Circulating tumor DNA to help differentiate true progression of melanoma vs pseudoprogression in patients treated with anti-PD-1

I've been yelling for some time about the need to develop, refine and put into practice valid, reliable blood assays....whether they are measuring circulating DNA, tumor cells, various other tumor makers, white blood cells, any other floating bits and bobs...in order to diagnosis melanoma, determine the most effective treatment, and recognize progression and/or effectiveness of that treatment.  Here is a link to a zillion of those reports/rants:  Blood assays, tumor markers, circulating DNA, you name it!!!! 

In fact, the report below is a follow-up report and specific look at pseudoprogression from this study:  2017: Circulating DNA predicts response to anti-PD1

Now, there's this -

Association Between Circulating Tumor DNA and Pseudoprogression in Patients With Metastatic Melanoma Treated With Anti-Programmed Cell Death 1 Antibodies.Lee, Long, Menzies, et al. JAMA Oncol. 2018 Feb 8.  

Longitudinal circulating tumor DNA (ctDNA) has been shown to predict response and survival in patients with metastatic melanoma treated with anti-programmed cell death 1 (PD-1) antibodies. Pseudoprogression, defined as radiologic finding of disease progression prior to response, has been a challenge to clinicians.

To establish whether ctDNA at baseline and up to week 12 of treatment can differentiate between the radiologic findings of pseudoprogression and true progression in patients with metastatic melanoma.

This explorative biomarker study examined circulating BRAF and NRAS mutations in a cohort of 125 patients with melanoma receiving PD-1 antibodies alone or in combination with ipilimumab between July 3, 2014, and May 24, 2016. Pseudoprogression was defined retrospectively as radiologic progression not confirmed as progressive disease at the next radiologic assessment. Plasma samples of ctDNA at baseline and while receiving treatment were taken for analysis prospectively over the first 12 weeks of treatment. Favorable ctDNA profile (undetectable ctDNA at baseline or detectable ctDNA at baseline followed by greater than 10-fold decrease) and unfavorable ctDNA profile (detectable ctDNA at baseline that remained stable or increased) were correlated with response and prognosis.

Early differentiation of pseudoprogression from true progression using longitudinal ctDNA profile.

According to guidelines by Response Evaluation Criteria in Solid Tumors (RECIST), progressive disease occurred in 29 of the 125 patients (23.2%). Of the 29 patients, 17 (59%) were 65 years or younger, 18 (62%) were men, 9 (31%) had pseudoprogression, and 20 (69%) had true progression. Of the 9 patients (7%) with confirmed pseudoprogression, all patients had a favorable ctDNA profile. At a median follow-up of 110 weeks, 7 of 9 patients (78%) were alive. All but 2 patients with true progression had an unfavorable ctDNA profile. Sensitivity of ctDNA for predicting pseudoprogression was 90% and specificity was 100%. The 1-year survival for patients with RECIST-defined progressive disease and favorable ctDNA was 82% vs 39% for unfavorable ctDNA. Overall survival was longer in patients with a partial response (54 of 125 patients [43%]) compared with patients with progressive disease and a favorable ctDNA profile (11 of 125 patients [9%]).

The results demonstrate that ctDNA profiles can accurately differentiate pseudoprogression from true progression of disease in patients with melanoma treated with PD-1 antibodies. Results of this blood test performed at regular intervals during systemic treatment reflect tumor biology and have potential as a powerful biomarker to predict long-term response and survival.

Here researchers looked at 125 melanoma patients with BRAF and NRAS mutations treated with anti-PD-1 alone or in combination with ipi between July 2014 and May 2016.  They drew their blood before and during the first 12 weeks of their treatment and correlated those findings with the patient's response and prognosis.  Per the RECIST scale, progressive disease occurred in 29 of the 125.  9 had pseudoprogression and 20 had real progression.  "All but 2 of the patients with true progression had an unfavorable ctDNA profile.  Sensitivity of ctDNA for predicting pseudoprogression was 90% and specificity was 100%."  The 1 year survival for the folks with RECIST defined progression but WITH the favorable blood test ctDNA was 82%, while for folks with an unfavorable ctDNA it was only 39%.  "The results demonstrate that ctDNA profiles can accurately differentiate pseudoprogression from true progression of disease in patients with melanoma treated with PD-1 antibodies."

I think we've yammered about this stuff enough.  Consistent, available, defined blood assays need to be made readily available for melanoma patients!!!! C'mon man!!!! - c

ASCO 2015: Pembrolizumab (Keytruda) - characteristics predictive of response, atypical responses, and effect on brain mets so far....study still enrolling!

Clinical characteristics predictive of response to pembrolizumab in advanced melanoma.  J Clin Oncol 33, 2015.  Tsai, Loo, Khurar, Daud, et al.

Advanced melanoma patients (110) from 12/2011 - 10/2013, were given Pembro in 1 of 3 dosing patterns:  2mg/kgq3wk, 10q3wk, or 10q2wks.  In this set, overall response rate was 40%.  Factors that correlated with significantly higher overall response were:  LDH at or below normal (ORR = 52%), no previous ipi (48%), lung mets (52.8%).  Patient with liver mets had a worse response (ORR = 18%) as did those with liver and lung mets (31%).  Conclusion:  Normal LDH, no prior ipi, and lung mets correlated with better response to pembro.  Correlations were observed regardless of BRAF status, presence of brain mets, or site of primary (cutaneous vs uveal).

Atypical patterns of response in patients with metastatic melanoma treated with pembrolizumab.  J Clin Oncol 33, 2015.  Wolchok, Hamid, Ribas, Robert, Weber, Hodi, et al.

Immune-related response criteria were developed to better characterize the atypical response patterns observed with ipi.  Previously we showed that 7.2% of melanoma patients treated with the anti-PD1 monoclonal antibody pembro also demonstrate atypical response patterns and that immune-related response criteria (irRC) may better represent the clinical benefit of pembro than conventional RECIST.  Patients were given pembro at 2mg/kg q 3 wks, 10mg/kg q 3 wks, or 10mg/kg q 2 wks with imaging done q 12wks.  Early pseudoprogression was defined as more than 25% increase in tumor burden at first assessment that was not confirmed as progressive disease at the next assessment performed about 4 wks later.  Delayed pseudoprogression was defined as more than 25% increase in tumor burden at any point after the first assessment, followed by non-progressive disease at the next assessment.  Results:  655 patients.  327 had more than 28 wk f/u by imaging at the time of analysis and were assessed for atypical responses.  Overall, 29 (8.9%) patients experienced atypical response.  Early pseudoprogression was observed in 15 (4%) Late pseudoprogression was observed in 14 patients.  In the 592 patients who survived more than 12 wks, 331 (56%) had best overall response of non-progressive disease per RECIST and irRC.  177 (30%) had progressive disease per both criteria.  84 (14%) was progressive disease per RECIST by non-progressive disease per irRC. CONCLUSION:  Results of this expanded analysis are consistent with previous reports suggesting that pembro may result in atypical response patterns and that conventional response criteria may underestimate the therapeutic benefit. 

Safety and activity of pembrolizumab in melanoma patients with untreated brain metastases.
J Clin Oncol 33, 2015.  Kluger, Goldberg, Sznol, Chiang, et al.

Brain mets develop in 40% of metastatic melanoma patients.  Untreated brain mets are excluded from most clinical trials. Prior trials of metastatic melanoma show treatment with pembro produced a response rate of more than 30%.  A phase II study was started in patients with previously untreated or progressing melanoma brain mets (recruitment is ongoing).  Patients with brain mets from melanoma or non-small cell lung cancer are accepted if they have at least 1 asymptomatic 5-20mm brain met not requiring immediate local therapy or systemic steriods, and at least 1 brain met amenable to biopsy or resection.  Prior PD-1/PD-L1 are excluded.  Pembro is given 10mg/kg q 2 wks. Brain MRI is done q 4 wks and restaging is done q 8 wks.  RESULTS thus far:  Between April and December of 2014, 17 patients were accrued.  6 had BRAF mutations.  10 had previously received ipi.  5 were unevaluable for brain met response due to: rapid progression of disease in the body (3) and intralesional hemorrhage (1) and 1 patient was too early in treatment.  Of 12 evaluable patients:  brain met partial responses were observed in 3 patients (1 with prior ipi), stable disease was found in 2, progressive disease in 7 (2 with a mixed response and 1 with progressive disease by imaging but with pseudoprogression on histology). Brain met responses are ongoing at 7+, 6+, and 3+ months.  One complete response and 3 partial responses were observed in extra-cerebral metastatic disease, 3 of these 4 with concordant brain met response.  The only grade 3 adverse event from pembro was liver function abnormalities.  2 patients had seizures, 1 from perilesional edema, 1 from tumor growth.  They were treated with anti-convulsants and transient use of steroids.  

Here is the link to the study...as noted accrual is ongoing:  Pembro for brain mets

No corticosteroid treatment for symptomatic disease allowed, though low dose replacement therapy is.  No leptomeningeal or autoimmune disease allowed.  No other concurrent treatments.  No radiotherapy for 14 days prior.  Yale is only recruiting site listed.

For what it's worth! Wishing you all my best. - c  

ASCO 2016 - Using amount of progression as marker of response and OS with anti-PD1

Immune-related tumor response dynamics as a marker for survival and treatment benefit during PD-1 inhibitor therapy.  ASCO 2016.  #9521.  J Clin Oncol 34, 2016.    Nishino, Giobbie-Hurder, Bailey, Hodi, et al.

PD-1 inhibitors are promising anti-cancer agents and are associated with unique immune-related response patterns. We characterized patterns of tumor response dynamics on CT scans during PD-1 inhibitor therapy and investigated the association with overall survival (OS) in advanced melanoma patients (pts). Methods: Forty-nine advanced melanoma pts (22 males; median age: 55) treated with single-agent pembrolizumab at DFCI were retrospectively studied. Baseline and all follow-up CT during therapy were reviewed to quantify tumor burden using irRECIST, which uses unidimensional measurements and includes new lesions in tumor burden [Clin Cancer Res. 2013;19:3936-43]. Association between OS and tumor burden dynamics was studied. Results: Tumor burden change at best overall response ranged from -100% to 357% (median:-11%). Response rate was 41% . Spiderplot showed 3 distinct patterns of tumor response dynamics: A) tumor burden less than 20% increase from baseline throughout therapy (n = 27, 55%); B) tumor burden greater than/= to, 20% increase from baseline without subsequent response (n = 19, 39%); and C) pseudoprogression with initial tumor burden increase ( less than/= to, 20%) and subsequent response (n = 3, 6%). Pseudoprogressors were younger than others (median age: 40 vs. 56), and achieved response after irPD was confirmed on 2 consecutive scans. Using a 3-month landmark analysis, pts with less than 20% tumor burden increase from baseline at 3 months had longer OS than pts with greater than/=to 20% increase (12-month OS rate: 78 vs 51%). In extended Cox models, pts with < 20% tumor burden increase during therapy had significantly reduced hazards of death. Conclusions: Three distinct patterns of tumor response dynamics were noted during pembrolizumab therapy. Pseudoprogressors achieved response after experiencing confirmed irPD, indicating a limitation of the current strategy for immune-related response evaluation. Tumor burden less than 20% increase from baseline on follow-up CT scans was associated with longer OS, proposing a practical marker for survival and treatment benefit of PD-1 inhibitor therapy.

My take:

So....there are three patterns of response.  

1.  Tumor burden never increased more than 20% during treatment.

2.  Tumor burden that did increase, but no more than 20%, with no further improvement.

3.  Tumor burden that did increase, but no more than 20%, with subsequent improvement. (pseudoprogression...about 6% of patients) 

Early in treatment, within 3 months, if your tumor is essentially stable, or better, your overall survival is better.  If your tumor burden increases more than 20%....chances of response are unlikely.  Though there is the 5-6% of folks who demonstrate 'pseudoprogression' and later DO respond...however, this study points out that the amount of growth remains at a 20%, or less, increase.  Note:  This portion of responders with pseudoprogression at 5-6% is consistent with prior studies.

Clear as mud, right?  love, c

Radiological evaluation of response to melanoma treatments

Another reason liquid assays (as discussed here last month:  Blood tests to diagnose, check response to therapy, and use as follow-up in melanoma! ) would be so helpful:

Patterns of response to anti-PD-1 treatment: an exploratory comparison of four radiological response criteria and associations with overall survival in metastatic melanoma patients.  Khoja, Kibiro, Metser, et al. Br J Cancer. 2016 Oct 4.  

Radiological assessment of response to checkpoint inhibitors remains imperfect. We evaluated individual lesion and inter-patient response by response evaluation (RECIST) 1.1, immune-related response criteria (irRC), CHOI and modified CHOI (mCHOI) and correlated response with overall survival (OS). Thirty-seven patients with 567 measurable lesions treated with pembrolizumab in the Keynote 001 trial were studied. Association of response with OS was determined.  Response varied according to site; lung lesions had the highest rate of complete response (69 out of 163 (42%) vs other sites 71 out of 404 (18%). Delayed response post first scan was seen in 2 out of 37 (5%) deemed progressive (PD) by RECIST and 2 out of 14 (14%) deemed PD by irRC. Modified CHOI criteria showed response of 38% (14 out of 37). Change in tumour size and density on first follow-up assessment was associated with OS with each 1000 mm² increase in tumour size from baseline increasing the hazard of dying by 25.9%.  Response defined by any criteria had superior OS. Response by any criterion was prognostic. Novel patterns of response and changes on treatment in tumour density suggest complex anti-tumour responses to immunotherapy.  

Then there is this report on using ultrasound to determine progression vs pseudo progression ~
 
Ultrasonographic findings can identify 'pseudoprogression' under nivolumab therapy.   Imafuku, Hata, Kitamura, et al.  Br J Dermatol. 2016 Nov 22. 

'Pseudoprogression' is often seen in patients with melanomas who are treated with immune-checkpoint inhibitors such as nivolumab or ipilimumab. We sometimes evaluate metastatic lesions by imaging tests such as CT or PET-CT. 'Pseudoprogression' usually occurs upon the initial administration, which may make it difficult for the physician to determine the disease condition. In our two cases of metastatic melanoma treated with nivolumab (anti-PD-1 antibody), we examined the ultrasonography (US) of target lesions that could be accessed from the body surface, such as those of the regional lymph node or subcutaneous metastasis. In both cases, the US revealed a lesion approximately 10% greater in size after 40-50 days of nivolumab administration, even though the blood flow inside the tumour was reduced by about 20% within 50 days. From about 100 days after blood flow reduction was detected by US, the tumours began to decrease in size. However, contrast CT was unable to detect the association between tumour size and tumour blood flow. The present cases suggest that US could be a powerful tool for differentiating between 'pseudoprogression' and real progressive disease in patients treated with cancer immunotherapies such as those involving immune-checkpoint inhibitors. The misdiagnosis of progressive disease can lead to unnecessary alternations in the current treatment. Therefore, the US findings in our study could be clinically useful and educational for physicians.  

Good data to know when depending on radiology studies as evaluation of status and progression.  But wouldn't it be nice to just do a blood draw????  At least some of the time???? - c

Melanoma big dogs review results of pts treated with Pembro = Don't stop too soon!!!

I've posted it a zillion times from all sorts of articles and webinars ~ when dealing with immunotherapy... 'Be patient with the patient!'...(from the webinar by Weber and Agarwala).  Repeatedly we've been warned that "progression" and "pseudoprogression" early on has to be evaluated with a grain of salt...rather than considering the measure ineffective and  yanking patients off their therapy as one fellow rattie was in my Nivo trial back in 2010 before we learned better.  (Though, if you've forgotten....while Weber was looking for another treatment for him...he started to improve!!!!  And continued to do so....with no further treatment.)  Folks treated with various immunotherapies, and combo's of same, have had side effects that rendered continuation of such treatment impossible.  Yet....they continued to respond.  Here a cadre of melanoma big dogs look at the results of 655 patients treated with pembro and tell us that as many as 15% of those treated could have had their treatment effect disregarded if old time evaluative criteria continue to be utilized.....

Evaluation of Immune-Related Response Criteria and RECIST v1.1 in Patients With Advanced Melanoma Treated With Pembrolizumab.  Hodi, Weber, Daud, Hamid, Patnaik, Ribas, Wolchok, et al.  J Clin Oncol. 2016 Mar 7.

"We evaluated atypical response patterns and the relationship between overall survival and best overall response measured per immune-related response criteria (irRC) and Response Evaluation Criteria in Solid Tumors in patients with advanced melanoma treated with pembrolizumab in the phase Ib KEYNOTE-001 study.

Patients received pembrolizumab 2 or 10 mg/kg every 2 weeks or every 3 weeks. Atypical responses were identified by using centrally assessed irRC data in patients with greater than/= 28 weeks of imaging. Pseudoprogression was defined as greater than/= 25% increase in tumor burden at week 12 (early) or any assessment after week 12 (delayed) that was not confirmed as progressive disease at next assessment. Of the 655 patients with melanoma enrolled, 327 had greater than/= 28 weeks of imaging follow-up. Twenty-four (7%) of these 327 patients had atypical responses (15 [5%] with early pseudoprogression and nine [3%] with delayed pseudoprogression). Of the 592 patients who survived greater than/= 12 weeks, 84 (14%) experienced progressive disease per RECIST v1.1 but nonprogressive disease per irRC. Two-year overall survival rates were 77.6% in patients with nonprogressive disease per both criteria (n = 331), 37.5% in patients with progressive disease per RECIST v1.1 but nonprogressive disease per irRC (n = 84), and 17.3% in patients with progressive disease per both criteria (n = 177).

Atypical responses were observed in patients with melanoma treated with pembrolizumab. Based on survival analysis, conventional RECIST might underestimate the benefit of pembrolizumab in approximately 15% of patients; modified criteria that permit treatment beyond initial progression per RECIST v1.1 might prevent premature cessation of treatment."

Way to go, ratties.  Teaching the Big Dogs.  And dogs...thanks for listening! - c

The ipi/nivo combo - responses in melanoma patients ~

As with most things in melanoma land, this is a topic I've covered before!  Here are lots of reports from recent years that cover response rates and outcomes for melanoma patients treated with the ipi/nivo combo:  Results of the ipi/nivo combo in melanoma patients

Now there is a report breaking down those responses:

Site-specific response patterns, pseudoprogression, and acquired resistance in patients with melanoma treated with ipilimumab combined with anti-PD-1 therapy.  Pires da Silva, Lo, Quek, et al. Cancer. 2019 Oct 4.  Patients with metastatic melanoma have variable responses to combination ipilimumab and nivolumab. The objectives of this study were to examine the patterns of response and survival in patients treated with combination ipilimumab and anti-PD-1 therapy (IPI + PD1) and to explore the nature of pseudoprogression and acquired resistance. Patients with metastatic melanoma who received treatment with first-line IPI + PD1 had all metastases ≥5 mm measured on computed tomography/magnetic resonance imaging studies. The lesional response rate (LRR) and the overall response rate (ORR) were determined according to Response Evaluation Criteria in Solid Tumors, version 1.1. In total, 140 patients who had 833 metastases were studied. The ORR and the overall complete response (CR) rate decreased as tumor burden or the number of metastases increased. Metastases that had a CR (49%) were smaller than metastases without a CR (median, 13 vs 17 mm). Soft-tissue and lung metastases had the highest LRR (79% and 77%, respectively), whereas liver metastases had the lowest (46%). In multivariate analysis, patients with lung metastases had superior ORR and progression-free survival, whereas those with liver metastases had inferior ORR, progression-free survival, and overall survival. Pseudoprogression occurred in one-third of patients who had progressive disease as their best response, with an overall survival that was comparable to that of patients without disease progression. Acquired resistance occurred in 12% of responders after a median of 9.6 months, with an overall survival rate of 83% at 1 year from progression. Metastases in different anatomical locations display distinct response patterns and also are associated with overall response and survival with combination immunotherapy. Specific sites of disease may hold unique mechanisms of resistance and should allow for more personalized treatment.

This report looked at 140 patients as well as their combined 833 lesions.  Smaller tumors responded better than big ones.  Lung and soft tissue tumors responded better than tumors in the liver, leading to greater overall response rates, progression free survival, as well as overall survival in patients with lung mets versus those with liver tumors.  Pseudoprogression is real, but only occurs in 1/3 of patients with progressive disease.  And finally, about 12% of responders stopped responding at about 9-10 months.

None of this is real news.  We know that patients with the lowest disease burden respond best to immuotherapy.  Sadly, we have also known for some time that folks with liver mets have a very tough go of it.  These reports go back to 2015:  Liver mets and response to immunotherapy  While researchers have long noted and worked to address resistance in targeted therapy, it is not often discussed in regard to immunotherapy.  But, this report does note that 12% of melanoma peeps on ipi/nivo may at first respond but stop doing so some months later.

We've come a long way, but there is still much we need to learn to improve the plight of melanoma patients.  For what it's worth. - c

Yep! Immunotherapy can work in the brain...and pseudoprogression can be real!!

Melanoma brain metastasis pseudoprogression after pembrolizumab treatment. Cohen, Alomari, Vortmeyer, et al. Cancer Immunol Res. 2015 Dec 23

"The role of immunotherapy in treatment of brain metastases is unknown since most trials exclude patients with active brain lesions. As new immunomodulating agents gain approval for many malignancies, it is important to know if they have unique effects in the central nervous system (CNS). Here we present a case of a patient with progressing brain metastases treated with a single cycle of pembrolizumab, who presented with mental status changes 11 days thereafter. MRI of the brain showed enlargement of CNS lesions with intense central enhancement and diffuse perilesional edema. Histologic evaluation of a resected lesion revealed isolated clusters of tumor cells surrounded by reactive astrocytosis, scattered inflammatory cells and an abundance of microglial cells. Given the increasing use of immune checkpoint inhibitors in patients with brain metastases from melanoma and other diseases, recognition of pseudoprogression and management with immune suppression is essential."

Y'all know I've been yelling this for awhile:

1.  Yes, Virginia....immunotherapy works in the brain.  Anti-pd1 in melanoma: It works in the t-cells, brain, and everywhere else! 

2. It works even better combined with radiation.  Radiation for melanoma: better when combined with immunotherapy 

3.  No, we didn't allow folks with brain mets in treatments that could help soon enough!   

Should melanoma brain met patients be allowed trial participation?

A really good review of treatment data for melanoma brain mets 

ASCO 2015: pembrolizumab/keytruda trial enrolling folks with brain mets  

4.  Pseuodoprogression is real and it, along with other side effects, SHOULD be treated...even with prednisone (and other immune suppressing drugs) if needed when on immunotherapy!!!!!!  Those treatments do NOT impede response, but they can save your life and/or allow you to continue the therapy that will!!!  

Immune related side effects from immunotherapy can and SHOULD be treated!!!

Side effects and how to manage them in targeted and immunotherapy for melanoma

Whew!  Ok.  Rant over.  I feel better.  Now...let's get lots of other folks feeling better.  We KNOW this stuff now!!  Let's USE what the ratties, who put their lives on the line, taught us for the good of ALL peeps dealing with melanoma in the brain and elsewhere. - c

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

It goes without saying that over the years I have posted a zillion reports about all things immunotherapy:  anti-PD-1 ~ Pembrolizumab (also referred to as Pembro and Keytruda) as well as Nivolumab (also called nivo and Opdivo) both of which have very similar side effect profiles and a roughly 40% response rate when used alone; anti-CTLA-4 ~ ipilimumab (also called ipi and Yervoy) which has similar side effects but with greater frequency and intensity than the anti-PD-1 products {though many tolerate it well} with about a 15% response rate when used alone; as well as the ipi/nivo combo which has a response rate of 50+%. (Here's a link:  ASCO 2016: Checkmate 069 - ipi/nivo combo in Stage IV melanoma demonstrated a 68% ORR)  Consistently, treatment naive patients have responded best to all of the above, responses are the most durable we have ever had in any melanoma treatments, many folks continue to respond even if they have to stop treatment due to side effects.  We have also learned that side effects need to be treated as soon as possible, often with steroids, so as to save lives and prevent greater damage than has already occurred, AND the use of steroids, if needed, DOES NOT IMPEDE RESPONSE!!!!  Feel free to use the blog's search bubble to find more info and data on all of this.  Now researchers are looking at:

Pembro plus ipi:

Efficacy and safety of pembrolizumab (pembro) plus ipilimumab (ipi) for advanced melanoma.

ASCO 2017. J Clin Oncl, 35, 2017. Carlino, Atkinson, Cebon, et al.

Background: We previously showed that standard-dose pembro plus reduced-dose ipi has manageable safety and robust antitumor activity in patients (pts) with advanced melanoma. Here, we present more mature data, including 1-y landmark PFS and OS estimates. Methods: In the phase 1 KEYNOTE-029 expansion cohort (NCT02089685), pts with advanced melanoma, ECOG PS 0-1, no active brain metastases, and no prior immune checkpoint inhibitor therapy received pembro 2 mg/kg Q3W + ipi 1 mg/kg Q3W for 4 doses, then pembro alone for up to 2 y. Primary end point was safety. Efficacy end points were ORR, PFS, and DOR per RECIST v1.1 by independent central review and OS. Results: 153 pts were enrolled between Jan 13, 2015, and Sep 17, 2015. Median age was 60 y, 66% were male, 25% had elevated LDH, 56% had stage M1c disease, 36% were BRAF^V600mutant, and 13% received greater than/= to 1 prior therapy. As of Oct 17, 2016, median follow-up was 17 mo, and 64 (42%) pts remained on pembro. 110 (72%) pts received all 4 ipi doses. There were no treatment-related (TR) deaths. TRAEs occurred in all pts, were grade 3/4 in 69 (45%), and led to discontinuation of pembro and ipi in 17 (11%), ipi alone in 11 (7%), and pembro alone after ipi completion or discontinuation in 19 (12%). PD occurred in 1/11 pts who discontinued ipi alone and 4/17 pts who discontinued ipi and pembro. Of the 11 pts who discontinued ipi alone for a TRAE, 0 experienced recurrence of the same TRAE during pembro monotherapy and 2 discontinued pembro for a different TRAE (both elevated lipase). Immune-mediated AEs occurred in 90 (59%) pts and were grade 3/4 in 39 (25%). With 7 mo additional follow-up, there were 6 additional responses for an ORR of 61%; the CR rate increased from 10% to 15%. Median DOR was not reached (range, 1.6+ to 18.1+ mo), with 86/93 responders (92%), including 23/23 (100%) with CR, alive and without subsequent PD at cutoff. Median PFS and OS were not reached; 1-y estimates were 69% for PFS and 89% for OS. Conclusions: Pembro 2 mg/kg plus 4 doses of ipi 1 mg/kg has a manageable toxicity profile and provides robust, durable antitumor activity in pts with advanced melanoma. Clinical trial information: NCT02089685

Here 153 Stage IV melanoma patients (no brain mets) but some with increased LDH were given Pembro 2mg/kg and ipi at only 1mg/kg, together every three weeks for 4 doses and then pembro alone q 2 wks.  There were no treatment related deaths, though ALL patients had side effects, but were grade 3/4 in only 45%.  The way the data was examined ~ with one near endpoint and another 7 months later...proved...AGAIN...that responses can occur late....and as per Weber and Agarwala, when it comes to immunotherapy, "Give the patient time!" ~ for an ultimate ORR of 61% and CR of 15%.  So....these responses are no better than those demonstrated in the ipi/nivo combo.  But...what is interesting is that ipi was dosed at only 1mg/kg whereas in the ipi/nivo combo it is used at 3mg/kg. (AGAIN!!!  Why can't researchers [and Big Pharma!!!!] construct trials so that you can REALLY compare results!!!) At any rate, this tidbit of data may prove important in decreased side effects and it would be important/interesting to see if nivo with ipi at only 1m/kg would continue to do as well as the combo does currently.  I'm betting it would....but that's just me.

While the next couple of articles did not come out of ASCO this year...they pertain to the topic at hand...so I've included them here.

Here, researchers looked at the response to ipi after patients have progressed on pembro:

Antitumor activity of ipilimumab after pembrolizumab in patients with advanced melanoma  KEYNOTE-006 Poster Spotlight: G. Long (Australia).  European Cancer Conference, Jan 2017.

Background: The efficacy and safety of PD-1 inhibition in patients with advanced melanoma previously treated with the CTLA-4 inhibitor ipilimumab has been established in several studies, including the KEYNOTE-001 and 002 trials of pembrolizumab. Conversely, the efficacy of CTLA-4 inhibition with ipilimumab following anti–PD-1 therapy is not clearly established. We assessed outcomes in patients enrolled in KEYNOTE-006 (NCT01866319) who received ipilimumab monotherapy after pembrolizumab.

Methods: Patients in KEYNOTE-006 were randomized 1:1:1 to 2 years of pembrolizumab 10 mg/kg Q2W (n = 279) 10 mg/kg Q3W (n = 277) or to 4 doses of ipilimumab 3 mg/kg Q3W (n = 278). Treatment was continued until disease progression, intolerable toxicity, or patient or physician decision. After study treatment discontinuation, subsequent anticancer therapy and outcomes were reported.

Results: As of December 3, 2015, ipilimumab was recorded as a subsequent therapy for 129 pembrolizumab-treated patients, including 97 for whom ipilimumab was the first post-study therapy. Of these 97 patients, 64% had M1c disease, 33% had elevated serum LDH at baseline, and 16% had BRAF^V600-mutant tumors at baseline. Best response to pembrolizumab was PR in 16%, SD in 12%, nonCR/nonPD in 5%, PD in 62%, and nonevaluable/not assessed in 4%. Median duration of pembrolizumab before the start of ipilimumab was 18 weeks, and the median time between the last pembrolizumab dose and first ipilimumab dose was 5 weeks. Median duration of ipilimumab was 8 weeks. The reported ORR for ipilimumab was 14%, with a best overall response of CR in 3%, PR in 11%, SD in 33%, PD in 33%, and unknown in 23%; subsequent progression occurred in 40% of patients with PR and 48% with SD. Best response to pembrolizumab in the 13 patients who responded to ipilimumab was SD in 1, nonCR/nonPD in 2, PD in 8, and not assessed in 2. Best response to ipilimumab in the 16 responders to pembrolizumab who received greater/= to 1 ipilimumab dose was SD in 8, PD in 3, and unknown in 5. Fifty-seven of 97 patients had died, and median OS from randomization was 19.6 months.

Conclusions: Ipilimumab has antitumor activity following pembrolizumab in patients with advanced melanoma, including those whose best response to pembrolizumab was PD, with an ORR consistent with historical data.

So in 97 patients, most of whom had taken pembro for about 18 weeks with a PR in 16% and SD in 12%, PD in 62% (clearly, these were folks who were not responding to pembro as well as the usual data) were, in about 5 weeks placed on ipi at 3mg/kg, with most folks taking it for 8 weeks.  At that point, the ORR to ipi was 14% (which is what responses to ipi usually run at).  Additional data showed:  CR in 3%, PR in 11%, SD in 33%, PD in 33%.  While not great, this certainly shows that if you are not a responder to pembro....switching ASAP to ipi can gain a response of about 15%.  A similar response was attained in the last abstract noted in this post from ASCO 2015:  ASCO 2015: Nivo and Pembro after failing ipi. Ipi after failing anti-PD1.

Here researchers looked at how tumors, and subsequently the patients!!!, responded to pembro:

Immune-Related Tumor Response Dynamics in Melanoma Patients Treated with Pembrolizumab: Identifying Markers for Clinical Outcome and Treatment Decisions. Nishino, Giobbie-Hurder, Manos, et al. Clin Cancer Res. 2017 June 7.

Purpose: Characterize tumor burden dynamics during PD-1 inhibitor therapy and investigate the association with overall survival (OS) in advanced melanoma.
Experimental Design: The study included 107 advanced melanoma patients treated with pembrolizumab. Tumor burden dynamics were assessed on serial CT scans using irRECIST and were studied for the association with OS.
Results: Among 107 patients, 96 patients had measurable tumor burden and 11 had nontarget lesions alone at baseline. In the 96 patients, maximal tumor shrinkage ranged from -100% to 567% (median, -18.5%). Overall response rate was 44% (42/96; 5 immune-related complete responses, 37 immune-related partial responses). Tumor burden remained less than 20% increase from baseline throughout therapy in 57 patients (55%). Using a 3-month landmark analysis, patients with less than 20% tumor burden increase from baseline had longer OS than patients with greater than/= to 20% increase (12-month OS rate: 82% vs. 53%). In extended Cox models, patients with less than 20% tumor burden increase during therapy had significantly reduced hazards of death.  Four patients (4%) experienced pseudoprogression; 3 patients had target lesion increase with subsequent response, which was noted after confirmed immune-related progressive disease (irPD). One patient without measurable disease progressed with new lesion that subsequently regressed.
Conclusions: Tumor burden increase of less than 20% from the baseline during pembrolizumab therapy was associated with longer OS, proposing a practical marker for treatment decision guides that needs to be prospectively validated. Pseudoprogressors may experience response after confirmed irPD, indicating a limitation of the current strategy for immune-related response evaluations. Evaluations of patients without measurable disease may require further attention.

Here 96 patients with measureable disease were given pembro.  ORR was the expected 44%.  Folks whose tumor burden increased less than 20% from their baseline, once therapy was started, did best, and this was 55% of the peeps in the study.  They ended up with a longer OS than those whose known tumor burden increased more than 20% from baseline while on pembro.  Of course!  If your tumors mostly just shrink while on treatment...you do better!!!   BUT!  The pseudoprogression thing is real for some...albeit in small numbers...3 patients had target lesions increase in size but went on to gain a response and 1 patient that didn't have measureable disease when they started treatment developed a new lesion that then regressed.

Well, there you have it.  Things remain about as clear as mud if you are a melanoma patient who is progressing on immunotherapy as to trying to decide what to do next!!!  But....it is clear...that there is hope.  Love and luck to all the ratties - c