Wednesday, June 7, 2017

ASCO 2017: Outcomes after stopping immunotherapy in melanoma


Trying to figure out how long a patient needs to take immunotherapy, be it nivo or pembro alone, or the ipi/nivo combo....is unclear.  Docs (including my own, Dr. Weber) have proposed that a "certain amount of drug is beneficial...beyond that amount, the patient will gain no additional benefit and instead will only be at risk for increase side effects".  That makes sense.  I completely agree with it. However, EXACTLY how much IS that "certain amount" ?????  Ratties are providing data to researchers as they try to figure that out.  In my case, Weber has been clear that we probably took nivo much longer than we needed to in our 2 1/2 year long trial.  Many studies looking at outcomes and "tails" on the response and duration of response data curves seem to be converging around the 2 year mark.  There was this heartening report last year:  ASCO 2016 - Nivo plus ipi, CheckMate 069 trial....18 month OS similar even if you stop meds due to side effects!!!  which as titled, showed that folks that had to stop the ipi/nivo combo early, due to side effects, did as well as those who continued treatment, at the 18 month outcome mark.

Here is this report dealing with advanced melanoma patients who took pembro (keytruda):

Real life outcome of advanced melanoma patients who discontinue pembrolizumab (PEMBRO) in the absence of disease progression.
ASCO 2017. J Clin Onc 35, 2017. Jansen, Rozeman, Foppen, et al.

Background: PEMBRO improves survival of patients (pts) with advanced melanoma. Optimal duration of treatment in responding pts hasn’t been established. Methods: 12 European hospitals collected data from 509 pts treated with PEMBRO outside an interventional clinical trial. Outcome was evaluated for pts who discontinued PEMBRO in the absence of progressive disease [PD]. Results: After a median follow up of 56 wks [range 1-135], median PFS was 22 wks and median OS was 70 wks for the total population. PEMBRO is ongoing in 66 [13%] pts, 344 [68%] pts stopped PEMBRO because of PD, and 99 [19%] pts discontinued PEMBRO without evidence of PD (of which 65 [13%] pts upon pt/MD decision, 26 [5%] pts due to a PEMBRO-related AE of grade less than 4 and 8 [2%] pts due to a grade 5 PEMBRO-unrelated AE). Pts discontinuing PEMBRO without PD had a significant better ECOG PS, less advanced tumor stage, less frequent brain metastases and more often a normal LDH at baseline. There was no significant difference between pts stopping due to AE or upon pt/MD decision. The median time on treatment for the 65 pts who stopped PEMBRO upon pt/MD decision was 55 wks [range 9-112].Their best objective response rate [BORR] was 80% [31 [48%] CR, 21 [32%] PR, 12 [18%]SD, 1[2%]NE]. After a median follow-up of 26 wks [range 1-75] after the last PEMBRO dose, 3 [5%] pts progressed (after 9, 14 and 15 wks). PEMBRO was reintroduced in 1 patient resulting in a CR. The median time on treatment of the 26 pts who stopped PEMBRO due to an AE in the absence of PD was 27 wks [range 1-103]. Their BORR was 77%. After a median follow-up of 50 wks [range 12-109] following the last PEMBRO dose, 9 [35 %] pts progressed. Median time to PD was 26 wks [range 7-108]. PD was not correlated with BOR. PEMBRO was reintroduced in 4 pts resulting in 1 CR, 1 PD, 1 SD and 1 NE. Conclusions: In this real life experience, advanced melanoma pts who discontinue PEMBRO treatment upon pt/MD decision, in the absence of PD or AE, were at low risk for short-term recurrence. Pts stopping PEMBRO due to an AE in the absence of PD (having a shorter exposure to PEMBRO and longer FU after discontinuing treatment) seem to have a higher risk for subsequent PD.

OK....here's my best outline of the data above:
*  N = 509 advanced melanoma patients...prior treatment unclear...were treated with pembro only
*  overall - Med PFS (progression free survival) = 22 weeks
*  overall - Med OS (overall survival) = 70 weeks
*  N = 344 stopped pembro due to disease progression
*  N = 8 stopped tx due to significant side effects - "grade 5 not related to pembro" {don't really know what that means}
*  N = 26 stopped tx due to grade 4 side effects.  Of these:  med tx time = 27 weeks.  At 50 week f/u after their last dose,  9 had progressed. Pembro was restarted in 4 leading to - 1 CR, 1 PD, 1 SD, 1 NE.
*  N = 99 stopped tx without evidence of PD.  This group were those that had had decreased tumor stage, less frequent brain mets, and more often normal LDH at baseline.  Of these 99 patients, 65 made this decision to stop treatment as a plan with their doc.  Med time of the tx = 55 wks.  Of these there were 21 with CR and 12 with PR.  At 26 weeks after last dose, 3 had progressed.  Pembro was restarted in 1 and they gained a CR.

Here - this study looked at patients who had never been given ipi and were treated with pembro for 2 years or until progression:

Long-term outcomes in patients (pts) with ipilimumab (ipi)-naive advanced melanoma in the phase 3 KEYNOTE-006 study who completed pembrolizumab (pembro) treatment.
2017 ASCO. J Clin Oncol 35, 2017. Robert, Long, Schachter,...Hamid, ….Ribas, ….et al.

Background: Pembro demonstrated superior PFS and OS vs ipi in ipi-naive pts with advanced melanoma in the phase 3 KEYNOTE-006 study. Here, we present long-term outcomes for all pts and in those pts who completed pembro therapy. Methods: Eligible pts (N = 834) were randomized 1:1:1 to pembro 10 mg/kg Q2W, pembro 10 mg/kg Q3W, or ipi 3 mg/kg Q3W for 4 doses. Treatment was continued for 2 yr (pembro only) or until disease progression, intolerable toxicity, or pt/investigator decision to discontinue. Per protocol, pts could interrupt pembro for less than/= to 12 wk before discontinuation was required. Tumor imaging was performed at wk 12, then every 6 wk up to wk 48 and every 12 wk thereafter. After the prespecified final analysis, response assessments were per immune-related response criteria (irRC) by investigator review. Results: As of the data cutoff (Nov 3, 2016), median follow-up in the total population was 33.9 mo (range, 32.1-37.6). 33-mo OS rates were 50% in the pooled pembro arms (n = 556) and 39% in the ipi arm (n = 278); 33-mo PFS rates were 31% and 14%. ORR was 42% and 16%. Median duration of response was not reached for pembro (range 1.0+ to 33.8+ mo) or ipi (1.1+ to 34.8+ mo); 46 (68%) pembro-treated pts and 7 (58%) ipi-treated pts had a response lasting greater than/= to 30 mo. Among the 104/556 (19%) pts who completed pembro, median exposure to pembro was 24.0 mo (range 22.1-25.9). After a median follow-up of 9.0 mo after completion of pembro, 102 (98%) pts were alive. Responses were durable in pts who completed pembro; 9.7 mo after completion of pembro, estimated PFS was 91% (80-96) in all 104 pts, 95% (69-99) in pts with complete response (n = 24), 91% (74-97) in pts with partial response (n = 68), and 83% (48-96) in pts with stable disease (n = 12). Conclusions: Pembro provides durable efficacy after stopping the protocol-specified duration of treatment in pts with ipi-naive advanced melanoma in KEYNOTE-006. The estimated risk for progression or death nearly 10 mo after completing pembro is 9% and does not appear to differ by best response to pembro. 

Here's my best outline:
*  N = 834 treatment naive patients with advanced melanoma were divided into 3 groups -
            1.  Pembro10mg/kg q 2wk for 2 years or until disease progression
            2.  Pembro 10mg/kg q 3 wk for 2 years or until disease progression
            3.  Ipi 3mg/kg q 3 wk X 4 doses
* At 33 month f/u for Pembro patients:  OS = 50%, PFS = 31%, ORR = 42%
* At 33 month f/u for ipi patients:  OS = 39%, PFS = 14%, ORR = 16%
{Notice that the ORR are exactly what we expect of ipi and anti-PD-1 - 15% vs 40% ORR}
*  Of 104 patients who completed roughly 24 months of pembro, 9 months later, 102 were alive.
*  Responses in these 104 patients were durable.  9.7 months after completion:   PFS = 91% overall, 95% in those with a CR, 91% in those with PR, and 83% in patients with stable disease.  {Not sure that those percentages are THAT statistically different.}

This report looks at outcomes for patients who took anti-PD-1 alone or the ipi/nivo combo:

Outcomes of patients with melanoma who discontinue immunotherapy.
ASCO 2017. J Clin Onco 35, 2017. Rosner, Bogatch, Postow.

Background: The question of when to discontinue (d/c) anti-program death-1 (PD-1) monotherapy (mono) or nivolumab in combination with ipilimumab (combo) immunotherapy (IT) is unknown. Methods: After IRB approval, a single center (Memorial Sloan Kettering Cancer Center), retrospective study was performed of 162 pts with unresectable stage III or IV melanoma treated with either mono (n = 106) or combo (n = 56) IT. Objective response rate (ORR), progression free survival (PFS), and overall survival (OS) were calculated for all pts from the 1stdose of IT. For pts (n = 40; mono and n = 40; combo) who d/c IT due to reasons (Table) other than progression or death, starting from the last date of IT, we then reported PFS, time to treatment failure (TTF) defined as any subsequent surgery/radiation/systemic therapy, and OS. Results: For pts that were alive at time of analysis, the median follow up was 28 mos. For all 162 pts, ORR was 38.7% (mono) and 60.7% (combo); median PFS and OS were 12 months (mos) and 25 mos for mono; 34 mos and not reached (NR) for combo, respectively. From the last dose of IT, the PFS, TTF, and OS for 40 mono pts and 40 combo pts who d/c IT for reasons other than progression/death are shown in Table. Reasons included CR, toxicity, or other (most commonly protocol completion or prolonged PR). Conclusions: Outcomes in this cohort of pts with long follow-up treated with mono or combo IT are similar to results from other clinical trials. Pts who d/c IT for reasons other than progression/death were a highly selected group. Nonetheless, favorable PFS, TTF, and OS were seen after IT d/c, even in pts who did not obtain a CR.




mono (106) combo (56)
age years 60 60
sex (% female) 45 41
unresectable stage III (%) 2 11
Stage M1A (%) 19 11
Stage M1B (%) 24 21
Stage M1C (%) 56 57
Prior therapy (%) 96 23
Brain mets (%) 22 2
% with LDH above ULN 38 34
med duration of tx (mo) 5 7
CR (%) 10 16
PR (%) 28 45
SD (%) 15 25
PD (%) 46 14
D/C for tox n=10 n=27
med PFS (mo) 10.5 NR
med TTF (mo) 11 NR
med OS (mo) NR NR
D/C CR n=9 n=4
med PFS NR NR
med TTF NR NR
med OS NR NR
D/C for other n=21 n=9
med PFS 16 NR
med TTF 21.5 NR
med OS NR NR

My summary of all reports above:
Anti-PD-1 alone works better than ipi and the ipi/nivo combo works better than anti-PD-1 alone.
Those who have the least disease, fewest brain mets, and pretty normal LDH do better.
Something around 2 years of dosing is looking like what will be taken as a tx endpoint.
Folks who complete 2 years of therapy, esp if they gain a complete response, do best.
Melanoma sucks.

So...much like a student who studies hard, does well on the test - melanoma patients who do well in the study, do well longer.  We ratties have been giving our homework our all in these studies.  Now, researchers...figure out how to make sure more of us do well in the study....so that we can all do better later. - les

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