Then there's melanoma, GCC and me - Study shows increased secondary cancer risk after immunotherapy!!!!! Adjuvant treatment of Stage II GCC = no improvement in OS!!! Well! Isn't that nice???

As most of you reading these pages know, I was diagnosed with Stage IIIb melanoma in 2003, advanced to Stage IV in 2010 with brain and lung mets, subsequently enrolled in a Phase 1 Nivolumab (Opdivo) trial, taking nivo for 2 1/2 years.  On what was to be my last follow-up scan in 2018, something was found in my appendix.  Removal and biopsy indicated Stage II Ex-goblet cell adenocarcinoma of the appendix.  Appendiceal cancer is very rare - found in only 1-2 people per million in the US.  Of those, my type of appendiceal cancer is rarer still!  I completed (almost) a three month, 4 dose regimen of adjuvant CAPOX (Capecitabine and Oxaliplatin).

Currently, that means I am ~

219 months (18 YEARS!!!!) post my original melanoma diagnosis in 2003 at the age of 39
139 months Stage IV (11 and 1/2 years!!!)
133 months NED (well....for melanoma at least)
131 months after starting nivo (Opdivo)
101 months (more than 8 years) AFTER my last nivo infusion in June 2013.

I am also:  
39 months post my diagnosis of adenocarcinoma ex-goblet cell carcinoid (GCC) and the removal of my appendix with its 10.5 cm tumor, my ascending colon including ileocecal valve, gall bladder and ovaries
36 months (3 years!) post completion of 3 months adjuvant CAPOX chemo for same

Then there's this:

Assessment of Trends in Second Primary Cancers in Patients With Metastatic Melanoma From 2005 to 2016.  Deng, Wang, Liu, et al.  JAMA Dec 2020.

Importance: To date, the risk of developing second primary cancers (SPCs) after the first primary melanoma has not been studied in the era of immune checkpoint inhibitors (ICIs).

Objective: To assess differences in the risk of SPCs in patients with primary melanoma before (2005-2010) and after (2011-2016) the introduction and approval of ICIs.

Design, setting, and participants: Population-based cohort study using the Surveillance, Epidemiology, and End Results database from January 2005 to December 2016 of patients diagnosed with metastatic melanoma. Data were analyzed from January 4 to June 30, 2020.

Exposures: Receipt of immunotherapy or other anticancer agents.

Main outcomes and measures: The primary outcome was the development of second primary cancers in patients with melanoma. Standardized incidence ratios (SIRs) were calculated for the development of SPCs before and after the introduction of ICIs.

Results: Among 5016 patients with diagnosed metastatic melanoma, 2888 (58%) were younger than 65 years at the time of diagnosis, and 3441 (69%) were male. From 2005 to 2010, SIRs were 3.24 for small intestine cancer, 1.93 for lung and bronchus cancer, 2.77 for kidney cancer, and 7.29 for myeloma. From 2011 to 2016, SIRs were 9.23 for small intestine cancer, 1.54 for lung and bronchus cancer, 2.66 for kidney cancer, and 5.90 for myeloma. The overall risk of developing SPCs in individuals who survived the first primary melanoma was 65% higher in the pre-ICIs period and 98% higher in the post-ICIs period than the overall cancer incidence rate in the general population.

Conclusions and relevance: In this study, an increase in the overall risk of second primary cancers after melanoma after the introduction of immune checkpoint inhibitors was observed. The pattern of SPCs has been altered in the era of systemic therapy. Close monitoring and screening for SPCs may be warranted in patients with metastatic melanoma.

Well damn!  I think of you so often, my sweet Julie!!!!  And that last sentence - "Close monitoring and screening for Second Primary Cancers may be warranted in patients with metastatic melanoma."  Tell that to oncs and more importantly to insurance companies!!!!!!!!!!!!!!!!!!!!!  Though - before anyone panics I will add these thoughts:

1.  This study is not the end all be all.

2.  When you are dealing with melanoma - especially Stage IV as I was - you are facing death or treatment.  So, what choice is there, really?  Besides, despite Stage IV melanoma, despite immunotherapy side effects, despite a second cancer and the side effects from that treatment - I'm Still Here!!!!!!!!

3.  There are variables besides immunotherapy that have to be considered here as well - 

    a) The propensity of these patients to develop cancer - for whatever reason.

    b) The 9 gazillion scans used as follow-up/treatment management in these patients.

    c) The use of radiation in these patients as part of their treatment.

There may well be more, but those come to me at the moment.  In cancer world, we know that treatment, though necessary, is not benign.

Next up -

Gotta say, I thought I was a beast when I got through my 2 1/2 year nivo trial.  Working roughly 10-12 hours Mon, Tue, Wed as a pediatric NP in a busy office.  Driving the two hours to Atlanta on Thursday morning to catch the flight down to Tampa that afternoon.  Spending the night in the good ol La Quinta.  Treatment at the butt crack of dawn on Friday.  A mad dash back to the airport for the flight back to Atlanta.  Two hour drive home.  Usually arriving back in Chattown around midnight.  Rinse and repeat every 2 weeks for 6 months, then every 3 months for 2 years, missing only 3 days of work during that time.  Perhaps I was just insane.  Check out this post-it note sent home to B from a dear coworker during that time:  Friends in need are friends indeed! Here's to the caregivers!!!  Still, for all the fatigue, wheezing, arthralgias, rashes and oral lesions - immunotherapy was a walk in the park compared to CAPOX.  That shit kicked my ass - literally and figuratively!  Now, there's this.... 

Is adjuvant chemotherapy beneficial for stage II-III goblet cell carcinoid/goblet cell adenocarcinoma of the appendix?  Zakka, Williamson, Jiang, et al.  Surg Oncol.  2020 Dec.

Background: Goblet cell carcinoma (GCC), formerly known as goblet cell carcinoid, of the appendix constitutes less than 14% of all primary appendiceal neoplasms. Surgical resection is the main treatment and the role of adjuvant chemotherapy (AC) is not established. This study aims to evaluate the impact of AC in stage II-III appendiceal GCC.

Methods: Patients with pathological stage II and III GCC who underwent surgical resection between 2006 and 2015 were identified from the National Cancer Database (NCDB) using ICD-O-3 morphology and topography codes: 8243/3 (goblet cell carcinoid) and C18.1. Patients treated with neoadjuvant systemic and/or radiation therapy and adjuvant radiation were excluded. Univariate and multivariable analyses were conducted, and Kaplan-Meier Curves were used to compare overall survival (OS) based on treatment received with Log-rank test.

Results: A total of 619 patients [over 9 years!!!] were identified. 54.4% males and 89.0% Caucasian; median age 56 (range, 23-90) years. Distribution across pathological stages II-III was 82.7% (N = 512) and 17.3% (N = 107) respectively. AC was administered in 9.4% (N = 48) of stage II and 47.7% (N = 51) of stage III patients. For stage II patients, AC was not associated with better OS. By contrast, in stage III patients, AC was associated with better OS. In the entire cohort 5-year OS for patients that received AC was 85.5% (74.0%, 92.1%) versus 82.7% (77.5%, 86.8%) with no AC. For stage II patients, 5-year OS was 96.9% with AC vs. 89.1% with no AC. For stage III patients, 5-year OS was 77.1% with AC vs. 42.8% with no AC.

Conclusion: AC was associated with improved OS in patients with pathological stage III GCC of the appendix, but not with pathological stage II.

Well, ain't that a bitch??!!!  Now this - 

Outcomes in Peritoneal Carcinomatosis from Appendiceal Goblet Cell Carcinoma Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (CRS/HIPEC).  Zambrano-Vera, Sardi, Munoz-Zuluaga, et al.  Ann Surg Oncol.  2020 Jan 27.

Background: Appendiceal goblet cell adenocarcinoma (GCA) is often misclassified and mistreated due to mixed histologic features. In general, cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is standard of care for peritoneal carcinomatosis (PC) from mucinous appendiceal tumors; however, in PC from GCA, data are limited and the role of CRS/HIPEC is controversial. We report outcomes in PC from appendiceal GCA treated with CRS/HIPEC.

Patients and methods: A prospective institutional database of 391 CRS/HIPEC patients with appendiceal carcinomatosis from 1998 to 2018 was reviewed. Twenty-seven patients with GCA were identified. Perioperative variables were described. Survival was estimated using the Kaplan-Meier method.

Results: GCA occurred in 7% (27/391) of appendiceal CRS/HIPEC patients. Seven (26%) cases were aborted. Two patients underwent a second CRS/HIPEC for peritoneal recurrence. Median age at diagnosis was 53 years (range 39-72 years), and 12 (60%) were female. All underwent previous surgery. Seven (35%) had prior chemotherapy and received a median of 5 cycles (range 3-8). Median PCI was 6 (range 1-39). Complete cytoreduction was achieved in 95% (19/20). Grade III complications occurred in three (15%) patients, and no perioperative deaths occurred. Median follow-up was 97 months. Overall survival at 1, 3 and 5 years was 100%, 74% and 67%, respectively. Progression-free survival at 1, 3, and 5 years was 94%, 67% and 59%, respectively.

Conclusion: CRS/HIPEC should be considered as the main treatment option for patients with PC from appendiceal GCA. When performed at a CRS/HIPEC specialty center, 5-year OS of 67% can be achieved.

Poor peeps!  I hope I never have to undergo that shit!!!!  Man!  Don't you love how researchers state things like "When performed at a CRS/HIPEC specialty center, 5-year OS of 67% can be achieved." - as though 33% of patients dying within 5 years is a good thing?  Sigh.....

Y'all know I've been yelling for YEARS, as recently as earlier this month, about ctDNA use in melanoma - rather - how it SHOULD be used in melanoma!!! - A Zillion Posts  Now, there's this -

Analysis of Plasma Cell-Free DNA by Ultradeep Sequencing in Patients With Stages I to III Colorectal Cancer.  Reinert, Henriksen, Christensen, et al.  JAMA Oncol.  2019, May.

Importance:  Novel sensitive methods for detection and monitoring of residual disease can improve postoperative risk stratification with implications for patient selection for adjuvant chemotherapy (ACT), ACT duration, intensity of radiologic surveillance, and, ultimately, outcome for patients with colorectal cancer (CRC).

Objective:  To investigate the association of circulating tumor DNA (ctDNA) with recurrence using longitudinal data from ultradeep sequencing of plasma cell-free DNA in patients with CRC before and after surgery, during and after ACT, and during surveillance.

Design, Setting, and Participants:  In this prospective, multicenter cohort study, ctDNA was quantified in the preoperative and postoperative settings of stages I to III CRC by personalized multiplex, polymerase chain reaction–based, next-generation sequencing. The study enrolled 130 patients at the surgical departments of Aarhus University Hospital, Randers Hospital, and Herning Hospital in Denmark from May 1, 2014, to January 31, 2017. Plasma samples (n = 829) were collected before surgery, postoperatively at day 30, and every third month for up to 3 years.

Results:  A total of 130 patients with stages I to III CRC (mean age, 67.9 years; 74 male) were enrolled in the study; 5 patients discontinued participation, leaving 125 patients for analysis. Preoperatively, ctDNA was detectable in 108 of 122 patients. After definitive treatment, longitudinal ctDNA analysis identified 14 of 16 relapses (87.5%). At postoperative day 30, ctDNA-positive patients were 7 times more likely to relapse than ctDNA-negative patients. Similarly, shortly after ACT ctDNA-positive patients were 17 times  more likely to relapse. All 7 patients who were ctDNA positive after ACT experienced relapse. Monitoring during and after ACT indicated that 3 of the 10 ctDNA-positive patients (30.0%) were cleared by ACT. During surveillance after definitive therapy, ctDNA-positive patients were more than 40 times more likely to experience disease recurrence than ctDNA-negative patients. In all multivariate analyses, ctDNA status was independently associated with relapse after adjusting for known clinicopathologic risk factors. Serial ctDNA analyses revealed disease recurrence up to 16.5 months ahead of standard-of-care radiologic imaging (mean, 8.7 months; range, 0.8-16.5 months). Actionable mutations were identified in 81.8% of the ctDNA-positive relapse samples.

Conclusions and Relevance:  Circulating tumor DNA analysis can potentially change the postoperative management of CRC by enabling risk stratification, ACT monitoring, and early relapse detection.

How could this not be a good thing, right???? So, I put my money where my mouth is.  Several months ago, I had the Signatera - Circulating tumor DNA blood test done.  The company analyzed a sample from my appendiceal tumor to create an assay generated by the mutations in my specific tumor to know what to look for in a simple blood draw.  It was negative.  Meaning - no bits or bobs of the tumor DNA they searched for was in my blood sample.  This is in no way an advert for that particular company. (Though medical folks from the company answered ALL B's questions in several phone calls, so that is something!!!)  This is simply a report of what I did, the research behind it, and how it went.  I told B I ought to do a two-fer and have them look for melanoma as well as GCC!!  Surprisingly, he was not amused!  Such a party pooper!  Poor boy.  

So, to finish up 2021 with a bang, a couple of weeks ago, routine follow-up scans were clear - the strange ascites that keep jogging around with me was diminished, so that's good, I guess.  Yesterday, I had a visit with my onc and labs (to follow relative proteins, iron, folate and such) drawn.  An uneventful event, though I had to be stuck twice.  Such is the life of a cancer patient.  And to think - having had bilateral complete lymphadenectomies of both arms in 2003 and 2007 - I was told never to have so much as a blood pressure check in either.  Well!!!  That went out the window YEARS ago!  I am moving to annual scans and doc visits with labs every 6 months.  Clearly, I am to be seen sooner if I have any problems. Though how to ID said 'problems' is a little unclear.  Leaving the visit, I told B I was tired of being a cancer patient.  But, as quickly as I said it I realized that when you ARE a cancer patient, getting to be one for so many years is pretty lucky, no?  Neuropathies to hands and feet continue.  B religiously applies Voltaren to my feet each night.  Again, not an advert.  I'm not really sure it does anything, but he is convinced.  We've tried a variety of things - icy hot type preparations, Blue emu something or other, a hemp oil ta-dah.  These well and truly did nothing at all!!!  I've learned to manage my bowel situation, though some days are better than others.  I still run and sew and work and play.  At the end of the day - especially at the end of THREE /18 crazy years - what more can one ask for?

Wishing each of you peaceful moments, much love, and a zillion small joys in the coming year.   ~ les

And, yes.  The observant among you will note that it took me a year to post the data included here.  Sometimes it takes a minute to face your reality. And, yes.  I am smiling. - c

FDG-PET vs CT - predicting outcomes and following melanoma patients treated with immunotherapy -

Lots of melanoma patients ask questions about what sort of follow-up radiographic tests they should seek.  Perhaps these articles will shed some light...

Predictive value of FDG-PET imaging for relapse in metastatic melanoma patients treated with immunotherapy.  Mesnard, Bodt-Milin, Eugene, et al.  J Eur Acad Dermatol Venereol. 2020 Mar 27.

Anti-PD1 immunotherapy has shown a sustainable clinical activity in patients with metastatic melanoma. However, strong predictive factors of the long-term response or risk of relapse remain to be identified.

To determine whether FDG-PET imaging could be superior to CT-scan in distinguishing residual tumors versus the absence of tumor in patients with a partial response (PR) or stable disease (SD) and if a complete metabolic response (CMR) was associated with better outcomes.

Retrospective study conducted in all patients with metastatic melanoma treated with anti-PD1 immunotherapy between October 2014 and October 2017 considered to be in complete remission. The primary outcome was the occurrence of a relapse during the follow-up. CT-scan and FDG-PET scan had to be performed within a maximum of 2 months of treatment discontinuation. For CT imaging, the response evaluation criteria in solid tumors (RECIST) 1.1 were used and included: progressive disease (PD), SD, PR, complete response (CR). For FDG-PET imaging, the metabolic responses were classified as progressive metabolic disease, stable metabolic disease, residual FDG avidity (RFA), and CMR.

Twenty-six patients were in complete remission after collegial decision. Two patients had a SD on CT-scan and a CMR on FDG-PET scan and none of them relapsed. Ten patients had a PR on CT-scan and a CMR on FDG-PET scan and none of them relapsed. The mean treatment duration to achieve a complete remission was 7 months (3-23). A univariate analysis showed that a RFA assessed on the FDG-PET scan was significantly associated with a relapse.

Most patients with a PR on the CT-scan and a CMR on the FDG-PET scan should be considered with a CR. Our study showed that FDG-PET imaging could play a crucial role in predicting the long-term outcome and help to decide whether treatment should be discontinued.

FDG PET/CT for tumoral and systemic immune response monitoring of advanced melanoma during first-line combination ipilimumab and nivolumab treatment. Iravani, Osman, Weppler, et al.  Eur J Nucl Med Mol Imaging.  2020 April 21.

PURPOSE: We aimed to investigate the role of FDG-PET/CT in monitoring of response and immune-related adverse events (irAEs) following first-line combination-immune checkpoint inhibitor (combination-ICI) therapy for advanced melanoma. 

METHODS: We retrospectively reviewed outcomes in patients who had (1) first-line nivolumab plus ipilimumab; (2) pre- and post-treatment FDG-PET/CT scans (pre-FDG-PET/CT and post-FDG-PET/CT) within 2 and 4 months of starting ICI, respectively; and (3) at least one lesion assessable by PET response criteria in solid tumors (PERCIST). Extracranial response was monitored by 3 monthly FDG-PET/CT. Whole-body metabolic tumor volume (wbMTV) was measured pre- and post-treatment and correlated with outcome. FDG-PET/CT manifestations of irAE were defined as new increased non-tumoral uptake on post-FDG-PET/CT and were correlated with clinical presentation. 

RESULTS: Thirty-one consecutive patients, median age 60 years (range, 30-78), were identified from 2016 to 2018. The median number of combination-ICI cycles to the first post-FDG-PET/CT response assessment was 3 (interquartile range (IQR), 2-4). The best-overall responses were complete metabolic response (CMR) in 25 (80%), partial metabolic response (PMR) in 3 (10%), and progressive metabolic disease (PMD) in 3 (10%) patients. Patients with PMD had significantly higher pre-treatment wbMTV. At a median follow-up of 21.5 months, 26 (84%) patients were alive with median progression-free and overall survival not reached. Secondary progression occurred in 9/31 (29%) patients at a median of 8.2 months, of those majority (78%) was detected by FDG-PET/CT. Of 36 findings on post-FDG-PET/CT suggestive of irAE, 29 (80%) had clinical confirmation. In 3 (7%), the FDG-PET/CT findings preceded clinical presentation. The most common FDG-PET/CT detectable irAEs were endocrinopathies (36%) and enterocolitis (35%). 

CONCLUSION: FDG-PET/CT response evaluation predicts the long-term outcome of patients treated with first-line combination-ICIs. Long-term treatment response monitoring for detection of extracranial secondary progression is feasible by FDG-PET/CT. Beyond response assessment, FDG-PET/CT frequently detects clinically relevant irAEs, which may involve multiple systems contemporaneously or at various time-points and may precede clinical diagnosis.

The value of 18 F-FDG PET/CT for predicting or monitoring immunotherapy response in patients with metastatic melanoma: a systematic review and meta-analysis.  Ayati, Sadeghi, Kiamanesh, et al.  Eur J Nucl Med Mol  July 29, 2020.

Purpose: To investigate the ability of 18F-FDG PET/CT to assess the response of patients with metastatic melanoma to immunotherapy.  
Methods: A comprehensive search of the literature for studies examining the prognostic value of 18F-FDG PET/CT in monitoring the response of patients with metastatic melanoma to immunotherapy was performed. We also screened the references of the selected articles to identify any other relevant studies. Detailed data were extracted and categorized. Comprehensive meta-analysis software was used for analysis.  
Results: Twenty four eligible articles were included in the systematic review. Based on the baseline 18F-FDG PET/CT imaging, the pooled hazard ratios of MTV, SLR, SUV/SULmax, SUV/SULpeak, and TLG for overall survival (OS) were 1.777, 3.425, 0.941, 1.704, and 1.755, respectively. The conventional and modified response assessment criteria exhibited a pooled sensitivity of 64% and 94% and a pooled specificity of 80% and 84%, respectively, for the early 18F-FDG PET/CT scan. On the other hand, based on the late 18F-FDG PET/CT scan, the pooled sensitivity of 67% and 92% and pooled specificity of 77% and 76% were observed for the conventional and modified criteria, respectively. PET-detectable immune-related adverse events (irAEs) were associated with the response to therapy.  
Conclusions: The baseline SUVpeak, MTV, and TLG parameters represent promising predictors of the final response of metastatic melanoma patients to immunotherapy. Modified response assessment criteria are potentially an appropriate method for monitoring immunotherapy. irAEs are also valuable for predicting eventual clinical benefit of treatment.

Performance of Long-Term CT and PET/CT Surveillance for Detection of Distant Recurrence in Patients with Resected Stage IIIA-D Melanoma.  Turner, Dieng, Khanna, et al.  Ann Surg Oncol.  Jan 2021.

Background: Follow-up for patients with resected stage IIIA-D melanoma may include computed tomography (CT) or positron emission tomography (PET)/CT imaging to identify distant metastases. The aim of this study was to evaluate the test performance over follow-up time, of structured 6- and 12-monthly follow-up imaging schedules in these patients.

Methods: We conducted a retrospective analysis of consecutive resected stage IIIA-D melanoma patients from Melanoma Institute Australia (2000-2017). Patients were followed until a confirmed diagnosis of distant metastasis, end of follow-up schedule, or death. Test accuracy was evaluated by cross-classifying the results of the test against a composite reference standard of histopathology, cytology, radiologic imaging, and/or clinical follow-up, and then quantified longitudinally using logistic regression models with random effects.

Results: In total, 1373 imaging tests were performed among 332 patients. Distant metastases were detected in 110 (33%) patients during a median follow-up of 61 months (interquartile range 38-86), and first detected by imaging in 86 (78%) patients. 152 (68%) patients had at least one false-positive result. Sensitivity of the schedule over 5 years was 79% and specificity was 88%. There was no evidence of a significant difference in test performance over follow-up time or by American Joint Committee on Cancer (AJCC) substage. The positive predictive value ranged between 33 and 48% over follow-up time, reflecting a ratio of 1:2 false-positives per true-positive finding.

Conclusions: Regular 6- or 12-monthly surveillance imaging using CT or PET/CT has reasonable and consistent sensitivity and specificity over 5-year follow-up for resected stage IIIA-D melanoma patients. These data are useful when discussing the risks and benefits of long-term follow-up.

For what it's worth.  I think it is clear that for patients with a "partial response" the FDG-PET can provide important clarification.  - c

Intralesionals for melanoma - some new reports

I was a fan of intralesional therapies for melanoma long before they were used with any frequency in real live melanoma peeps! I first posted about Rose Bengal (the name I much prefer to the current PV-10) in 2012!!  Rose Bengal sustains high response rate in Melanoma patients!!!  These days the medications used intralesionally for melanoma patients has grown.  Even this list isn't comprehensive:

CAVATAK - derived from the Coxsackievirus
T-VEC - also called OncoVEX, Imlygic,  or Talimogene Laherparepvec - uses the herpes virus with GM-CSF
PV-10 - derived from Rose Bengal
HF10 - also derived from HSV
SD101 - a TLR9 agonist
IL-2 and IL-12 (tavo) -  are also being used

This link, including an update from June of this year, will give you - A zillion more posts on all things intralesional  Now, there are these ~

False positive FDG uptake in melanoma patients treated with talimogene laherparepvec (T-VEC).  Mulder, Stahlie, Verver, et al.  J Surg Oncol.  Jul 2021.

Talimogene laherparepvec (T-VEC) is a genetically modified herpes simplex virus-1-based oncolytic immunotherapy and has been approved for the local treatment of unresectable (stage IIIB/C and IVM1a) cutaneous melanoma. During T-VEC treatment, tumor response is often evaluated using [18F]2-fluoro-2-deoxy- d-glucose(FDG) positron emission tomography/computed tomography (PET/CT). In a Dutch cohort (n = 173), almost one-third of patients developed new-onset FDG uptake in uninjected locoregional lymph nodes during T-VEC. In 36 out of 53 (68%) patients with new nodal FDG uptake, nuclear medicine physicians classified this FDG uptake as "suspected metastases" without clinical or pathological confirmation in the majority of patients. These false positive results indicate that new-onset FDG uptake in locoregional lymph nodes during T-VEC treatment does not necessarily reflect progressive disease, but may be associated with immune infiltration. In current clinical practice, physicians should be aware of the high false positive rate of FDG uptake during treatment with T-VEC in patients with melanoma. Therefore, pathological examination of lymph node lesions with new FDG uptake is recommended to differentiate between progressive disease and immune infiltration after treatment with T-VEC.

Given the real (and wonderful) possibility of "by-stander response" - ie the positive response in lesions NOT injected when intralesional therapy is used - why oh why would you assume that uptake visible on scans is progression you silly silly radiology peeps???!!!!  Live and learn people!  Live and learn!

Durability of Complete Response to Intralesional Interleukin-2 for In-Transit Melanoma.  Khoury, Knapp, Fyfe, et al.  J Cutan Med Surg.  Jul-Aug 2021.

Background: Intralesional injection of interleukin-2 (IL-2) for in-transit melanoma (ITM) is associated with a high rate of complete response. However, there is a paucity of data on treatment durability and long-term outcomes.

Methods: Consecutive patients with ITM, treated with intralesional IL-2 therapy, at the Tom Baker Cancer Center were identified from April 2009 to August 2019. All patients received at least 4 cycles (every 2 weeks) of IL-2 (5 MIU/mL). Complete response was defined as sustained (ie, 3 months) clinical complete remission of all known in-transit disease.

Results: Sixty-five patients were treated with curative intent for in-transit disease with intralesional IL-2. Complete clinical response was identified in 44.6% (29/65). In this subset of patients, the median number of lesions per patient was 9 (range 1-40). The median total dose of IL-2 was 0.8 mL (IQR 0.4-1.5) per lesion. One patient received isolated limb infusion and 13.8% (4/29) received systemic immunotherapy as part of their initial management. At a median follow-up of 27 months (IQR 16-59), 34.5% (10/29) developed recurrent disease. Of these patients, 50.0% (5/10) presented with synchronous in-transit and distant metastases. The median time to recurrence was 10.5 months (IQR 5.8-16.3).

Conclusion: With long-term follow-up, 65.5% of complete responders have a durable response to intralesional IL-2 therapy. In this cohort of patients, local in-transit recurrence is most likely to occur within 12 months and is often associated with concomitant distant disease.

Treatment of in-transit melanoma metastases using intralesional PV-10.  Thompson, Saw, Dalton, et al.  Melanoma Res.  June 2021.

Melanoma in-transit metastases (ITMs) can sometimes be difficult to manage by surgical excision due to their number, size or location. Treatment by intralesional injection of PV-10, a 10% solution of rose bengal, has been reported to be a simple, safe and effective alternative, but more outcome data are required to confirm its value in the management of ITMs. Two hundred and twenty-six melanoma ITMs in 48 patients were treated with intralesional PV-10 supplied under a special-access scheme. By 8 weeks a complete response in all injected ITMs was achieved in 22 patients (46%) and a partial response in 19 patients (40%). Of 19 patients who had uninjected metastases, 3 (16%) had a response in these. The most common adverse event was transient localised pain in injected tumours. New ITMs developed in 25 patients within 8 weeks, and later in another 8 patients. Repeat injection cycles were given to 21 patients: 13 of these received repeat injection into partially responding or nonresponding tumours, 5 had new ITMs, as well as partially-responding lesions injected, and 3 received injection into new ITMs only. Twenty-two patients received subsequent systemic therapy. At 1 year 37 of the 48 patients were alive, 28 with melanoma, and at 2 years 27 were alive, and 19 with melanoma. Injection of PV-10 was simple and safe and resulted in tumour involution in most patients and sometimes in noninjected tumours. However, many patients developed new lesions; these were treated by further PV-10 injections or with alternative therapies.

T-VEC for stage IIIB-IVM1a melanoma achieves high rates of complete and durable responses and is associated with tumor load: a clinical prediction model.  Stahlie, Franke, Zuur, et al.  Cancer Immunol Immunother.  August 2021.

Background: Talimogene laherparepvec (T-VEC) is a genetically modified herpes simplex type 1 virus and known as an effective oncolytic immunotherapy for injectable cutaneous, subcutaneous and nodal melanoma lesions in stage IIIB-IVM1a patients. This study set out to identify prognostic factors for achieving a complete response that can be used to optimize patient selection for T-VEC monotherapy.

Methods: Patients with stage IIIB-IVM1a melanoma, treated with T-VEC at the Netherlands Cancer Institute between 2016-12 and 2020-01 with a follow-up time greater than 6 months, were included. Data were collected on baseline characteristics, responses and adverse events (AEs). Uni- and multivariable analyses were conducted, and a prediction model was developed to identify prognostic factors associated with CR.

Results: A total of 93 patients were included with a median age of 69 years, median follow-up time was 16.6 months. As best response, 58 patients (62%) had a CR, and the overall response rate was 79%. The durable response rate (objective response lasting greater than 6 months) was 51%. Grade 1-2 AEs occurred in almost every patient. Tumor size, type of metastases, prior treatment with systemic therapy and stage (8Th AJCC) were independent prognostic factors for achieving CR. The prediction model includes the predictors tumor size, type of metastases and number of lesions.

Conclusions: This study shows that intralesional T-VEC monotherapy is able to achieve high complete and durable responses. The prediction model shows that use of T-VEC in patients with less tumor burden is associated with better outcomes, suggesting use earlier in the course of the disease.

Much like every other treatment in the melanoma arsenal, intralesional therapy (no matter the type you choose) is not a 100% cure nirvana.  Still, to my mind, it is a valuable weapon available to melanoma patients with in-transit lesions and as a supplement to Stage III and IV patients being treated simultaneously with systemic therapy.  As ever, those with the lowest tumor burden do best.  And sadly, nobody does the Even Steven clinical trials I want to see, placing similar patients on the various intralesionals - with and without equivalent systemic therapies - and THEN comparing outcomes!!!!  Why not, oh brilliant researchers?  WHY?????

For what it's worth - c

Ipilimumab or ipi/nivo combo after recurrence in patients previously treated with immunotherapy ~

How to treat a melanoma recurrence when you have already been treated with ipi or anti-PD-1 (nivo/Opdivo or pembro/Keytruda) as single agents or the ipi/nivo combo has been a question for sometime now.  From 2017 there were these:

Response to ipi or ipi/nivo after failing anti-PD1 as single agent in Stage IV melanoma

ASCO 2017: Nivo or Ipi/Nivo combo in melanoma after progression on ipi or anti-PD-1

ASCO 2017: ipi plus pembro, ipi after pembro and identifying markers for outcome with pembro for advanced melanoma

There was this in 2020:  How to deal with recurrence on or after anti-PD-1 as adjuvant or treatment for active melanoma disease

And also, this:  After progression on anti-PD1 / anti-PDL1 treatment of melanoma

Now, there are these:

Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: a multicentre, retrospective, cohort study.  Da Silva, Ahmed, Reijers, et al.  Lancet Oncol.  June 2021.

Background: Anti-PD-1 therapy (hereafter referred to as anti-PD-1) induces long-term disease control in approximately 30% of patients with metastatic melanoma; however, two-thirds of patients are resistant and will require further treatment. We aimed to determine the efficacy and safety of ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab) compared with ipilimumab monotherapy in patients who are resistant to anti-PD-(L)1 therapy (hereafter referred to as anti-PD-[L]1).

Methods: This multicentre, retrospective, cohort study, was done at 15 melanoma centres in Australia, Europe, and the USA. We included adult patients (aged greater/= to 18 years) with metastatic melanoma (unresectable stage III and IV), who were resistant to anti-PD-(L)1 (innate or acquired resistance) and who then received either ipilimumab monotherapy or ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab), based on availability of therapies or clinical factors determined by the physician, or both. Tumour response was assessed as per standard of care (CT or PET-CT scans every 3 months). The study endpoints were objective response rate, progression-free survival, overall survival, and safety of ipilimumab compared with ipilimumab plus anti-PD-1.

Findings: We included 355 patients with metastatic melanoma, resistant to anti-PD-(L)1 (nivolumab, pembrolizumab, or atezolizumab), who had been treated with ipilimumab monotherapy (n=162) or ipilimumab plus anti-PD-1 (n=193) between Feb 1, 2011, and Feb 6, 2020. At a median follow-up of 22·1 months, the objective response rate was higher with ipilimumab plus anti-PD-1 (60 of 193 patients) than with ipilimumab monotherapy (21 of 162 patients). Overall survival was longer in the ipilimumab plus anti-PD-1 group (median overall survival 20·4 months) than with ipilimumab monotherapy (8·8 months). Progression-free survival was also longer with ipilimumab plus anti-PD-1 (median 3·0 months) than with ipilimumab (2·6 months). Similar proportions of patients reported grade 3-5 adverse events in both groups (59 [31%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 54 [33%] of 162 patients in the ipilimumab group). The most common grade 3-5 adverse events were diarrhoea or colitis (23 [12%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 33 [20%] of 162 patients in the ipilimumab group) and increased alanine aminotransferase or aspartate aminotransferase (24 [12%] vs 15 [9%]). One death occurred with ipilimumab 26 days after the last treatment: a colon perforation due to immune-related pancolitis.

Interpretation: In patients who are resistant to anti-PD-(L)1, ipilimumab plus anti-PD-1 seemed to yield higher efficacy than ipilimumab with a higher objective response rate, longer progression-free, and longer overall survival, with a similar rate of grade 3-5 toxicity. Ipilimumab plus anti-PD-1 should be favoured over ipilimumab alone as a second-line immunotherapy for these patients with advanced melanoma. 

In this report, it is evident that the ipi/nivo combo did better as follow-up to progression on anti-PD-1 as a single agent, than the response that was provided by ipi alone.

Now, what to do if you took the combo from the start?

Re-induction ipilimumab following acquired resistance to combination ipilimumab and anti-PD-1 therapy.  Hepner, Atkinson, Larkin, et al.  Eur J Cancer.  Aug 2021.

Purpose: Combination immunotherapy with nivolumab and ipilimumab has a high initial response rate in advanced melanoma; however, up to 55% of patients later progress. The efficacy and safety of ipilimumab re-induction in the setting of acquired resistance (AR) to combination immunotherapy is unknown.

Methods: Patients with advanced melanoma who initially achieved a complete response, partial response or sustained stable disease to induction combination immunotherapy then progressed and were reinduced with ipilimumab (alone or in combination with anti-PD-1) and were analysed retrospectively. Demographics, disease characteristics, efficacy and toxicity were examined.

Results: Forty-seven patients were identified from 12 centres. The response rate to reinduction therapy was 12/47 (26%), and disease control rate was 21/47 (45%). Responses appeared more frequent in patients who developed AR after ceasing induction immunotherapy (30% vs. 18%). Time to AR was 11 months. After a median follow-up of 16 months, responders to reinduction had a median progression-free survival of 14 months, and in the whole cohort, the median overall survival from reinduction was 17 months. Twenty-seven (58%) immune-related adverse events (irAEs) were reported; 18 (38%) were grade 3/4, and in 11 of 27 (40%), the same irAE observed during induction therapy recurred.

Conclusions: Reinduction with ipilimumab ± anti-PD-1 has modest clinical activity. Clinicians should be attentive to the risk of irAEs, including recurrence of irAEs that occurred during induction therapy. Future studies are necessary to determine best management after resistance to combination immunotherapy.

This report notes that despite failing the ipi/nivo combo, a repeated course can provide response and disease control.

Here's something to consider if serious adverse reactions have been an impediment to repeating treatment using immunotherapy ~

Low-dose ipilimumab combined with anti-PD-1 immunotherapy in patients with metastatic melanoma following anti-PD-1 treatment failure.  Klee, Kurzhals, Hagelstein, et al.  Melanoma Res. July 2021.

Combined immunotherapy is associated with a significant risk of severe and potentially fatal immune-related adverse events (irAEs). Therefore, we retrospectively analyzed the side profile and efficacy of low-dose ipilimumab (1 mg/kg, IPI1) combined with anti-PD-1 immunotherapy in patients who progressed after anti-PD-1 monotherapy. Nine patients with unresectable stage III or IV melanoma treated with combined low-dose ipilimumab (1 mg/kg, IPI1) and anti-PD-1 immunotherapy, following progression after anti-PD-1 treatment, were identified. Treatment response and irAEs were recorded. Grade 3 irAEs occurred in one-third of patients. Interestingly, there were no grade 4 or 5 irAEs. In fact, four out of the nine patients experienced no irAEs at all. One patient discontinued combined immunotherapy due to immune-related colitis. The mean time to the onset of grade 3 irAEs was 14.3 weeks. The objective response rate was 33.3% and a disease control rate of 66.7% was achieved. Median progression-free survival (PFS) was 5.7 months and median overall survival (OS) was 21.6 months. The median PFS when IPI1 and anti-PD-1 treatment was administered in the second-line setting was not reached, but only 2.8 months when used in subsequent treatment settings. Combined IPI1 and anti-PD-1 immunotherapy was well tolerated. Its use in the third-line or above setting was associated with a significantly poorer prognosis than in the second-line setting. Larger, prospective studies are required to evaluate the safety and efficacy of this dosing regimen following anti-PD-1 treatment failure.

After progressing on anti-PD-1, these patients were treated with a low dose ipi/usual dose nivo combo.  Side effects were decreased and responses were attained.

Hang tough, peeps.  Melanoma doesn't make it easy, but there is hope.  - c

Forever Changed - Quality of Life after Melanoma (and how to help) - Research from 2019 to ASCO 2021

Very few folks really grasp what it is like to LIVE with cancer - unless you are that person.  Granted, if you are lucky, as I am, you have a few of those understanding peeps in your life, but most folks want to move on from the whole experience.  The cancer patient doesn't have that luxury.  Obviously, we cancer peeps approach our existence in different ways.  Some are almost paralyzed by fear of cancer's return.  Some are able to deal with things fairly well until some "symptom"- likely caused by something completely unrelated, crops up - leading to absolute and debilitating certainty that their cancer is back.  Others are undone by follow-up scans and the anxiety awaiting results provokes.  Even the thought of  lovely future events, become almost frightening and worrisome in the life of a cancer patient as we have less certainty of being around to enjoy them than does the average cancer-free person.  While some of us, due to our own personality, the support we have, the approach we take to life (and death), and just simple quirks of fate, deal with our cancerous existence more easily, we ALL face fearful moments.  When dealing with only one cancer diagnosis, albeit Stage IV melanoma, BEFORE I was able to attain systemic treatment of any sort, but AFTER the removal of the upper lobe of one lung and radiation to a brain met, I wrote this:  Looking forward - September 2010  And here, in 2018, NED for melanoma for 8 years, but unaware that in a few short months I will be diagnosed with an incredibly rare Ex-goblet cell adenocarcinoma of the appendix, I penned this:  Where I've been, where I'm going ~ Fractals!    Then, in the midst of chemo for Cancer #2, these were my musings:  Polka dot binding personally produced ~ Possible inspo #SEWFROSTING ~ and Profound Ponderings

That's a smattering of my approach to dealing with MY life with cancer - here's what the data shows:

Health-related quality of life, emotional burden, and neurocognitive function in the first generation of metastatic melanoma survivors treated with pembrolizumab: a longitudinal pilot study.  Rogiers, Leys, DeCremer, et al. Support Care Cancer. 2019 Nov.

The aim of this study was to assess the evolution of health-related quality of Life (HRQoL), emotional burden, and neurocognitive function in the first-generation metastatic melanoma survivors treated with pembrolizumab.

Survivors were defined as patients who achieved a durable remission for at least 6 months after initiating pembrolizumab in a single-center observational study (N = 141). A semi-structured interview was performed at baseline. Neurocognitive computerized testing and patient-reported outcomes were collected at 4 time points to assess HRQoL using the EORTC QLQ-C30 and the HADS to assess anxiety and depression.

Out of 35 eligible patients, 25 were recruited and completed baseline assessment (18 female; median age 58 years [range 28-86]; 24 completed the 1-year follow-up phase. Median time since diagnosis was 30 months (range 12-84); median time since initiation of pembrolizumab was 19 months (range 6-42). At all visits, survivors reported a significantly lower global HRQoL, lower physical, emotional, cognitive, role, and social functioning compared with the European Mean of the healthy population. Fifteen patients (64%) had clinical levels of anxiety/depression at one time point during follow-up. The clinical interview revealed that 12 patients (48%) suffered from Cancer-Related-Post-Traumatic-Stress disorder, of whom 7 (28%) developed transient suicidal ideation, 1 patient made a suicide attempt. Neurocognitive testing revealed cognitive impairment in 8 patients (32%).

Metastatic melanoma survivors, treated successfully with pembrolizumab, are at risk for suffering from emotional distress and neurocognitive impairment with a persistent impact on their HRQOL. Timely detection in order to offer tailored care is indicated.

More than half of the 25 peeps in this study - 30 months post their melanoma diagnosis and 19 months since starting pembro - experienced significant anxiety/depression, almost half suffered from traumatic stress, and more than a quarter pondered suicide, with one attempting.  Not that we needed a study to tell us, but even effective treatment for melanoma leaves many with scars.

Then, there's this:  

Longitudinal associations between coping strategies, locus of control and health-related quality of life in patients with breast cancer or melanoma.  Toscano, Blanchin, Bourdon, et al.  Qual Life Res.  2020 Jan 1.

A diagnosis of breast cancer or melanoma is a traumatic life event that patients have to face. However, their locus-of-control (LOC) beliefs and coping strategies as well as the associations with health-related quality of life (HRQoL) changes over time are still not well known and rarely compared by cancer site.

The objective of this longitudinal study was to assess the association of LOC (Cancer Locus-of-Control Scale) and coping (Brief Cope) changes, with change in HRQoL (EORTC QLQ-C30) over time in newly diagnosed breast cancer and melanoma patients at 1, 6, 12, and 24 month post-diagnosis. Mixed models were used to compare LOC and coping longitudinal changes as well as their associations with HRQoL changes in early-stage breast cancer and melanoma patients.

Overall, 215 breast cancer and 78 melanoma patients participated in the study. At baseline, HRQoL levels were often higher for breast cancer compared to melanoma patients. For breast cancer and melanoma patients, negative coping strategies and perceived control over the course of illness were negatively and positively associated with HRQoL changes, respectively. For breast cancer patients only, emotional coping and internal causal attribution were negatively associated with HRQoL changes. For both cancer sites, living with a partner correlated with worse HRQoL.

Understanding coping strategies and LOC beliefs used by patients soon after their cancer diagnosis and over the course of illness can help identifying psychological and supportive care to modify maladaptive thoughts and beliefs and promote more adaptive behaviors to ultimately improve patients' well-being and HRQoL.

To be honest, not entirely sure what this word salad is saying - other than how folks respond to life after the life changing experience of either breast cancer or melanoma varies and is impacted by many things.  I do think having almost 3 times the number of breast cancer patients than those with melanoma may well skew any comparisons made between the two.

Then, this:

Patient-reported outcomes in melanoma survivors at 1, 3 and 5 years post-diagnosis: a population-based cross-sectional study.  Lisy, Lai-Kwon, Ward, et al. Qual Life Res. 2020 Mar 5.

There is a lack of population-based data describing patient reported outcomes (PROs) in melanoma survivors which could guide the development of interventions and resources. This study assessed overall quality of life (QoL), self-reported symptoms and unmet information needs in melanoma survivors 1, 3 or 5 years post-diagnosis.

A cross-sectional postal survey was conducted in Victoria, Australia, with eligible melanoma survivors identified from a population-based cancer registry. Patient-reported outcome measures included the EuroQoL 5-Dimension 5-Level (EQ-5D-5L), and self-reported symptoms, difficulties and information needs. Associations between demographic, disease and care-related factors and QoL were also assessed.

A total of 476 melanoma survivors participated in the study (response rate 46.5%). Anxiety and depressive symptoms were more prevalent in survivors compared to the general population (30.7% vs 21.6%). Fear of cancer recurrence (48.3%) and fear of cancer spreading (37.8%) were the most commonly reported symptom items, and approximately one in five melanoma survivors had unmet information needs related to psychological aspects of living with melanoma. Recurrent melanoma, living in a nursing home, chronic comorbidities, and melanoma diagnosed at greater than 2 mm thickness were associated with lower QoL.

A large proportion of melanoma survivors reported ongoing quality of life deficits, fear of cancer recurrence, as well as unmet information needs up to 5 years after diagnosis. Patients may benefit from tailored informational resources and interventions that address the psychological aspects of living with and beyond melanoma.

Among these 476 melanoma peeps, the researchers found they were more anxious and depressed than the average Joe.  (Gotta love science!) Almost half feared a cancer recurrence and over a third feared cancer spreading.  One in five felt that they were not coping well and had no support to facilitate improvement in that regard.  Being in a nursing home, having other illnesses or a more vicious melanoma diagnosis made things worse.  Well, duh!

Now, this:

Feasibility and Acceptability of Fear-Less: A Stepped-Care Program to Manage Fear of Cancer Recurrence in People with Metastatic Melanoma.  Lynch, Katona, Jefford, et al.  J Clin Med.  2020 Sept.

Immunotherapies and targeted therapies have revolutionized treatment of metastatic melanoma and improved survival rates. However, survivors treated with novel therapies are vulnerable to high levels of fear of cancer recurrence or progression (FCR). Existing FCR interventions have rarely been trialled in people with advanced cancer. The current study aimed to evaluate the acceptability and feasibility of Fear-Less: a stepped-care model to treat FCR in people with metastatic melanoma treated with immunotherapy or targeted therapy. Sixty-one outpatients with metastatic melanoma were screened using the Fear of Cancer Recurrence Inventory Short Form (FCRI-SF) and Fear of Progression Questionnaire Short Form (FoP-Q-SF). Survivors with subthreshold FCR were stratified to a self-management intervention while those with clinical levels of FCR were provided with an individual therapy, Conquer Fear. Survivor experience surveys and rescreening were administered post-intervention completion. Results indicated that Fear-Less was an acceptable and feasible FCR intervention. Results provided preliminary support for the potential impact of Fear-Less in reducing FCR. Fear-Less is a promising first step in providing an acceptable and feasible stepped-care model to treat FCR in survivors with metastatic disease.

Not clear what the Fear-Less intervention provided, but I would say it is likely that should ANYONE in the cancer care circle provide attention, interest and support to and for the stress cancer and its treatments engender - it would be beneficial.

And finally, this from ASCO and the Wizard:

Association of health-related quality of life (HRQoL) and treatment safety with nivolumab (NIVO) in patients (pts) with resected stage IIIB/C or IV melanoma: Analysis of CheckMate 238 four-year follow-up (FU) data.   Weber, Gogas, Sun, et al.  ASCO 2021.

Background:  In CheckMate 238, NIVO 3 mg/kg vs ipilimumab 10 mg/kg showed significantly longer recurrence-free survival and a lower rate of grade 3–4 treatment-related adverse events (TRAEs) in pts with completely resected stage IIIB/C or IV melanoma. This analysis assessed the association of long-term HRQoL and TRAEs in NIVO-treated pts in this trial.

Methods:  HRQoL was assessed using EORTC QLQ-C30 (global health status [GHS] and physical/emotional functioning) and EQ-5D-3L visual analogue scale (VAS) questionnaires administered after randomization, during 1 y of treatment (wk 5, 7, 11, 17, 25, 37, and 49), at posttreatment FU visits 1 and 2 (FU1 and FU2; 30 and 114 days after last dose), and at survival FU visits up to 4 y after last dose (EQ-5D-3L only). NIVO-treated pts were grouped based on whether they had experienced a grade 3–4 TRAE, any-grade TRAE leading to NIVO discontinuation, or any-grade select (immune-related) TRAE on treatment or up to 100 days after last dose. Longitudinal change from baseline (BL) in scores was assessed for pts with and without TRAEs having patient-reported outcome data at BL and greater than/= to1 post-BL assessment (HRQoL population) using descriptive statistics. QLQ-C30 subscale and VAS changes of 10 and 7, respectively, were considered clinically meaningful.

Results: The HRQoL population comprised 446 of 453 pts randomized to NIVO. EQ-5D-3L assessments were completed by 81% of survivors (263/324) after 4 y post-randomization. Grade 3–4 TRAEs occurred in 17% of NIVO-treated pts (77/446). A slight trend toward deterioration of GHS from BL on treatment was noted, with clinically meaningful deterioration at posttreatment FU1 and FU2. For the VAS, a similar trend on treatment was noted, with a clinically meaningful deterioration after NIVO discontinuation and a return to BL level by the start of survival FU. For pts without grade 3–4 TRAEs, mean change from BL scores remained stable (ie, no clinically meaningful deterioration on treatment or during FU). Any-grade TRAEs led to NIVO discontinuation in 9% of pts (42/446); HRQoL findings were similar to those for pts with grade 3–4 TRAEs. The most common any-grade TRAE was fatigue (35%). No clinically meaningful deterioration in VAS was noted for any select TRAE during FU except for hyperthyroidism (8%), with which deterioration occurred at FU1. EORTC QLQ-C30 physical and emotional functioning results will be presented.

Conclusions: In CheckMate 238, pts with TRAEs showed early HRQoL deterioration after NIVO discontinuation, but HRQoL returned to BL levels with no sustained deterioration during survival FU. Overall, HRQoL was maintained on treatment and over a long-term FU period in pts with resected melanoma receiving adjuvant NIVO. Clinical trial information: NCT02388906.

In this study, not surprisingly, folks felt pretty rough while on treatment, reporting a decreased "global health status".  Folks with side effects had it worse, especially those who had to stop Nivo due to those side effects.  But, overall, this report contends that folks made it back to baseline at a later follow-up.  Hmm, Weber.  Did they though?  First of all, it is important to note that these were (apparently) adjuvant patients - not advanced melanoma patients.  Secondly, there are many studies noting patients try to give their doc the answer they seem to want to hear.  Nobody's fault in any of this.  Just the way the cookie crumbles when doing a qualitative study.

So ~ What did we learn here?  Not much we didn't already know.  Cancer sucks.  Cancer and its treatments cause a great deal of physical distress along with anxiety and depression.  Nobody really knows how much, but it is clear that the more side effects you have, the worse off your health, and the less external support - the more difficult it all becomes.  Sadly, I have no answers.  Other than....

• Do the best you can.
• Know that you are not alone - even though it can feel very much as though you are. Everybody else is struggling to tread water, too!
• Seek out, even though it is ever so hard when struggling, support resources - cancer groups (whether in-person or on-line), social services, help from friends and family.
• Ask your oncologist for psychological support services.  Larger groups often have them in house.  Others can certainly refer you.

If you are a care giver, I'm sure figuring out "what to do" seems unknowable.  There are many resources on-line that give good tips.  These are a couple posts I put together (with links within the last) that you may find helpful - 

What to say and do....and NOT!!...for a cancer FRIEND (not patient)!

ASCO 2017: Friends in need are friends indeed! Here's to the caregivers!!!

Wishing each of you my very best ~ les

ASCO 2021 - NEOadjuvant treatments - immunotherapy vs targeted and nivo plus relatlimab (anti-LAG3)

Having covered adjuvant therapy yesterday, today I turn to NEOadjuvant treatments.  In 2018 I wrote -

"Adjuvant therapy, is when a treatment is given AFTER signs of obvious disease have been removed, usually with surgery.  And we have very good data that adjuvant treatments, both with targeted and immunotherapy, work in melanoma to prevent progression in many of those patients.  After all, that is what the NED Stage IV ratties in my nivo trial proved from 2010 - 2013!!!!  NEO-adjuvant therapy, is when a treatment is given BEFORE melanoma has been removed. "

Here are a zillion Neoadjuvant reports.  Now, there are these:

Pathological response and survival with neoadjuvant therapy in melanoma: a pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC).  Menzies, Amaria, Rozeman, et al.  Nat Med.  Feb 2021.

The association among pathological response, recurrence-free survival (RFS) and overall survival (OS) with neoadjuvant therapy in melanoma remains unclear. In this study, we pooled data from six clinical trials of anti-PD-1-based immunotherapy or BRAF/MEK targeted therapy. In total, 192 patients were included; 141 received immunotherapy (104, combination of ipilimumab and nivolumab; 37, anti-PD-1 monotherapy), and 51 received targeted therapy. A pathological complete response (pCR) occurred in 40% of patients: 47% with targeted therapy and 33% with immunotherapy (43% combination and 20% monotherapy). pCR correlated with improved RFS (pCR 2-year 89% versus no pCR 50%) and OS (pCR 2-year OS 95% versus no pCR 83%). In patients with pCR, near pCR or partial pathological response with immunotherapy, very few relapses were seen (2-year RFS 96%), and, at this writing, no patient has died from melanoma, whereas, even with pCR from targeted therapy, the 2-year RFS was only 79%, and OS was only 91%. Pathological response should be an early surrogate endpoint for clinical trials and a new benchmark for development and approval in melanoma.

Hmmm....  While targeted therapy is almost magical in BRAF positive melanoma peeps for melting away tumors and those responses have proven at times to be durable, that durability can be fickle.  This report (while not necessarily about neoadjuvant administration) is similarly illuminating:

First-line immunotherapy versus targeted therapy in patients with BRAF-mutant advanced melanoma: a real-world analysis.  Pavlick, Zhao, Lee, et al.  Future Oncol. Feb 2021.

Aim: To compare effectiveness of nivolumab + ipilimumab (NIVO + IPI) versus BRAF + MEK inhibitors (BRAFi + MEKi) in patients with BRAF-mutant advanced melanoma in the real-world setting. 

Materials & methods: This study used the Flatiron Health electronic medical record database. Results: After adjusting for differences in baseline characteristics, NIVO + IPI was associated with a 32% reduction in risk of death versus BRAFi + MEKi. At a mean follow-up of 15-16 months, 64% of NIVO + IPI patients and 43% of BRAFi + MEKi patients were alive; subsequent therapy was administered to 33 and 41% of patients, respectively. After first-line NIVO + IPI, 20% of patients died before subsequent therapy, whereas 32% died after first-line BRAFi + MEKi. 

Conclusion: In this real-world study, patients treated with first-line NIVO + IPI showed significant survival benefit versus those receiving first-line BRAFi + MEKi.

Then there's this, from ASCO....

Neoadjuvant and adjuvant nivolumab (nivo) with anti-LAG3 antibody relatlimab (rela) for patients (pts) with resectable clinical stage III melanoma.  Amaria, Postow, Tetzlaff, et al.  ASCO 2021

Background:  Neoadjuvant therapy (NT) for pts with clinical stage III melanoma remains an active area of research interest. Recent NT trial data demonstrates that achieving a pathologic complete response (pCR) correlates with improved relapse-free (RFS) and overall survival (OS). Checkpoint inhibitor (CPI) NT with either high or low dose ipilimumab and nivolumab regimens produces a high pCR rate of 30-45% but with grade 3-4 toxicity rate of 20-90%. In metastatic melanoma (MM), the combination of nivo with rela (anti Lymphocyte Activation Gene-3 antibody) has demonstrated a favorable toxicity profile and responses in both CPI-naïve and refractory MM. We hypothesized that NT with nivo + rela will safely achieve high pCR rates and provide insights into mechanisms of response and resistance to this regimen.

Methods:  We conducted a multi-institutional, investigator-initiated single arm study (NCT02519322) enrolling pts with clinical stage III or oligometastatic stage IV melanoma with RECIST 1.1 measurable, surgically-resectable disease. Pts were enrolled at 2 sites and received nivo 480mg IV with rela 160mg IV on wks 1 and 5. Radiographic response was assessed after completion of NT; surgery was conducted at wk 9 and specimens were assessed for pathologic response per established criteria. Pts received up to 10 additional doses of nivo and rela after surgery, with scans every 3 mo to assess for recurrence. The primary study objective was determination of pCR rate. Secondary objectives included safety, radiographic response by RECIST 1.1, event-free survival (EFS), RFS, and OS analyses. Blood and tissue were collected at baseline, at day 15, day 28, and at surgery for correlative analyses.

Results:  A total of 30 pts (19 males, median age 60) were enrolled with clinical stage IIIB/IIIC/IIID/IV (M1a) in 18/8/2/2 pts, respectively. 29 pts underwent surgery; 1 pt developed distant metastatic disease while on NT. pCR rate was 59% and near pCR ( less than10% viable tumor) was 7% for a major pathologic response (MPR, pCR + near pCR) of 66%. 7% of pts achieved a pPR (10-50% viable tumor) and 27% pNR (greater than/= to 50% viable tumor). RECIST ORR was 57%. With a median follow up of 16.2 mos, the 1-year EFS was 90%, RFS was 93%, and OS was 95%. 1-year RFS for MPR was 100% compared to 80% for non-MPR pts. There were no treatment related gr 3/4 AEs that arose during NT; 26% of pts had a gr 3/4 AE that began during adjuvant treatment.

Conclusions:  Neoadjuvant and adjuvant treatment with nivo and rela achieved high pCR and MPR rates with a favorable toxicity profile in the neoadjuvant and adjuvant settings. Pts with MPR had improved outcomes compared to non-MPR pts. Translational studies to discern mechanisms of response and resistance to this combination are underway. Clinical trial information: NCT02519322.

Perhaps neoadjuvant care will become the way of the future.  Thanks ratties.

best - c

ASCO 2021 - Outcomes of treatments on advanced disease - Reasons for HOPE!!!!!

 As disheartening as it can be to experience treatment that does not do all that we need it to or have dear ones who do not respond to current melanoma treatments - therapies for melanoma have come a long way, baby!!!!  Not only are more folks than ever before responding to therapy - these responses are proving durable!  Here are some outcome studies ~

Five-year overall survival from the anti-PD1 brain collaboration (ABC Study): Randomized phase 2 study of nivolumab (nivo) or nivo+ipilimumab (ipi) in patients (pts) with melanoma brain metastases (mets).  Georgina V. Long, Victoria Atkinson, Serigne Lo, et al.  ASCO 2021.

Background:  Preliminary data from the ABC (76 pts) and CheckMate 204 (94 pts) trials showed that nivo and nivo+ipi have activity in active melanoma brain metastases, with durable responses in a subset of pts. Here, we report updated 5-yr data from all pts enrolled on the ABC trial (NCT02374242).

Methods:  This open-label ph2 trial enrolled 3 cohorts of pts with active melanoma brain mets naïve to anti-PD1/PDL1/PDL2/CTLA4 from Nov 2014-Apr 2017. Pts with asymptomatic brain mets with no prior local brain therapy were randomised to cohort A (nivo 1mg/kg + ipi 3mg/kg, Q3Wx4, then nivo 3mg/kg Q2W) or cohort B (nivo 3mg/kg Q2W). Cohort C (nivo 3mg/kg Q2W) had brain mets i) that failed local therapy, ii) with neuro symptoms and/or iii) with leptomeningeal disease. Prior BRAF inhibitor (BRAFi) was allowed. The primary endpoint was best intracranial response (ICR) ≥wk12. Key secondary endpoints were IC PFS, overall PFS, OS, & safety.

Results: A total of 76 pts (med f/u 54 mo) were enrolled; median age 59y, 78% male. For cohorts A, B and C: elevated LDH 51%, 58% and 19%; V600BRAF 54%, 56% and 81%; prior BRAFi 23%, 24%, 75%. Efficacy and toxicity are shown in the table. There were no treatment-related deaths. 1/17 deaths in cohort A & 4/16 in cohort B were due to IC progression only.

Conclusions:  Nivo monotherapy and ipi+nivo are active in melanoma brain mets, with durable responses in the majority of patients who received ipi+nivo upfront. A study of upfront ipi+nivo+/-SRS is underway (NCT03340129).Clinical trial information: NCT02374242.

My takeaway - Immunotherapy works for brain mets!  BUT - most folks need the combo!!!!

As was mentioned briefly in yesterday's post - the ipi/nivo combo can be a rough road in regard to side effects and a good 40% of patients cannot tolerate all of the approved doses.  However, as far back ASCO 2016 we knew that folks who had to stop therapy early due to side effects, responded about as well as those who completed all doses:  ASCO 2016 - Nivo plus ipi, CheckMate 069 trial....18 month OS similar even if you stop meds due to side effects!!!  This study wanted to see if those responses were durable ~

Survival outcomes associated with fewer combination ipilimumab/nivolumab doses in advanced-stage melanoma.  Ma, Sun, Sitto, et al.  ASCO 2021.

Background:  Standard combination ipilimumab/nivolumab (I/N) is given as 4 induction doses for advanced stage melanoma. While many patients receive less than 4 doses due to treatment-related toxicities, it is unclear if fewer doses of I/N may still provide long term clinical benefit. Our aim is to determine if response assessment after 1 or 2 doses of I/N can predict long-term survival and if fewer doses of I/N can achieve similar survival outcomes.

Methods:  We performed a single-center, retrospective analysis on a cohort of patients with metastatic or unresectable melanoma from 2012 to 2020 who were treated with standard I/N. Cox regression of progression free survival (PFS) and overall survival (OS) models were performed to assess the relationship between response assessment after 1 or 2 doses of I/N and risk of progression and/or death. Clinical benefit response (CBR) was assessed, defined as SD (stable disease) + PR (partial response) + CR (complete response) by imaging or physical examination. Among patients who achieved a CBR after 1 or 2 doses of I/N, a multivariable Cox regression of survival was used to compare 3 or 4 vs 1 or 2 doses of I/N adjusted by age, gender, pre-treatment LDH level, BRAF mutation status, primary melanoma site, time to initial assessment, brain metastasis, and liver metastasis.

Results:  199 patients were identified and considered evaluable in our study. Median follow up was 28.8 months. Patients with CBR after 1 dose of I/N had improved PFS and OS compared to progressive disease (PD). Patients with CBR (vs PD) after 2 doses of I/N also had improved PFS and OS. The survival risk comparing 3 or 4 vs 1 or 2 doses of I/N were HR 0.82 for PFS and HR 0.56 for OS.

Conclusions:  Clinical benefit response (CBR) after 1 or 2 doses of I/N may be predictive of long-term survival in advanced stage melanoma. Patients who have CBR after 1 or 2 doses of I/N may achieve a similar survival benefit with fewer doses of I/N. Longer follow up and prospective studies are warranted to validate our findings.

Per this report, it looks as though those who showed benefit to therapy early, did indeed have similar survival, even when they took fewer that the 4 recommended combo doses!

This study looked at the characteristics of peeps who lived 5 years past immunotherapy for melanoma ~

Characteristics and probability of survival for patients with advanced melanoma who live five or more years after initial treatment with immune checkpoint blockade (ICB).  Loo, Goldman, Panageas, …Chapman…Wolchok…Postow, et al.  ASCO 2021.

Methods:  We retrospectively reviewed all patients treated at Memorial Sloan Kettering for unresectable stage III/IV melanoma who survived at least five years following their first dose of ICB (N = 151). Demographics, disease characteristics, and nature of progression were examined. Overall survival (OS) was calculated from 5 years post-ICB. Time to Treatment failure (TTF) was calculated conditionally from 5 years out until next therapy, progression, or death.

Results:  Of the 151 long-term survivors, median age at first ICB treatment was 62 years (range 22-83), with 101 (66.9%) male and 50 (33.1%) female patients. Stage at first ICB treatment was unresectable stage III (26, 17.2%), M1a (21,13.9%), M1b (39, 25.8%), M1c (52, 34.4%), M1d (13, 8.6%). Melanoma subtype was cutaneous (122, 80.8%), unknown primary (24, 15.9%), mucosal (3, 2%), and acral (2, 1.3%). First ICB was ipi (108, 71.5%), PD-1 (nivo or pembro) (5, 3.3%), and nivo+ipi (37, 24.5%). The best overall response to first ICB was CR (76, 50.3%), PR (27, 17.9%), SD (16, 10.6%) and PD (32, 21.2%). Of the patients who progressed after initial ICB, 38 received subsequent systemic treatment as follows: PD-(L)1 in 20 (53%), BRAF ± MEK in 9 (23.7%), ipi in 7 (18.4%), and chemotherapy in 2 (5.3%). Median duration of follow-up among survivors (N = 138) was 93 months (range 60-192). From 5 years post-ICB, 85% (95% CI: 73-92%) survived an additional 5 years. In those who made it to 5 years without treatment failure (N = 72), the probability of remaining failure-free was 92% (95% CI: 86-99%) at 7 years. Of the 151 patients, only 4 patients (2.6%) experienced disease progression after 5 years. Three patients had radiographic or pathologic disease progression in the lymph nodes and one in the subcutaneous tissue. No patients progressed in the lungs, visceral organs, or CNS after 5 years. At time of analysis, 13 (8.6%) patients died after 5 years post ICB, none died of progressive melanoma. 6 patients died of unknown causes, 2 died of other causes, and 5 died of other non-melanoma cancer-related causes.

Conclusions:  Patients who survive five years after their initial immunotherapy have excellent overall survival and treatment failure-free survival. Given the anxiety surrounding survivorship and late progression, long-term survivors should be reassured of their excellent prognosis. These data suggest that aggressive follow-up schedules and imaging of melanoma patients after 5 years of survival may not be required.

WHOOP!  WHOOP!!!  The C-word (NO!  Not cancer!  CURE!!) was not used, but this data on peeps 5 years out who may no longer need scans to follow up and can carry on with their lives is AWESOME!  On a personal note, Weber let me off the hook for continued follow-up for melanoma at 8 years post my Stage IV diagnosis. I am currently 11 years out.

This study looked at peeps treated with nivo alone vs the ipi/nivo combo.  Now we are blessed to look at 6.5 year outcomes. These reports would not exist without the lives and dedication of all the ratties; and sometimes a special mouse!!!  Thanks, Edster!!!!

CheckMate 067: 6.5-year outcomes in patients (pts) with advanced melanoma. Wolchok, Chiarion-Sileni, Gonzalez, et al.  ASCO 2021.

Background: In the phase 3 CheckMate 067 trial, a durable and sustained clinical benefit was achieved with nivolumab (NIVO) + ipilimumab (IPI) and NIVO alone vs IPI at 5-y of follow-up (overall survival [OS] and progression-free survival [PFS] rates: 52%, 44%, 26% and 36%, 29%, 8%, respectively). Here we report 6.5-y efficacy and safety outcomes.

Methods:  Eligible pts with previously untreated unresectable stage III or IV melanoma were randomly assigned in a 1:1:1 ratio and stratified by PD-L1 status, BRAF mutation status, and metastasis stage. Pts received NIVO 1 mg/kg + IPI 3 mg/kg for 4 doses Q3W followed by NIVO 3 mg/kg Q2W (n = 314), NIVO 3 mg/kg Q2W + placebo (n = 316), or IPI 3 mg/kg Q3W for 4 doses + placebo (n = 315) until progression or unacceptable toxicity. Co-primary endpoints were PFS and OS with NIVO + IPI or NIVO vs IPI. Secondary endpoints included objective response rate (ORR), descriptive efficacy assessments of NIVO + IPI vs NIVO alone, and safety.

Results:  With a minimum follow-up of 6.5 y, median OS was 72.1 mo with NIVO + IPI, 36.9 mo with NIVO, and 19.9 mo with IPI (table). Median time from randomization to subsequent systemic therapy was not reached with NIVO + IPI, 25.2 mo with NIVO, and 8.0 mo with IPI; 36%, 49%, and 66% of pts, respectively, received any subsequent systemic therapy. Median treatment-free interval (which excluded pts who discontinued follow-up prior to initiation of subsequent systemic therapy) was 27.6 mo (range, 0–83.0), 2.3 mo (range, 0.2–81.6), and 1.9 mo (range, 0.1–81.9) with NIVO + IPI, NIVO, and IPI, respectively. Of the pts alive and in follow-up, 112/138 (81%; NIVO + IPI), 84/114 (74%; NIVO), and 27/63 (43%; IPI) were off treatment and never received subsequent systemic therapy; 7, 8, and 0 pts, respectively, were still on treatment. Grade 3/4 treatment-related adverse events were reported in 59% of NIVO + IPI-treated pts, 24% of NIVO-treated pts, and 28% of IPI-treated pts. Since the 5-y analysis, no new safety signals were observed and no additional treatment-related deaths occurred.

Conclusions:  This 6.5-y analysis represents the longest follow-up from a phase 3 melanoma trial in the modern checkpoint inhibitor combination therapy and targeted therapy era. The results show durable improved outcomes with NIVO + IPI and NIVO vs IPI in pts with advanced melanoma. We observed improvement in OS, PFS, and ORR with NIVO + IPI over NIVO alone. Clinical trial information: NCT01844505.

My takeaway - AGAIN - though nivo alone works for many (look at me!!) - BUT - data shows responses and durability were better with the ipi/nivo combo.  Way to rock it out, ratties!!  Thanks, dear Ed!

Finally, a non-ASCO report from earlier this year looking at folks who chose to stop anti-PD-1 monotherapy with nivo (Opdivo) or pembro (Keytruda) at 1 year of therapy ~

Real-world experience with elective discontinuation of PD-1 inhibitors at 1 year in patients with metastatic melanoma.  Pokorny, McPherson, Haaland, et al.  J Immunother Cancer.  Jan 2021.

Background: Randomized trials evaluating programmed cell death protein 1 (PD-1) inhibitors in metastatic melanoma either permitted treatment for 2 years (pembrolizumab) or more (nivolumab). The optimal duration of therapy is currently unknown due to limited data, and shorter therapies may be effective.

Methods: Data of patients with metastatic cutaneous melanoma treated with single-agent PD-1 inhibitors at Huntsman Cancer Institute from January 1, 2015, to December 31, 2018, was reviewed to identify a continuous series of patients who made the joint decision with their provider to electively discontinue therapy at 1 year (greater than 6 months and less than 18 months) in the setting of ongoing treatment response or disease stability. Patients were excluded if they received PD-1 inhibitors with other systemic therapy, had prior exposure to PD-1 therapy, or discontinued treatment due to disease progression or immune-related adverse event. Best objective response (BOR) per RECIST V.1.1 at treatment discontinuation, progression-free survival (PFS), and retreatment characteristics was analyzed.

Results: Of 480 patients who received PD-1 inhibitors, 52 met the inclusion criteria. The median treatment duration from first to the last dose was 11.1 months (95% CI 10.5 to 11.4). BOR was complete response in 13 (25%), partial response in 28 (53.8%), and stable disease in 11 (21.2%) patients. After a median follow-up of 20.5 months (range 3-49.2) from treatment discontinuation, 39 (75%) patients remained without disease progression, while 13 (25%) had progression (median PFS 3.9 months; range 0.7-30.9). On multivariable analysis, younger age, history of brain metastasis, and higher lactate dehydrogenase at the time of anti-PD-1 discontinuation were associated with recurrence. Patients with recurrent melanoma were managed with localized treatment, anti-PD-1 therapies, and BRAF-MEK inhibitors. All patients except one were alive at data cutoff.

Conclusion: In this large real-world, observational cohort study, the majority of patients with metastatic melanoma after 1 year of anti-PD-1 therapy remained without progression on long-term follow-up. The risk of disease progression even in patients with residual disease on imaging was low. After prospective validation, elective PD-1 discontinuation at 1 year may reduce financial and immunotherapy-related toxicity without sacrificing outcomes.

In my 2010, nivo as a single agent, phase 1 study, we took nivo for 2 1/2 years on a rather different schedule than is utilized currently (every 2 weeks for 6 months, then every 3 months for 2 years) and at dosages of 1mg/kg (my cohort), 3 mg/kg, and 10 mg/kg.  The 3mg/kg dosage is basically what is used today.  Still, even with all that, Weber often said that he felt we were treated too long and explained that while a certain amount of drug would be helpful, beyond that, benefit was nil and the risk of side effects was increased.  Today - whether we are looking at anti-PD-1 as a single agent or the ipi/nivo combo - researchers are still trying to figure out exactly what that "certain amount" is.  It is likely that the answer may vary person to person.  As this study pointed out, the ratties who elected to stop therapy at one year had experienced treatment response or stable disease.  Clearly, that is an important factor.  Additionally, in this rather small study of 52 patients, recurrence was associated with those who were younger, had a history of brain mets and elevated LDH when therapy ceased.  Interesting, in that I was 39 at diagnosis and 46 with brain mets at the start of my trial.  However, I took nivo for 2 1/2 years, never had an elevated LDH and have yet to have a melanoma recurrence.  So many variables.  So many different peeps.  It is a hard road to walk, much less to predict.

Hang tough, guys.  There is hope! - c