressive tumor with a poor prognosis. There is limited understanding of real-world utilization patterns and outcomes associated with immunotherapies like the anti-programmed death 1 (PD-1) antibody pembrolizumab in advanced melanoma patients.
- Assessing the clinical benefit of cancer treatments in real-world settings is often hampered by lack of high-quality structured data for classical endpoints. In particular, objective remission measured by Response Evaluation Criteria in Solid Tumors (RECIST) and progression-free survival (PFS) status data derived from that have limitations in clinical practice.
- Time on treatment (ToT) and time to next treatment (TtNT) are composite endpoints measuring time from initiation to discontinuation of treatment and start of a subsequent treatment or death, respectively. They may potentially serve as an indicator for clinical tumor control and a surrogate marker for treatment benefit.
- In clinical tumor registration, ToT, TtNT, and overall survival (OS) are all robust and reliable endpoints and can also be reliably retrieved retrospectively from medical chart data.
- The ADOReg platform was developed in 2014 and collects data on melanoma patients treated at one of 50 certified skin cancer centers. ADOReg captures approximately one-third to one-half of all metastatic patients in Germany, and participating member hospitals and practices are distributed evenly within Germany. Physicians in these centers have unrestricted access to PD-1 inhibitors and targeted therapies.

Methods:
Study Design and Data Source:
Retrospective database study of real-world pembrolizumab utilization captured in the ADOReg registry.
Information on demographics, clinical history, treatment episode details, and clinical outcomes is collected utilizing standard electronic case report forms covering the whole disease and treatment history in routine practice
Study Population:
Inclusion Criteria:
- Advanced melanoma (unresectable stage III or stage IV) diagnosis at pembrolizumab initiation
Initiated pembrolizumab between June 1, 2014, and December 31, 2017
- Received at least 1 dose of pembrolizumab
- Aged 18 years or older on start date of pembrolizumab (ie, index date)
Exclusion Criteria:
– Received pembrolizumab in a clinical trial
– Treated with pembrolizumab for an indication other than advanced melanoma

Statistical Analysis:
- Demographic and baseline variables were calculated and displayed according to standard methods
- Survival parameters were calculated by Kaplan-Meier method using index date as the baseline date and appropriate definitions of event time points, ie, end of treatment for rwToT, clinical or radiologic progression for rwPFS, start of subsequent treatment or death for rwTtNT, and death due to any reason for rwOS
- Kaplan-Meier analyses were stratified for line of treatment, origin of primary, and presence of brain metastasis
- The correlation between rwToT, rwPFS, rwTtNT, and rwOS was analyzed using nonparametric rank correlation
- Database cutoff: June 20, 2019

Results:
- At the time of pembrolizumab initiation, the majority of patients had stage IV disease (Table 1). Of 664 patients, 402 were treatment-naïve and 262 were pretreated
- Most of the 664 patients were of known cutaneous origin (80.7%), while 4.5% were of ocular origin, 2.6% were of mucosal origin, and 12.2% had melanoma of unknown primary
- In first line, the median rwTtNT was markedly longer than in second line (11 mo vs 9.1 mo). However, in third line or higher, the median rwTtNT was 11.7 months. This was also reflected by 1-year next-treatment rates of 49.2%, 43.3%, and 49.5% in first, second, and third line plus, respectively
- Median rwTtNT was longest for unknown primary and cutaneous melanoma but markedly shorter for ocular and mucosal melanoma. In contrast, the presence vs absence of brain metastasis did not significantly affect median rwTtNT
- Out of the different outcome parameters, rwTtNT correlated highest with rwOS, while rwPFS showed the lowest correlation and rwToT was in between

Conclusions:
- In comparison to rwPFS, rwTtNT appears to be of higher relevance and discriminatory power and may be a valuable endpoint in real-world populations receiving immunotherapy
- Patients with brain metastasis show a comparable rwTtNT with pembrolizumab to the overall population
- For patients in higher line of treatment, rwTtNT suggests that treatment with pembrolizumab is likely to be a valuable option
- Data for patients with ocular or mucosal melanoma still reflects the more aggressive course in these subpopulations

Mohr P., Chandwani S., Leiter U. et al. (2019) Real-World Time to Next Treatment in Advanced Melanoma Patients Treated With Pembrolizumab in the German ADOReg Melanoma Registry. Poster presented at SMR Congress 2019

Background:
In melanoma, potential benefits of therapies after PD-1 inhibitor failure, including those BRAF positive patients who have already received combined BRAF-/MEK inhibitors before anti PD-1 are poorly defined. We therefore analyzed the treatment patterns and outcome of systemic therapies for patients after anti-PD-1 failure.

Methods:
From the ADOReg registry, patients fulfilling the following inclusion criteria were consecutively included until a number of 200 cases was reached. 1) Ipilimumab naive patients with unresectable metastatic cutaneous or mucosal melanoma. 2) Failure from treatment with a single agent anti PD-1 antibody. 3) Known BRAF status and, in case of BRAF-V600 mutation, BRAF-/MEK-inhibitor treatment prior to anti PD-1 treatment. 4) Consecutive systemic treatment started within a maximum of 6 months after anti PD-1 failure.

Objectives:
Rate of objective remissions (ORR), disease control (DCR), survival (OS), tolerability and disease patterns correlated to the use of different treatments after PD-1 treatment failure in real-life conditions in Germany. Results: In total 23.5 % of the patients received ipilimumab single agent, 38.5 % received the combination of ipilimumab and nivolumab (Ipi/Nivo), and the remaining various regimens. (Table) Ipi/Nivo resulted in an ORR significantly higher than for Ipi alone (p=0.02). In 18 patients receiving BRAF-/MEK inhibitor re-challenge, ORR was comparable to Ipi/Nivo. Conventional Chemotherapy was still in frequent use (dacarbazine n =33; other n=17), but response rates were low (ORR 6%). Some remission were also achieved by use of talimogene laherparepvec (n=2 out of 4).

Conclusions:
Treatment patterns of patients after anti-PD-1 failure differ remarkably. Although lower than reported in treatment naive patients, the combination of Ipilimumab and Nivolumab appeared favorable as compared to all other regimens, except for BRAF-/MEK inhibitor re-challenge which produced similar remission rates. Still, chemotherapies including dacarbazine are in clinical practice, though giving only poor outcome.

Weichenthal M., Ugurel S., Leiter U. et al. (2019) Salvage therapy after failure from anti-PD-1 single agent treatment: A Study by the German ADOReg melanoma registry. Journal of Clinical Oncology. 2019;37(15 suppl.). DOI: 10.1200/JCO.2019.37.15_suppl.9505. Poster presented at ASCO 2019

https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.15_suppl.9505

Background:
- Advanced melanoma, in particular unresectable stage III and stage IV disease, is an aggressive tumor with a poor prognosis. There is limited understanding of real-world utilization patterns and outcomes associated with immunotherapies like the anti-programmed death 1 (PD-1) antibody pembrolizumab in advanced melanoma patients.
- Assessing the clinical benefit of cancer treatments in real-world settings is often hampered by lack of high-quality structured data for classical endpoints. In particular, objective remission measured by Response Evaluation Criteria in Solid Tumors (RECIST) and progression-free survival (PFS) status data derived from that have limitations in clinical practice.
- Time on treatment (ToT) and time to next treatment (TtNT) are composite endpoints measuring time from initiation to discontinuation of treatment and start of a subsequent treatment or death, respectively. They may potentially serve as an indicator for clinical tumor control and a surrogate marker for treatment benefit.
- In clinical tumor registration, ToT, TtNT, and overall survival (OS) are all robust and reliable endpoints and can also be reliably retrieved retrospectively from medical chart data.
- The ADOReg platform was developed in 2014 and collects data on melanoma patients treated at one of 50 certified skin cancer centers. ADOReg captures approximately one-third to one-half of all metastatic patients in Germany, and participating member hospitals and practices are distributed evenly within Germany. Physicians in these centers have unrestricted access to PD-1 inhibitors and targeted therapies.

Methods:
Study Design and Data Source:
Retrospective database study of real-world pembrolizumab utilization captured in the ADOReg registry.
Information on demographics, clinical history, treatment episode details, and clinical outcomes is collected utilizing standard electronic case report forms covering the whole disease and treatment history in routine practice
Study Population:
Inclusion Criteria:
- Advanced melanoma (unresectable stage III or stage IV) diagnosis at pembrolizumab initiation
Initiated pembrolizumab between June 1, 2014, and December 31, 2017
- Received at least 1 dose of pembrolizumab
- Aged 18 years or older on start date of pembrolizumab (ie, index date)
Exclusion Criteria:
– Received pembrolizumab in a clinical trial
– Treated with pembrolizumab for an indication other than advanced melanoma

Statistical Analysis:
- Demographic and baseline variables were calculated and displayed according to standard methods
- Survival parameters were calculated by Kaplan-Meier method using index date as the baseline date and appropriate definitions of event time points, ie, end of treatment for rwToT, clinical or radiologic progression for rwPFS, start of subsequent treatment or death for rwTtNT, and death due to any reason for rwOS
- Kaplan-Meier analyses were stratified for line of treatment, origin of primary, and presence of brain metastasis
- The correlation between rwToT, rwPFS, rwTtNT, and rwOS was analyzed using nonparametric rank correlation
- Database cutoff: June 20, 2019

Results:
- At the time of pembrolizumab initiation, the majority of patients had stage IV disease (Table 1). Of 664 patients, 402 were treatment-naïve and 262 were pretreated
- Most of the 664 patients were of known cutaneous origin (80.7%), while 4.5% were of ocular origin, 2.6% were of mucosal origin, and 12.2% had melanoma of unknown primary
- In first line, the median rwTtNT was markedly longer than in second line (11 mo vs 9.1 mo). However, in third line or higher, the median rwTtNT was 11.7 months. This was also reflected by 1-year next-treatment rates of 49.2%, 43.3%, and 49.5% in first, second, and third line plus, respectively
- Median rwTtNT was longest for unknown primary and cutaneous melanoma but markedly shorter for ocular and mucosal melanoma. In contrast, the presence vs absence of brain metastasis did not significantly affect median rwTtNT
- Out of the different outcome parameters, rwTtNT correlated highest with rwOS, while rwPFS showed the lowest correlation and rwToT was in between

Conclusions:
- In comparison to rwPFS, rwTtNT appears to be of higher relevance and discriminatory power and may be a valuable endpoint in real-world populations receiving immunotherapy
- Patients with brain metastasis show a comparable rwTtNT with pembrolizumab to the overall population
- For patients in higher line of treatment, rwTtNT suggests that treatment with pembrolizumab is likely to be a valuable option
- Data for patients with ocular or mucosal melanoma still reflects the more aggressive course in these subpopulations

Mohr P., Chandwani S., Leiter U. et al. (2019) Real-World Time to Next Treatment in Advanced Melanoma Patients Treated With Pembrolizumab in the German ADOReg Melanoma Registry. Poster presented at SMR Congress 2019

Tumour entity: Malignant Melanoma
Main applicant/contact (further applicants): Zimmer, Lisa (Zaremba, Anne)

Tumour entity: Squamous Cell Carcinoma
Main applicant/contact (further applicants): Tietze, Julia (Weichenthal, Michael)

Tumour entity: Malignant Melanoma
Main applicant/contact (further applicants): Tietze, Julia (Weichenthal, Michael)

Tumour entity: Malignant Melanoma
Main applicant/contact (further applicants): Tietze, Julia (Weichenthal, Michael)

Tumour entity: Malignant Melanoma
Main applicant/contact (further applicants): Schilling, Bastian (Kreft, Sophia)

Tumour entity: Malignant Melanoma
Main applicant/contact (further applicants): Rösch, Alexander (Hinney, Anke; Ugurel, Selma)

Tumour entity: Malignant Melanoma
Main applicant/contact (further applicants): Pföhler, Claudia (Ugurel, Selma)

Tumour entity: Malignant Melanoma
Main applicant/contact (further applicants): Mohr, Peter (Weichenthal, Michael)

Tumour entity: Basal Cell Carcinoma
Main applicant/contact (further applicants): Leiter, Ulrike

Tumour entity: Malignant Melanoma
Main applicant/contact (further applicants): Gutzmer, Ralf

Tumour entity: Malignant Melanoma
Main applicant/contact (further applicants): Griewank, Klaus (Livingstone, Elisabeth; Lodde, Georg)

Tumour entity: Malignant Melanoma
Main applicant/contact (further applicants): Franklin, Cindy (Ugurel, Selma)

Tumour entity: Merkel Cell Carcinoma
Main applicant/contact (further applicants): Becker, Jürgen (Ugurel, Selma)

Tumour entity: Malignant Melanoma
Main applicant/contact (further applicants): Gutzmer, Ralf

Tumour entity: Malignant Melanoma
Main applicant/contact (further applicants): Heppt, Markus; Schlaak, Max

Tumour entity: Malignant Melanoma
Main applicant/contact (further applicants): Loquai, Carmen (Stege, Henner)