Background

Immune checkpoint inhibitors (ICI) have improved survival for a proportion of patients (pts) with metastatic melanoma (MM). This has resulted in a cohort of long-term responders whose survivorship experience remains virtually undescribed. We characterised survivorship issues faced by these pts using a cross-sectional survey.

Methods

Eligible pts had MM, aged >18, ≥ 6 months post initiation of ICI, and attained an objective response or stable disease at the time of enrolment. A 72-item questionnaire including items from validated measures and customised questions covering physical and psychological effects, impact on lifestyle, access to information, and availability of supports was administered. The impact of treatment status (on vs off) and duration on ICI (<12 or > 12 months) was assessed.

Results

105/120 pts (88%) responded from August-December 2017. 69 received ICI [median age 63 (range 24-88); 42 (61%) male; 49 (71%) on 1^st line therapy]. 39 (56%) were on treatment. 30 (43%) were off treatment – 63% due to toxicity, 23% due to completion of induction ipilimumab, 13% due to a sustained response with two years of anti-PD1 therapy. 41 (59%) reported at least 1 long-term toxicity due to treatment. The most common physical symptoms were fatigue (62, 90%), dry/itchy skin (51, 74%) and arthralgias (30, 58%). The prevalence and severity of symptoms were similar regardless of treatment status or duration on treatment. Psychological morbidity was common including concerns about stopping treatment (50, 86%) and the long-term side effects of ICI (51, 74%), and anxiety awaiting results (50, 72%). Fear of cancer recurrence (FCR) was prevalent (56, 81%). Pts reported difficulties with domestic tasks (36, 52%) and recreational activities (43, 62%). Most valued a survivorship care plan (SCP) (63, 91%) and screening for other cancers (67, 97%).

Conclusions

The clinical focus in long-term survivors of MM needs to shift towards the early identification of patient concerns and unmet needs, and the development of appropriate resources to manage these issues. Pts may benefit from regular discussions regarding ICI treatment duration and long term toxicities, tailored psychological support and a SCP with recommendations for screening.

Legal entity responsible for the study

Peter MacCallum Cancer Centre.

Funding

Skin and Melanoma Unit, Peter MacCallum Cancer Centre.

Disclosure

D. Milne: Honoraria, Consulting/advisory roles: MSD, BMS, Novartis; Research Funding Merck. S.K. Sandhu: Honorarium for advisory board: Merck, BMS, Genetech. M. Jefford: Travel assistance: Roche, 2018. All other authors have declared no conflicts of interest.

Background

Although PD-L1 expression is considered to be imperfect, it remains one of the logical biomarkers for predicting the treatment response to anti-PD-1 antibodies. However, the correlation between PD-L1 expression and clinical outcome in addition to the PD-L1 positivity rate in rare subtypes of melanoma is unclear.

Methods

To evaluate the PD-L1 positivity rate and the correlation between PD-L1 expression and clinical outcomes after nivolumab monotherapy in patients with metastatic melanoma including rare subtypes, we carried out a retrospective study using a database of National Cancer Center Hospital, Tokyo, Japan. PD-L1 status was evaluated as the percentage of tumor cells exhibiting positive membrane staining as detected using the PD-L1 IHC 28-8 pharmDx kit (Dako).

Results

We identified 147 patients with metastatic melanoma who received nivolumab monotherapy from September 2014 to February 2017. Median age was 65 (range, 17 - 92), and 74 patients (50%) were male. Non-acral cutaneous, acral cutaneous, mucosal, uveal, and unknown primary melanomas were seen in 43 (29%), 28 (19%), 54 (37%), 14 (10%), and 8 (5%) patients, respectively. Positive PD-L1 expression determined by 5% cutoff was seen in 38 (57%) out of 67 patients who had adequate tumor specimens for PD-L1 testing obtained before starting nivolumab. PD-L1 positivity rate in each subtypes were 60% (12 of 20) in non-acral cutaneous, 33% (6 of 18) in acral cutaneous, 75% (15 of 20) in mucosal, 0% (0 of 4) in uveal, and 100% (5 of 5) in unknown primary melanoma. The median progression-free survival (95%CI) in melanoma patients with negative, positive, and unknown PD-L1 status was 8.0 (3.0 – 13.0), 9.0 (6.4 – 11.6), and 3.0 (2.4 – 3.6) months, respectively (p = 0.013). The median overall survival (95%CI) in melanoma patients with negative, positive, and unknown PD-L1 status was 24.0 (20.8 – 27.2), 21.0 (15.6 – 26.4), and 10.0 (4.5 – 15.5) months, respectively (p = 0.219).

Conclusions

PD-L1 positivity rate varies among different subtypes of melanoma. PD-L1 expression seems not to be a definitive biomarker to predict clinical outcome after nivolumab monotherapy in various subtypes of melanoma.

Legal entity responsible for the study

National Cancer Center Hospital, Tokyo, Japan.

Funding

This work was supported in part by the National Cancer Center Research and Development Fund (29-A-3) and the Practical Research for Innovative Cancer Control from the Japan Agency for Medical Research and Development (AMED) (JP18ck0106352).

Disclosure

K. Namikawa: Honoraria: Ono Pharmaceutical, Bristol-Myers Squibb, MSD, Novartis Pharmaceutical, Toray industries, Takara bio, Eisai, outside the submitted work. N. Yamazaki: Research grant: Ono Pharmaceutical, Bristol-Myers Squibb, Novartis Pharma, MSD, Merck, Takara Bio, Amgen, Sysmex; Honoraria: Ono Pharmaceutical, Bristol-Myers Squibb, Novartis Pharma, MSD, Takara Bio. All other authors have declared no conflicts of interest.

Background

Uveal melanoma is the most common primary intraocular malignancy in adults. Despite successful local therapy, almost half of all patients develop metastases, with the majority relapsing in the liver. Unlike cutaneous melanoma, there are no effective systemic treatments for metastatic uveal melanoma, with dismal response rates seen with immune checkpoint inhibitors. This prospective study was conducted to evaluate the safety and efficacy of radiosensitising chemotherapy in combination with Ytrrium-90 microspheres in patients with uveal melanoma with liver-only metastases.

Methods

This single arm, open labeled, non-randomized study enrolled 10 patients with liver-only metastatic uveal melanoma between November 2012 and January 2018 at the Austin Hospital. Eligible patients received intrahepatic yttrium-90 microspheres followed by intravenous cisplatin (20mg/m²) for five days.

Results

Ten patients were enrolled with a median follow up of 30 months (range 7 – 44). Five (50%) were female, five (50%) had an elevated LDH and one (10%) had prior anti-PD-1 therapy. The combination was well tolerated with no ≥Grade 3 toxicity observed. The liver ORR was 33% (3/9), the median PFS in the liver was 3 months (95% CI 3 - NA) and the extra-hepatic PFS was 3 months (95% CI 3 - NA). 78% (7/9) received an immune checkpoint inhibitor on disease progression, with no responses seen. The median OS was 10 months (95% CI 7 - NA).

Conclusions

The combination of cisplatin with yttrium-90 microspheres was well tolerated however it was associated with intra-hepatic disease control of relatively short duration. No responses were seen in patients treated with immune checkpoint inhibitors post radioembolisation. Translational studies are required in order to determine if locoregional therapies are capable of enhancing immune responses and thereby improving responses to immune checkpoint inhibitors.

Clinical trial identification

Austin 04888.

Legal entity responsible for the study

Sirtex.

Funding

Sirtex.

Disclosure

All authors have declared no conflicts of interest.

Background

Metastatic osteosarcoma outcomes are dismal, despite costly and complex high-dose methotrexate (HDMTX)–based therapies. This is challenging especially in lower and middle-income countries (LMICs) with limited resources & increasing patient volumes. We need to reallocate resources to efficient but sustainable strategies, like exploring Non-HDMTX based protocols and aggressive multimodality approach in this setting.

Methods

All consecutive treatment-naïve patients with metastatic osteosarcoma were prospectively treated on the “OGS-12” protocol, which involved administration of eight sequential doublets of the three most active drugs (doxorubicin, cisplatin, and ifosfamide), universal growth factor prophylaxis and targeted nutritional support if required. Four cycles were administered as neoadjuvant therapy (NACT) followed by planned curative intent surgery and metastasectomy when feasible, followed by four cycles of adjuvant chemotherapy (ACT).

Results

Four ninety-five patients were enrolled in the OGS-12 protocol from 2011 to 2016, of whom 110 (22%) had metastatic disease; the median age was 17 years. The majority of patients were nutritionally challenged with high-risk features like high LDH (80%), high SAP (91%). After NACT, 57% of patients were histologically good responders (gHR) that is ≥ 90% tumor necrosis. Five-year event-free survival (EFS) & overall survival(OS) rates were 24% & 20%, respectively, in the intent-to-treat and 43% & 29%, respectively, in the per-protocol populations. Significant grade 3/4 toxicities were febrile neutropenia (29%), thrombocytopenia (39%), and anemia (56%). Ability to perform metastectomy for improved OS, compliance to therapy for improved EFS, and gHR for both improved EFS and OS were identified as independent prognostic markers.

Conclusions

Adoption of an aggressive multimodality approach including the novel, low-cost, Non-HDMTX–based, dose-dense "OGS-12" protocol, enhanced supportive care & compliance, with metastectomy resulted in internationally comparable outcomes of metastatic osteosarcoma patients. This rational and sustainable, economically efficient strategy is worthy of wide adaption.

Legal entity responsible for the study

Dr Jyoti Bajpai, Tata Memorial Cancer Center.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Clinicopathological features and prognosis of wild-type GIST defined as GIST lacking mutations in KIT and PDGFRA genes are unknown. We conducted the panel analysis of wild-type GIST.

Methods

Cohort 1: Total 255 pts with primary GISTs underwent surgery in 2 hospitals were consecutively registered between 2003 and 2014. Cohort 2: Total 515 pts with high-risk GISTs by Modified NIH classification diagnosed in 127 hospitals were prospectively registered between 2012 and 2015. Median follow-up periods of Cohort 1 and 2 were 3.4 and 4.2 years, respectively. Genotyping was performed using surgical specimens with conventional PCR/sequencing of KIT and PDGFRA, and, then, targeted sequencing with NCC Oncopanel ver. 5 for wild-type GIST.

Results

Wild-type GISTs found in Cohort 1 and 2 were 17 (6.7%) and 19 (3.7%), respectively. Compared with KIT-mutated GISTs, wild-type and PDGFRA-mutated GISTs showed lower mitotic counts (p = 0.009) and better recurrent-free survival (p = 0.004) in Cohort 1. Age at diagnosis was significantly younger in wild-type GIST than KIT- and PDGFRA-mutated GISTs. Frequency of high risk GISTs was similar among 3 mutation groups. Total 36 wild-type GISTs from two Cohorts located in the stomach (n = 16), small intestine (18), lower esophagus (1) or extra-GI (1). Panel analysis found mutations in NF1 (13), SDH complex (6; SDHA=3 and SDHB=3), BRAF (5), and no known GIST-associated mutation in 7 (the other 5 were not analytical due to poor or no DNA). BRAF-mutated (4 out of 5) and NF1-GISTs (10 of 13) mainly located in the small intestine, and SDH-mutated (5 of 6) located in the stomach. Multiple GISTs were recognized in 10 pts including 6 (46% of NF1) NF1- and 3 (50%) SDH-mutated GISTs. Among genotypes, there were no difference in tumor size and mitotic counts, but SDH-mutated GISTs were significantly younger than the other wild-type GISTs. Among 13 NF1-GIST pts, only 1 had family history and 5 pts met the diagnostic criteria of NF1. With a median follow-up of 3.4 years, new relpases were found in 10 pts with high risk GISTs. 15 out of 24 high risk wild-type GISTs received adjuvant therapy and 6 pts of 15 had relapses even under imatinib.

Conclusions

Wild-type GIST is a heterogeneous disease and relapse was associated with high-risk features despite imatinib-adjuvant.

Clinical trial identification

UMIN000009531.

Legal entity responsible for the study

STAR Registry Goup.

Funding

The National Cancer Center Research and Development Fund.

Disclosure

All authors have declared no conflicts of interest.

Background

Histologic response (HR) to neoadjuvant chemotherapy (NACT) is a robust prognosticator in non-metastatic osteosarcoma, however, it is accessible only after NACT completion. We need to identify novel early phase prognostic markers to individualize therapy.

Methods

Prognostic markers were studied in a large cohort of osteosarcoma patients treated with 3 sequential non-high dose methotrexate(HDMTX) based combination chemotherapy protocols in a single tertiary care center in India for over 2 decades.

Results

A total of 41, 94 & 385 treatment naive, consecutive, non-metastatic, extremity osteosarcoma patients received OGS-99(year 2000-2005), OGS-99-enhanced (2010) & OGS-12 protocols (2011-2016) respectively. At a median follow-up of 19(2-160), 86(2-99) & 39(6-78) months, the 5 year EFS rates were 38%, 50%, 62% and 5 year OS rates were non-evaluable, 60% & 77% in OGS-99, OGS enhanced & in OGS-12 respectively. Apart from HR to NACT, we found, other novel prognosticators like ECOG PS, completion of the protocol (compliance), female gender, and occurrence of febrile neutropenia (FN) (Table). ECOG PS can affect tolerance & thereby compliance; which can also be affected by undue concern for safety, resource constraints, and other patient-related factors and can affect survival. FN may be an indicator of chemosensitivity. Further, an infection may cause an immune-mediated antitumor activity resulting in better survival. Historically, “Coley- toxins” was known to induce remission in sarcoma. Interestingly, there is a possible link between cancer outcome, circadian system & varied, gender-specific clock-controlled gene expression. This might explain superior survival in females.Table: 408O

Prognostic markers in univariate & multivariate analysis

Conclusions

Based on this comparatively large cohort of successive nonmetastatic osteosarcoma patients experience for over 2 decades, we conclude that besides histological response, female gender, ECOG -PS, compliance, and FN are reliable novel, early phase predictors, and merits further exploration to establish their role.

Legal entity responsible for the study

Dr Jyoti Bajpai.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.