CheckMate 067 - 4 year outcomes for nivo/ipi combo vs nivo alone in melanoma patients

I have been following the data (and contributing to some) around immunotherapy for over 8 years!  So of course I've followed the CheckMate 067 trial.  Here are just a few early reports:   CheckMate 067 - ipi/nivo combo

Now, this ~

Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Hodi, Chiarion-Sileni, Gonzalez, et al. Lancet Oncol. 2018 Oct 18.  

Previously reported results from the phase 3 CheckMate 067 trial showed a significant improvement in objective responses, progression-free survival, and overall survival with nivolumab plus ipilimumab or nivolumab alone compared with ipilimumab alone in patients with advanced melanoma. The aim of this report is to provide 4-year updated efficacy and safety data from this study.  

In this phase 3 trial, eligible patients were ... previously untreated, unresectable, stage III or stage IV melanoma, known BRAF^V600 mutation status, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 1:1:1 to receive intravenous nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks, or nivolumab 3 mg/kg every 2 weeks plus placebo, or ipilimumab 3 mg/kg every 3 weeks for four doses plus placebo. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by PD-L1 status, BRAF mutation status, and metastasis stage. The patients, investigators, study site staff, and study funder were masked to the study drug administered. The co-primary endpoints were progression-free survival and overall survival. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all patients who received at least one dose of study drug. The results presented in this report reflect the 4-year update of the ongoing study with a database lock date of May 10, 2018. This study is registered with ClinicalTrials.gov, number NCT01844505.  

Between July 3, 2013, and March 31, 2014, 945 patients were enrolled and randomly assigned to nivolumab plus ipilimumab (n=314), nivolumab (n=316), or ipilimumab (n=315). Median follow-up was 46·9 months (IQR 10·9-51·8) in the nivolumab plus ipilimumab group, 36·0 months (10·5-51·4) in the nivolumab group, and 18·6 months (7·6-49·5) in the ipilimumab group. At a minimum follow-up of 48 months from the date that the final patient was enrolled and randomised, median overall survival was not reached (38·2-not reached) in the nivolumab plus ipilimumab group, 36·9 months (28·3-not reached) in the nivolumab group, and 19·9 months (16·9-24·6) in the ipilimumab group. The hazard ratio for death for the combination versus ipilimumab was 0·54 and for nivolumab versus ipilimumab was 0·65. Median progression-free survival was 11·5 months (95% CI 8·7-19·3) in the nivolumab plus ipilimumab group, 6·9 months (5·1-10·2) in the nivolumab group, and 2·9 months (2·8-3·2) in the ipilimumab group. The hazard ratio for progression-free survival for the combination versus ipilimumab was 0·42 and for nivolumab versus ipilimumab was 0·53. Treatment-related grade 3-4 adverse events were reported in 185 (59%) of 313 patients who received nivolumab plus ipilimumab, 70 (22%) of 313 who received nivolumab, and 86 (28%) of 311 who received ipilimumab. The most common treatment-related grade 3 adverse events were diarrhoea in the nivolumab plus ipilimumab group (29 [9%] of 313) and in the nivolumab group (nine [3%] of 313) and colitis in the ipilimumab group (23 [7%] of 311); the most common grade 4 adverse event in all three groups was increased lipase (15 [5%] of 313 in the combination group, ten [3%] of 313 in the nivolumab group, and four [1%] of 311 in the ipilimumab group). Serious adverse events were not analysed for the 4-year follow-up. In total for the study, there were four treatment-related deaths: two in the nivolumab plus ipilimumab group (one cardiomyopathy and one liver necrosis), one in the nivolumab group (neutropenia), and one in the ipilimumab group (colon perforation). No additional treatment-related deaths have occurred since the previous (3-year) analysis.

The results of this analysis at 4 years of follow-up show that a durable, sustained survival benefit can be achieved with first-line nivolumab plus ipilimumab or nivolumab alone in patients with advanced melanoma.

At this point, these results are not surprising.  The ipi/nivo group median overall survival was not reached at 38 months, not reached for nivo alone at 36 months, and was 19 months in the ipi only group.  Side effects greatest with 59% of patients experiencing them with ipi/nivo, experienced by 22% taking nivo alone, and by 28% on ipi as a single agent.  The most common grade 3 side effect was diarrhea/colitis.  The most common grade 4 side effects was increased lipase.

Thanks, ratties!!! May we all continue to beat our assigned expiration dates!!! - c

ASCO 2016 - CheckMate 067 - ipi/nivo combo in treatment naive .... and some thoughts....

Running today I was thinking of many things.  Happy to hear the birds and watch Mr. and Mrs.  Towhee.  Happy to be running well...yep, still putting in my miles...despite melanoma...despite weird right arm pit pain that's a given with all my various surgeries in that area and right hip pain that has stabilized a bit....despite turning 52 soon!!!  Thrilled for Mat; his good scans and happy birthdays.  A bit worried for other dear ones facing more treatments and unknowns.  Not overjoyed about my own scans in August.  But, excited about some travel plans, working on my French and Spanish, sewing projects, and my general work and life...  Pondering the loss of a strong man, who I watched as a child with Howard Cosell, never deserving the cage of mind and body that was his Parkinsonian-like condition.  Slightly crushed for another dear one, Reverend Carol, such a strong and encouraging spirit of leadership and strength for many years in melanoma world, now dealing with some melanoma mess of her own.  So....when I think of my own problems and being tired of melanoma info and posting endless data that, while better than any melanoma has ever had, still sucks great big green hairy wizard balls!!!!  I look to real leaders... 

From Muhammed Ali:  "The service you do for others is the rent you pay for your room here on Earth."

From  Rev. Carol Taylor's blog, Attitude of Gratitude, Lets give thanks.blogspot.com

"If you have melanoma, find support. Plug into the online community. We are thriving on Facebook. If you aren't on FB, Melanoma Research Foundation has a great page of support (click on Find Support). Be sure to share your story with others. Make a difference. Somehow. You matter. Your journey matters. Others need to hear what you have to say. And who knows? You just might save a life or two though you may never be told.
If you have melanoma, give support. Don't just take it, give it back. We all need cheerleaders in our corner. We all need prayer warriors..."

And yes, my dear...you really are....Queen of Melanoma World!!!  I kneel before your tiara and tattoo printed compression sleeves, wishing you well...and doing my best to...give it back.

In that vein, check out the ASCO post below with the results of the ip/nivo study that has already been beat to death in the media and on this blog.  But perhaps, more importantly, I give you this:

"Live every day as it it were your last, because some day....you are going to be right!" ~ Muhammad Ali

Much love, c
 

Updated results from a phase III trial of nivolumab (NIVO) combined with ipilimumab (IPI) in treatment-naive patients (pts) with advanced melanoma (MEL) (CheckMate 067).  ASCO 2016.  # 9505.  J Clin Oncol 34, 2016.  Wolchok, Chiarion-Sileni, Gonzalez, et al.

Background: In CheckMate 067, NIVO (anti-PD-1) plus IPI (anti-CTLA-4) significantly improved progression-free survival (PFS) and objective response rate (ORR) vs IPI alone in pts with MEL. We report updated efficacy and safety results from this study. Methods: Treatment-naïve pts (N=945) were randomized 1:1:1 to NIVO 1 mg/kg Q3W with IPI 3 mg/kg Q3W for 4 doses (followed by NIVO 3 mg/kg Q2W), NIVO 3 mg/kg Q2W with placebo, or IPI 3 mg/kg Q3W for 4 doses with placebo, until progression or unacceptable toxicity. Pts were stratified by PD-L1 status, BRAFmutation status, and M-stage. Co-primary endpoints were PFS and overall survival (data remain immature). Secondary endpoints included efficacy by PD-L1 status and safety. Results: At greater than or = to, 8 months of follow-up, median PFS continued to be significantly longer for NIVO/IPI and NIVO vs IPI , and was numerically longer for NIVO/IPI vs NIVO alone. Median duration of response in 181/314 (57.6%) NIVO/IPI responders has not been reached, and was 22.3 and 14.4 months in 138/316 (43.7%) NIVO and 60/315 (19.0%) IPI responders, respectively. Median PFS was also numerically longer with NIVO/IPI vs NIVO or IPI regardless of PD-L1 tumor expression. For NIVO/IPI, NIVO, and IPI groups, median PFS was 15.5, 5.6, and 4.0 months in pts with a BRAF mutation and was 11.3, 7.1, and 2.8 months in pts with wild-type BRAF, respectively. The frequency and types of drug-related grade 3/4 AEs were consistent with earlier reports (NIVO/IPI, 56.5%; NIVO, 19.8%; IPI, 27.0%). Conclusions: NIVO/IPI and NIVO alone continue to demonstrate superior clinical activity vs IPI monotherapy. NIVO/IPI appears to have greater efficacy than either agent alone, regardless of PD-L1 expression or BRAF mutation status.

Median PFS (95% CI)	NIVO+IPI	NIVO	IPI
ITT population	11.5 (8.9–16.7)	6.9 (4.3–9.5)	2.9 (2.8–3.4)
HR  vs NIVO	0.76 (0.60–0.92)a	—	—
PD-L1 expression
greater/=5%	NR (9.7–NR)	22.0 (8.9–NR)	3.9 (2.8–4.2)
HR vs NIVO	0.87 (0.54–1.41)a	—	—
less than5%	11.1 (8.0–22.2)	5.3 (2.8–7.1)	2.8 (2.8–3.1)
HR vs NIVO	0.74 (0.58–0.96)a	—	—

Combo's looking good....but if PD-L1 positive...just do nivo!!??

What's new in melanoma?  Combination!  Ascierto, Marincola, Atkins.  J Transl Med.  Jul 4 2015.

Melanoma was again a focus of attention at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting, in particular the use of combination treatment strategies involving immunotherapies and/or targeted agents. New data on targeted therapies confirmed previous findings, with combined BRAF inhibitor (vemurafenib) plus MEK inhibitor (cobimetinib) improving progression-free survival (PFS) compared to vemurafenib monotherapy in patients with BRAFV600 mutation-positive tumors (CoBRIM trial). Positive results were also seen with combined dabrafenib and trametinib in patients with BRAF V600E/K metastatic melanoma and encorafenib plus binimetinib in BRAFV600-mutant cutaneous melanoma. Even more interesting news centered on the use of combination immunotherapy, in particular the randomized, double-blind CheckMate 067 study in which median PFS with nivolumab plus ipilimumab was 11.5 months, compared to 2.9 months with ipilimumab alone and 6.9 months with nivolumab alone. Of interest, in patients with ≥5% PD-L1 expression, median PFS was 14 months with the combination or with nivolumab alone compared with 3.9 months in the ipilimumab group, while in the PD-L1 negative cohort, the combination remained superior to both monotherapies. Given that combination therapy was accompanied by a high occurrence of side-effects, this raises the suggestion that combination therapy might be reserved for PD-L1 negative patients only, with PD-L1 positive patients achieving the same benefit from nivolumab monotherapy. However, overall survival data are awaited and the equivalence of single agent to the combination remains unconvincing. Interesting data were also reported on the combination of T-VEC (talimogene laherparepvec) with ipilimumab, and the anti-PD-1 agent MEDI4736 (durvolumab) combined with dabrafenib plus trametinib. Emerging data also suggested that predictive markers based on immunoprofiling and mismatch repair deficiency may be of clinical use. In conclusion, the use of combination approaches to treat patients with melanoma, as well as other cancers, is no longer a just a wish for the future but is today a clinical reality with a rapidly growing evidence-base. Moreover, the most exciting consideration is that this is far from the end of the story, but rather a fantastic introduction.

Thoughts:
1.  What I've been saying....COMBO's!!!!
2.  But, which one???
3.  If you are BRAFV600 positive and are ready for BRAFi...these combo's are doing very well:  vemurafenib with combimetinib, dabrafenib with trametinib, and encorafenib plus binimetinib.
4.  Combo immunotherapy:  CheckMate 067 showed us PFS of 11.5 months on the ipi/nivo combo vs 2.9 months on ipi alone and 6.9 months on nivo alone.  BUT!!!!!  In PD-L1 positive patients PFS was 14 months on just nivo vs 3.9 months for ipi.  In PD-L1 negative patients the ipi/nivo combo was better than either monotherapy.  SO!  Since the ipi/nivo combo has more side effects but gives you no better results if you are PD-L1 positive....it probably makes more sense to just do nivo alone!
5.  T-VEC with ipi and yet another anti-PD1 product (MEDI4736/durvolumab) with dabrafenib plus trametinib seem promising as well.
6.  Here's hoping that markers and combo's become more clarified and APPROVED very soon.
7.  Thanks, ratties!!!
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  

Nivo after nivo? Or nivo after progression? Can melanoma patients still attain a response???

A question frequently asked...with no absolute answer is.... What if I take nivo after I've progressed....having already been on nivo....or if currently on nivo??????  These reports begin an answer:

Efficacy and safety of retreatment with nivolumab in metastatic melanoma patients previously treated with nivolumab. Nomura, Otasua, Konda, et al.  Cancer Chemother Pharmacol. 2017 Oct 5. 

Nivolumab is a monoclonal antibody directed against programmed death-1 that has been shown to improve survival in patients with metastatic melanoma. However, the efficacy of nivolumab and other agents in melanoma remains limited. The objective of this study was to evaluate the efficacy and safety of retreatment with nivolumab in metastatic melanoma patients who previously progressed on nivolumab.

A retrospective review was performed on eight consecutive metastatic melanoma patients retreated with nivolumab who progressed on previous nivolumab. These patients received nivolumab 2 mg/kg every 3 weeks. Best responses to each treatment were assessed using RECIST 1.1.

Of eight metastatic melanoma patients, three patients received chemotherapy before first nivolumab. The median first nivolumab treatment period was 4.1 months. During first nivolumab, 3 (37.5%) patients achieved a partial response and 3 (37.5%) patients achieved stable disease as their best response. First nivolumab was discontinued due to disease progression in seven patients and grade 3 colitis in 1 patient. Patients were subsequently treated with ipilimumab (n = 6), vemurafenib (n = 1), or no other medical treatment (n = 1). The median treatment period between first and second nivolumab was 3.0 months. Four patients received radiation therapy between first and second nivolumab. The median second nivolumab treatment period was 4.3 months. Among the eight patients who received second nivolumab, 2 (25%) patients achieved a partial response and 3 (37.5%) patients achieved stable disease as their best response. Second nivolumab was discontinued due to disease progression in seven patients. One patient continues to receive second nivolumab. Among the four patients treated with ipilimumab and radiotherapy between first and second nivolumab, the response rate was 50% and the disease control rate was 75%.

This study showed that retreatment with nivolumab is an option for select metastatic melanoma patients after previous nivolumab treatment.

Here, 8 patients were given nivo (3 of them had chemo beforehand).  37.5% had a partial response.  37.5% had stable disease.  Nivo was stopped due to progression in 7 of the patients and colitis in 1.  6 were subsequently treated with ipi.  1 was given vemurafenib.  4 got radiation at that point.  Then...these 8 folks were given a new round of nivo.  2 attained a partial response.  3 attained stable disease. Eventually, 7 of them had to stop nivo again due to progression.  Interestingly, it sounds as though those that had radiation between therapies did better....at least for a while - though that is not entirely spelled out here.  

So, it seems that round two of nivo can give patients a reprieve.  Though for these 8 patients it doesn't sound as though it lasted long enough!

And....there's also this....

Nivolumab for Patients With Advanced Melanoma Treated Beyond Progression: Analysis of 2 Phase 3 Clinical Trials. Long, Weber, Larkin, ….Hodi, Wolchok.  JAMA Oncol. 2017 Jun 29.

Immune checkpoint inhibitors have demonstrated atypical response patterns, which may not be fully captured by conventional response criteria. There is a need to better understand the potential benefit of continued immune checkpoint inhibition beyond progression.

To evaluate the safety and potential benefit of nivolumab (anti-programmed cell death receptor 1) monotherapy beyond Response Evaluation Criteria in Solid Tumors (RECIST) v1.1-defined progression.

Pooled, retrospective analysis of data from phase 3 trials of nivolumab in treatment-naive patients with advanced melanoma (CheckMate 066 or CheckMate 067) conducted at academic and clinical cancer centers. Participants were patients treated beyond first disease progression, defined as those who received their last dose of nivolumab more than 6 weeks after progression (TBP group); and patients not treated beyond progression, who discontinued nivolumab therapy before or at progression (non-TBP group). Data analyses were conducted from November 6, 2015, to January 11, 2017.  Nivolumab (3 mg/kg every 2 weeks) administered until progression or unacceptable toxic effects. Patients could be treated beyond progression if deriving apparent clinical benefit and tolerating study drug, at the investigator's discretion.  Tumor response and safety in TBP and non-TBP patients.

Among 526 randomized patients (39% [n = 203] female; median age, 62 years [range, 18-90 years]), 306 (58%) experienced disease progression, including 85 (28%) TBP patients and 221 (72%) non-TBP patients. Twenty-four (28%) of the TBP patients had a target lesion reduction of greater than 30% after progression compared with baseline (TBP greater than 30% group). At the time of this analysis, 65 (76%) TBP patients and 21 (87%) TBP greater than 30% patients were still alive; 27 (32%) and 11 (46%), respectively, continued to receive treatment. Median (range) time from progression to last dose of treatment was 4.7 (1.4-25.8) months for TBP patients and 7.6 (2.4-19.4) months for TBP greater than 30% patients. Median (range) time from progression to greater than 30% tumor reduction was 1.4 (0.2-7.0) months. Treatment-related select grade 3 to 4 adverse events were similar in the TBP and non-TBP groups (5 [6%] and 9 [4%], respectively).

A substantial proportion of selected patients treated with frontline nivolumab who were clinically stable and judged to be eligible for treatment beyond RECIST v1.1-defined progression by the treating investigators derived apparent clinical benefit without compromising safety. Further analysis will help define the potential benefit of continued nivolumab treatment beyond progression.

Here they looked at the outcomes of 3 trials in which nivo was used....in 526  patients.  306 had progression.  But 85 of those who progressed were given nivo more than 6 weeks AFTER their known progression, while 221 were not. Of those 85 patients "treated beyond progression", 24 "had a target lesion reduction of greater than 30% after progression compared to baseline."  And at follow-up further down the line, many of those were still alive.

There is much we still don't understand about immunotherapy.  But, I think the statement Agarwala and Weber made to, "Be patient with the patient!" still holds.  Hang tough, ratties! And, thanks!  - c

Dr. Daud reviews ASCO 2016 - immunology updates for melanoma

Here is a link (not sure if you will be able to access it or not...you may have to log in via email, etc) to a review of ASCO 2016 presentations by Dr. Adil Daud, of San Francisco:  Primeoncology.org - 2016 Immunology oncology melanoma updates - Daud

As I mentioned when I did my review of ASCO abstracts in May and June, there was not much 'NEW' news....just confirmation of what previous studies were showing.  This review does not demonstrate much more than what we already know...but there are a few cool slides...for what it's worth:

Keynote - 001:  3 year overall survival (OS) in patients with advanced melanoma treated with Pembrolizumab (Keytruda)

• Most common immune related side effects in order of incidence were:  hypothyroidism, pneumonitis, colitis.
• No difference in OS between the 3 dosing arms (Pembro at 2mg/kg q 3wk, vs 10mg/kg q 3wk, vs 10mg/kg q 2 wks).
• Progression free survival (PFS) is better in the ipi naive patients.

Demonstrates complete responders and when they stopped taking pembro.

Median time to response = 3 months.

Median time to complete response = 13 months but some did not achieve complete response until 33 months.

If you've had a complete response, (and remember - these folks have STOPPED the med) your chance of a durable response is 97%.

 Keynote - 006:  Pembro vs Ipi

• OS with ipi @ 26 mo = 43%
• OS with pembro @ 26 mo = 55%
• PFS with ipi @ 26 mo = 14%
• PFS with pembro @ 26 mo = 30%
• However, if you are a responder to EITHER - the duration of response was about the same at 2 years.

Keynote - 006:  Pembro vs Ipi, efficacy by PD-L1 expression

• Treatment naive patients do best
• IF - you are PDL1 negative - you do better on ipi than if you're not (ie positive) in regard to PFS and OS.
• However, overall - anti-PD1 drugs still do better than ipi no matter if the patient if positive or negative for PD-L1.

Checkmate - 067:  Phase III ipi/nivo in treatment naive, advanced melanoma patients 

• 3 arms:  ipi/nivo or nivo alone or ipi alone
• ipi/nivo combo was best with ORR of 57%, followed by nivo at 44%, and ipi at 19%.
• BRAF mutant (BRAF positive) patients had a 67% ORR to the combo.  (NOTE:  Previously BRAF status had not been a proven factor in response rate.)

If you're PDL1 positive, nivo is as effective as the ipi/nivo combo when these numbers were examined statistically.

Checkmate - 064:  OS from randomized sequential nivo followed by ipi vs ipi followed by nivo.

I've had a cow and a rant...you name it...about this before:  2015: Sequential nivo then ipi = ORR of 41%. Ipi followed by nivo = ORR of 20%!!!! FDA! Are you listening???????
I really do hope that the FDA (and Dr. Flaherty) are paying attention!!! But...here you go:

Keynote - 029:  Pembro plus ipi - with ipi at only 1 mg/kg

• Bottom line - Just as effective as ipi/nivo combo where ipi is at 3 mg/kg, with fewer side effects. 

Masterkey 265:  Talimogene Laherparepvec (T-VEC) with pembro for unresectable Stage IIIB and IV melanoma patients

• T-VEC was given in injectable tumor and pembro was started via IV 5 weeks later.
• There were 21 patients.
• 6 patients had a complete response (all tumors were gone). 
• 8 patients had a partial response
• 70% of all injected LESIONS had a complete response
• 92% of injected lesions had a reduction
• 65% of NONinjected skin lesions got smaller
• 53% of NONinjected VISCERAL lesions got smaller

Dr. Daud's final points:  

Much love and appreciation to all the ratties!!! - c

Nivo/Opdivo now first line for ALL melanoma patients! BRAF positive or negative! Alone or with ipi!

FDA expands Nivolumab as first line for V600 BRAF positive patients!

In 2014, Nivo was FDA approved for use in advanced melanoma after patients had failed ipi and if BRAF positive, the BRAF inhibitors as well. In November of 2015, it gained additional approval for use as a first line drug for melanoma patients!!  BUT only if you were BRAF V600 wild type!!!!  This, in spite of numerous studies demonstrating that the response to anti-PD1 (Nivo or Pembro, actually) was the same no matter BRAF status! Here's a link with the history of Nivo/Opdivo approvals!

Now!  Check out the link at the very top. FINALLY! In all its wisdom, the FDA has recognized the results of the Checkmate-067 study in which patients treated with the nivo/ipi combo had "a reduced risk of progression by 58% compared with ipi alone in patients with advanced melanoma" while nivo alone "reduced risk of progression by 43% vs ipi" and whose outcomes for Nivo's use as a single agent or in combination with ipi were similar NO MATTER the patient's BRAF status.

Basics of the study:  945 untreated unresectable melanoma patients.  They were treated with:  Nivo 3mg/kg q 2 wks (n=316).  Ipi 3mg/kg every 3 wks (315). Ipi/nivo combo with nivo at 1mg/kg with ipi at 3mg/kg every three wks for 4 doses followed by nivo at 3mg/kg alone q2wks (314).

At 9 months:  Median PFS = 11.5 mo for combo, 6.9 mo for nivo, 2.9 mo for ipi.

PD-L1 positive patients  - PFS of 14 mo for both nivo arms vs 3.9 mo with ipi only.
PD-L1 negative patients - combo was better than single agent - with PFS of 11.2 mo with combo vs 5.2 mo with nivo alone and 2.8 mo with ipi alone.

Overall response rate:  50% with combo.  40% for nivo alone.  14% for ipi alone.
Complete response rate:  8.9% for combo. 8.5% for nivo alone.  1.9% for ipi alone.
BRAF mutant melanoma:  For combo median PFS = 11.7 months.  For nivo alone PFS = 5.6 mo.  For ipi PFS = 4 months.
BRAF wild-type:  For combo median PFS = 11.2 months.  For nivo alone PFS = 7.9 mo.  For ipi PFS = 2.8 months.

Most common side effects were the usual players:  diarrhea, colitis, increased lipase and ALT/AST levels....all to a greater extent with the combo.

Then today in the UK  there was this: Opdivo approved for advanced melanoma in England and Wales (although it is still not approved for NSC lung cancer there, yet).

About bloody time!!!!  NOW!!!!  Let's get some more approvals for Stage III/IV NED folks, shall we?????
Big thanks to Eric for finding and sharing!!  He beat B on this one!!!  - c