Pick your poison: Weber and Agarwala discuss combination therapy for melanoma

Combining immunotherapy and targeted drugs for melanoma: Weber and Agarwala
(Late note:  since publication of this post, the link above has been taken down.  However, the points below are my transcription of their commentary. - c, 2018)

The link above connects to a video discussion and slides by Dr. Jeffrey Weber and Dr. Sanjiv Agarwala regarding combination therapies and other treatment information as it relates to melanoma.  Much like the prior link I discussed, material is presented in an understandable manner in the form of a continuing education program for general oncologists and others in the field...from the horse's mouth.

Points I noted:

• BRAF is the only predictive marker for the use of BRAF inhibitors.
• 40-50% of melanoma is BRAF positive.
• The RAS-RAF-MEK-ERK MAP kinase pathway is a critical signaling path in melanoma.
• MELANOMA SUB-TYPES via landscape as origin:  
• Skin with sun damage = 50% BRAF, 20% NRAS, 0 KIT
• Skin without chronic sundamage = 22% BRAF, 0 NRAS, 19% KIT
• Mucosal = 9% BRAF, 12% NRAS, 25% KIT
• Acral = 22% BRAF, 16% NRAS, 24% KIT
• BRAF resistance develops due to reactivation of the MEK pathway.  This is why the addition of MEKi to BRAFi prevents that resistance, thereby increasing effectiveness and decreasing side effects.
•  The COMBI-d trial (dabrafenib plus trametinib vs dabrafenib alone), the Combi-V trial (dabrafenib and trametinib vs vemurafenib alone) and the CoBRIM trial (vemurafenib with cobimetinib vs vemurafenib and placebo) all demonstrate the effectiveness of combination therapy when compared to one targeted therapy alone.

Here's a link addressing BRAFi info out this year as well as earlier articles about BRAFi combo's:   BRAFi : What predicts resistance.
Here's a link regarding an article this year that addressed CoBRIM as well as PDL1 in immunotherapy combinations (which the docs address later in the video as well.):  Combos looking good but if PDL1 positive - just do nivo!

 IMMUNOTHERAPY:

• CTLA4 and PD1 put brakes on the immune system (in 2 different areas, in different ways), but ultimately prevent T cells from eradicating melanoma and other cancers.  When you turn CTLA4 and PD1 "off" with ANTI-CTLA4 (ipilimumab) and ANTI-PD1 (Nivolumab/Opdivo or Pembrolizumab/Keytruda) you allow T cells to engage and do their job.
• Studies with ipi show a plateau in overall survival of 22% at 3 years.
• When ipi is combined with GM-CSF, 1 year OS is 68% vs 52% in ipi alone.
• When ipi is combined with T-VEC (an intralesional therapy) you get a better response rate...about 55% combined complete and partial responses....than with either drug alone. NOTE: You can find more info on GM-CSF using the search bubble on my blog.  Here's a link to some of the latest on intralesional therapies out of ASCO 2015:  Intralesional therapy for melanoma: ASCO 2015
• Some questions remain with ipi: What is the optimal dose?  3mg/kg vs 10mg/kg? The 169 trial is a randomized Phase 3 trial, ongoing, looking at differences in dosage.  Trials are looking at whether ipi should be administered in the current 4 dose - then stop, protocol...or are maintenance doses helpful?  Weber feels 4 doses are sufficient, but trial results are still pending.
• Ipi as adjuvant?  The 1609 trial is looking at this question and the 10mg/kg dose is showing promise, results to be out in about a year or 2.
• Overall, ipi is showing a 10-15% response rate, BUT...there are significant numbers of those demonstrating 10 YEAR survival.
• Anti-PD1 (both products) give clearly greater responses than traditional chemo and better than ipi as well...with an overall response rate of about 40-45%.
• Folks with tumors that are positive for PD-L1 respond better to anti-PD1 products.   However, many problems remain with the clarity of the test, availability of the test, consistency of results, etc.  Therefore, it is a useful...though not a predictive...marker.
• Because CTLA4 and PD-1 work differently...combining the two antibodies....can provide even better responses.  Additionally, ipi failures can respond to anti-PD1 and anti-PD1 failures can respond to ipi.
• In an early combo study of nivo and ipi, patients experienced an ORR of 53% and 40% had significant tumor reduction.
• In another nivo/ipi combo study, there was a 61% response rate and 22% rate of complete response on the combo vs 11% and none with ipi alone.
• In PD-L1 positive patients: those in the combo had a 58% overall response vs 18% ORR to ipi alone.  PD-L1 negative patients: had an ORR of 55% to the combo vs 4% ORR to ipi alone.
• Responses were durable.  Almost all responders continued to maintain their response at a rate of 82%.  Even of patients who had to stop treatment due to side effects, 2/3 of them continued to respond.
• Grade 3/4 toxicities increase almost as much as the response in the combo with a rate of 55%, though almost all are reversible.
• In the CA209-067 study, the ipi/nivo combo was compared to ipi alone and nivo alone.  ORR were 57.6% for the combo, 19% for ipi alone and 43.7% for nivo alone.
• However, when looking at PD-L1 staining:  When positive, the difference between PFS with the ipi/nivo combo vs nivo alone is negligible. So the argument may be made to go with nivo alone...since the difference in response is minimal, but side effects are much less.  However, more definitive studies are needed.
• The ipi/nivo combo overall is providing increased response rates and increased progression free survival.  
• Survival may even be better with the combo than with sequential nivo or ipi.
• However, for PD-L1 positive patients (40% of the population) concurrent therapy may be no better than nivo alone, followed by ipi if there is progression.
• For PD-L1 negative patients, the majority of patients, the ipi/nivo combo is better than a single agent, though you have to keep in mind that fewer than 1/2 of responding patients are able to tolerate the combo longer than 24 weeks.
• A study is underway looking at planned sequential therapy giving patients ipi followed by nivo, OR nivo followed by ipi....with nivo maintenance....preliminary results to be out within a week at meeting in Vienna.
• HOW TO DECIDE, in the BRAF positive patient....between immunotherapy single vs combo vs BRAF inhibitors.  These docs report that they tend to treat indolent patients with anti-PD1 alone.  However, in patients with increased LDH and a heavy disease burden, they would lean toward using BRAFi or the ipi/nivo combo.  Or to put it another way:  BRAF positive and negative patients do equally well on anti-PD1, so BRAF positive patients with indolent disease and low tumor burden, would probably be wise to place on immunotherapy.  In fast growing disease, with a high disease burden...and BRAF positive...use a BRAF/MEK combo first.  If BRAF negative - use the ipi/nivo combo.
• Question with no current answer:  With a patient who initially responded to nivo, but then progresses...should you switch to ipi or ADD ipi?  Docs feel that a trial looking at survival with these two options should be done...though it is NOT underway currently.
• Final thought, ipi is no longer these doc's first line drug choice when used alone.  They feel that anti-PD1, even as a single agent, is going to prove to have durable responses. While ipi combo's are going to be very important.

Long, I know.  Hope it helps. - 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

Not really news, but once again: ipi/nivo combo is better than ipi alone!

Abstract 2860:  Improved clinical response in patients with advance melanoma treated with nivolumab combined with ipilimumab compared to ipilimumab alone.  Hodi, Postow, Pavlick, Agarwala, Wolchok, et al.  AACR 106th Meeting, April 2015.  Cancer Research.

Treatment-naive patients with advanced melanoma were randomized 2:1 to ipi 3mg/kg combined with nivo 1mg/kg or placebo (ie ipi alone) q3wks for 4 doses, followed by nivo 3mg/kg or placebo...q 2 wks until disease progression or toxicity.  

In BRAF wild type patients:  ORR = 60% in the nivo/ipi group vs 11% in the ipi group.  Complete  response was reported in 12 and 0 patients respectively.  Median change in target lesions was 57% reduction in the nivo/ipi group vs 4% increase for ipi alone.  Median duration of response was not reached in either group.   Median PFS was 8.9 months for combo, 4.7 months for ipi. In BRAF mutation positive patients, the results for ORR and PFS were similar.  

A higher rate of adverse events was noted in the combo group....leading to more frequent discontinuation.  Patients who discontinued the combo due to toxicity had a 67% response rate and most continue to respond.  Immune side effects were manageable with standard treatment interventions, and the majority resolved with immune-modulating meds.

So....stuff we already knew. The ipi/nivo combo provides better response rates and a greater decrease in size of target lesions compared to ipi alone...though with more side effects.  A great pearl: for those who had to stop the combo because of side effects, most CONTINUED TO RESPOND! And...BRAF status seemed to make NO difference.

And.....October 1 there was this:  BMS news release re FDA approval of nivo/ipi combo at least for some

Now why not for everybody...since we KNOW BRAF status is NOT related to success in this instance? Why not folks who are NOT treatment naive....since they may need it more than others? Those peeps may need to be informed that their response rate may be decreased from the treatment naive folks (remember the results from the sequential study!) but what results will they attain without a chance at the combo at all????!  It seems that the FDA has a very strange, tunnel vision approach to science and an inhumane approach to saving lives.  But, step by ever such small steps....we are getting more help to those in need!

Keep on truckin ratties! -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

Weber presentation on ipi combo's and combo's coming soon!

Here is a link to Weber's presentation in Paris July 2014:
Combination therapy presentation by Weber

My synopsis:

Nivolumab (anti-PD1) and ipilmumab (anti-CTLA-4) given concurrently-
Nivo at 1mg/kg and ipi at 3mg/kg for 4 doses then followed by nivo alone for 96 weeks.
Best results so far, but with significant toxicities.
Trial requires that when dose limiting toxicity develops, patient must stop trial.
Weber feels you can treat the patient with steroids and then safely resume with nivo alone.
Positive or negative BRAF status did NOT matter in regard to response.
PDL1 tends to "fall out" as a factor...folks positive or negative for it could still respond to concurrent therapy.
In concurrent cohorts = 43% overall response, 17% complete response, 79% 2 year survival
Though that still leaves 50% of patients who did not respond.

Nivo and ipi given sequentially-
Group with nivo first, followed by ipi - another with ipi first, followed by nivo
He is working on the study currently with Hodi.
The hope is that a higher dose of ipi can be administered in this manner without invoking dose limiting toxicity and yet increase response rates.

Ipi and Tvec-
The idea here is that one could prime an immune response by injecting a tumor with an oncolytic virus, eliciting a T-cell influx, and follow with systemic ipi.
Overall response rate of 56%, with 6 of 18 patients acquiring complete responses.
Weber likes the idea of priming tumors locally and following with systemic therapy, either ipi or anti-PD1.

Ipi and INCBO24360 (an IDO inhibitor)-
The problem with immunotherapy is that there are suppressive influences in the immune system - the absence of effector cells, the presence of t-reg suppressor cells (activated by LAG-3), myeloid suppressor cells, IDO (which is generated by antigen presenting cells as well as T-cells)....all working to prevent an immune response against melanoma! In this study, an IDO inhibitor was given (at either 25 or 50mg) orally, twice daily, everyday.  Ipi was given at 3mg/kg every 3 weeks.
Was well tolerated.  33% response rate.
Immunotherapy naive patients did better.
This study speaks to the ability to overcome micro-environmental immune suppression as well as increase the influx of effector cells by decreasing IDO.

Nivo and peptide vaccine-
Idea was that if you gave multi-peptide vaccine you could amplify the immune response against the peptide, and get a better response from nivo.  No evidence that this worked at all, though nivo itself did well.
100 patients, initial ones got peptide vaccines with escalating nivo dose, depending on cohort, every 2 weeks for 6 months, then nivo alone every 3 months for 2 years.
Cohort was added (later) that allowed patients who had dose limiting effects on ipi-
20 evaluable patients as one dropped out.
Got nivo alone (no vaccine).
8 confirmed partial responses and 3 stable patients at 24 weeks.  All patients who responded still remain in remission, with one being out 1 1/2 years.
Only 2 patients had dose limiting toxicity on nivo...rash and pneumonitis.
However, these were not the same DLT that they had experienced on ipi.
40% response rate.
Most anti-PD1 trials haven't allowed patients with prior bad responses to ipi.  Weber feels as these patients go to doctors seeking anti-PD1 as it comes on the market, they should be treated with it!
Back to general results-
The presence of peptides or not, ipi refractory or naive - made no difference in results.
26% response rate in these very ill patients, s/p multiple treatments.
NOTE by Weber:  The pembro studies demonstrate a significant difference in response rate between ipi naive and ipi refractory patients [with refractory doing less well].  "It makes you wonder- Are these drugs really the same?"
Looking at pretreatment parameters in the periphery and the tumor-
Only baseline MDSC, myeloid derived suppressor cells, proved to be significant.
These are CD14, HLA-DR low, CD11 B+ cells, classic myeloid derived suppressor cells which express high levels of PDL1 and other check point proteins.
Neutrophil derived MDSC cells were not related.
The more myeloid suppressor cells you have, the worse the patient did both in response rate and survival. 
Weber hopes to soon have results of the levels of MDSC from within the tumors of these patients and see how that level related to outcomes.
You can block MDSC by incubating it with PD1 antibody as well as other check point proteins, so he is writing a grant proposal currently to test a combo of nivo with MDSC depletion.
Measurements of the T-regs in the periphery - Levels decreased in responders, in non-responders it went up. For this reason, also thinks that nivo with T-reg depletion is worth investigation.
There was worse overall survival in female patients.
Given responses in this group with 2 1/2 year end-point of anti-PD1 infusion...Weber questions whether patients really need to continue anti-PD1 infusions until progression as the Pembro trials/indications have been written.

Ipi and Peg interferon-
Ipi at 3mg/kg every week for four doses with 3mg/kg peg interferon sub-q weekly for up to 3 years.
30 patients. 1 compete response. 13 partial responses. 3 with stable disease.  46% response rate.

Planned combo's-
Pembro and T-vec
Pembro and IDO inhibitor
Pembro plus BRAF plus MEK
MEDI 4736 and anti-PDL1
Nivo and anti CD137 (to start in the next month or so!!!)
Nivo and anti-LAG-3
Adjuvant ipi and Nivo (now being expanded with 1,500 patients!!!!)
     So far, in patients in the first cohort - there has been a 45% response rate, with only 20 patients and only at 8 month f/u...no relapses, and includes patients with Stage IV/IIIC melanoma.

So there you have it folks.  Hope this helps! - c

IPI/NIVO - results - in melanoma brain mets and long term follow-up in advanced melanoma

Yes.  I think the results ratties provided have finally gotten it through most researchers heads (though not the heads of all oncologists) that targeted therapy (via the BRAF/MEK combo for BRAF positive melanoma peeps) and immunotherapy WORK IN THE BRAIN!!!!  I have been reporting on this trial CheckMate 204 since 2015.  Now, there's this:

Efficacy and safety of the combination of nivolumab (NIVO) plus ipilimumab (IPI) in patients with symptomatic melanoma brain metastases (CheckMate 204).  2019 ASCO.  Tawbi, Forsyth, Hodi...Hamid...Postow, Pavlick...et al. J Clin Oncol 37, 2019 (suppl; abstr 9501)

Background: We previously reported efficacy and safety of NIVO+IPI in patients (pts) with untreated, asymptomatic, melanoma brain metastases (MBM) from the CheckMate 204 study. Here, we provide the first report of NIVO+IPI in pts with symptomatic MBM, and report updated data in pts with asymptomatic MBM. Methods:In this phase II trial, pts with  greater than/= to 1 measurable, nonirradiated MBM 0.5–3.0 cm were enrolled into two cohorts: (1) those with no neurologic symptoms or steroid Rx (asymptomatic; cohort A); and (2) those with neurologic symptoms, whether or not they were receiving steroid Rx (symptomatic; cohort B). In both cohorts, pts received NIVO 1 mg/kg + IPI 3 mg/kg Q3W × 4, then NIVO 3 mg/kg Q2W until progression or toxicity. The primary endpoint was intracranial clinical benefit rate (CBR; proportion of pts with complete response [CR] + partial response [PR] + stable disease [SD]  greater than/= to 6 mo). As of the clinical cutoff date on May 1, 2018, all treated pts (101 in cohort A and 18 in cohort B) had been followed for ~6 mo or longer. Results: In this updated analysis of cohort A (median follow-up of 20.6 mo), the CBR was 58.4% (Table). In cohort B, pts received a median of 1 NIVO+IPI dose and 2 of 18 pts (11%) received all 4 doses. At a median follow-up of 5.2 months in cohort B, intracranial objective response rate was 16.7% and the CBR was 22.2%. Grade 3/4 adverse events occurred in 54.5% of pts in cohort A and in 55.6% of pts in cohort B (6.9% and 16.7% in the nervous system, respectively), with one death related to treatment in cohort A (immune-related myocarditis). Conclusions: In pts with asymptomatic MBM, our updated results show a high rate of durable intracranial responses, further supporting NIVO+IPI as a first-line treatment in this population. Intracranial antitumor activity was observed with NIVO+IPI in pts with symptomatic MBM, but further study is needed to understand the biologic mechanisms of resistance to immunotherapy and to improve treatments in this challenging population. Clinical trial information: NCT02320058

Intracranial response	Asymptomatic (Cohort A; n = 101)	Symptomatic (Cohort B; n = 18)
Best overall response, n (%)
CR	29 (29)	2 (11)
PR	26 (26)	1 (5.6)
SD ≥6 mo	4 (4)	1 (5.6)
CBR, % (95% CI)	58.4 (48.2–68.1)	22.2 (6.4–47.6)

While I am glad to note those responses, you would be hard pressed to convince me to go with ipi/nivo alone...given all we have learned about the positive response systemic therapy COMBINED with radiotherapy provides.  You can read a zillion articles on the combo here:  
Radiation for melanoma

I am not even going to try to note ALL the posts and discussions I have reported regarding the ipi/nivo combo!  We have long known that the 15% response rate to ipi alone and the 40% average response rate to either anti-PD-1 product alone jumps to around 50+% with the ipi/nivo combo.  Just put "ipi/nivo" in the search bar to read the history for yourself.  Now, there's this:

Long-term follow-up of CA209-004: A phase I dose-escalation study of combined nivolumab (NIVO) and ipilimumab (IPI) in patients with advanced melanoma.  2019 ASCO.  Akins, Kirkwood, Wolchok, ..., Postow, ...Sznol.  J Clin Oncol 37, 2019.

Background: We previously reported a 3-year overall survival (OS) rate of 63% with NIVO+IPI concurrent therapy in the initial phase I dose-escalation study for the combination, conducted in patients (pts) with advanced melanoma. Here, we report OS after 5 years of overall study follow-up and assess survival rates after stopping treatment. Methods: Adults with previously treated or untreated unresectable stage III or IV melanoma, and ECOG performance status of 0 or 1, received NIVO + IPI Q3W × 4 as mg/kg in one of the following cohorts: (1) NIVO 0.3 + IPI 3; (2) NIVO 1 + IPI 3; (2a) NIVO 3 + IPI 1; (3) NIVO 3 + IPI 3; (8) NIVO 1 + IPI 3. Cohorts 1-3 received maintenance with NIVO Q3W × 4, then NIVO + IPI Q12W × 8 at assigned doses; cohort 8 received NIVO Q2W for up to 96 weeks. Patients were followed for the primary endpoint of safety and the secondary endpoints of response and progression-free survival for up to 2.5 years, then for the survival exploratory endpoint for up to an additional 3 years, for a maximum study participation of 5.5 years. Results: At a median follow-up of 43.1 months in all cohorts (N = 94), the 4- and 4.5-year OS rates were both 57%. The 4-year OS rates for pts with normal (n = 58) versus elevated LDH (n = 36) were 62% versus 49%; for pts with wild-type (n = 66) and mutant (n = 24) BRAF tumors, 4-year OS rates were 54% and 61%, respectively. Following the last dose of study drug (for any reason), overall post-treatment 1-, 2-, and 3-year OS rates were 74%, 65%, and 56%, respectively; in pts who discontinued due to study drug toxicity (n = 32), post-treatment 1-, 2-, and 3-year OS rates were 84%, 75%, and 65%, respectively, and in pts who discontinued for disease progression (n = 30), these were 52%, 34%, and 24%, respectively. Conclusions: This updated analysis from study CA209-004 showed favorable survival outcomes with NIVO+IPI, regardless of BRAF or LDH status, and provided evidence of long-term survival following discontinuation of treatment in pts with advanced melanoma. Clinical trial information: NCT01024231

Yep.  "...analysis from study CA209-004 showed favorable survival outcomes with NIVO+IPI, regardless of BRAF or LDH status, and provided evidence of long-term survival following discontinuation of treatment in pts with advanced melanoma."  NOW!  Let's make these numbers even better!!!

We are beautiful before, during, and after...

...the storm. ~ c

FDA approves Relatlimab plus Nivolumab (Opdivo) for advanced melanoma patients - the down and dirty on Opdualag!!!!

Finally, an additional FDA approved treatment for melanoma!!  With FDA approvals for the first immunotherapy and targeted therapy in melanoma in 2011, the addition of Nivo and Pembro in 2014, a few additional BRAF/MEK combo's in 2013 and 2018, T-VEC approved as an intralesional in 2015, immunotherapy approved as adjuvant in 2017, targeted as such in 2018 - that's been about it for new melanoma therapies.  I recently reported on study results for Relatlimab combined with Nivolumab (Opdivo) for treatment of advanced melanoma in February:  Relatlimab plus Nivolumab in advanced melanoma patients - better than Nivo (Opdivo) alone!  The main take-away from the data being:

1.  The combination of the anti-LAG-3 product relatlimab with anti-PD-1 agent Nivolumab provided better progression free survival than when melanoma patients with advanced disease were treated with nivo alone - "The median progression-free survival was 10.1 months (6.4 to 15.7) with relatlimab-nivolumab as compared with 4.6 months (3.4 to 5.6) with nivolumab. Progression-free survival at 12 months was 47.7% (41.8 to 53.2) with relatlimab-nivolumab as compared with 36.0% (30.5 to 41.6) with nivolumab. Progression-free survival across key subgroups favored relatlimab-nivolumab over nivolumab."

2.  Nivo and Pembro when used as single agents are both known (through data collection over many years) to have an approximate response rate of 40%.  The second article in the link above addressing relatlimab combined with nivo notes (though tallied as PFS):  "Median progression-free survival was 10.1 months in the combination arm and 4.6 months in the monotherapy arm. After 12 months’ follow-up, progression-free survival rates were 47.7% in the combination arm versus 36% in the monotherapy arm..."  The ipi/nivo combo is recognized to have a response rate of 50%+.  The fourth article in this 2021 post - ASCO 2021 - Outcomes of treatments on advanced disease - Reasons for HOPE!!!!! - notes:  "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)."  But, we know that PFS and OS is higher earlier on after treatment, so in the first article from this 2017 report - Do melanoma peeps with side effects to immunotherapy have a better response? - it notes:  " The 3-year OS rate of 63% is the highest observed for this patient population and provides additional evidence for the durable clinical activity of immune checkpoint inhibitors in the treatment of advanced melanoma."

3.  Though the combo had greater side effects than when nivo was taken alone - "Grade 3 or 4 treatment-related adverse events occurred in 18.9% of patients in the relatlimab-nivolumab group and in 9.7% of patients in the nivolumab group."  - we know that about 40% of patients on ipi/nivo have to stop the combo due to side effects, with about 55% experiencing grade 3/4 adverse events. 

4.  This post reviewed the Relativity trial of relatlimab and nivo in 2021 - Something "new" in melanoma treatment???? Anti-LAG-3! Again....  Despite the new data and having been reporting on anti-LAG-3 since 2014, I think my summation there still stands:

My take:  It seems that the combination of relatlimab and nivolumab (Opdivo) has a response rate that is slightly less than that of the ipi/nivo (Ipilimumab/Yervoy and Nivolumab/Opdivo) combo which has proven to be around 50+ percent, but one that is possibly better than the 40% response rate when anti-PD-1 (nivo or pembro) is used alone. Perhaps the two most important things these (still preliminary - after all these years) reports tell us is that ~

1.  Side effects, that can be so devastating and difficult in the ipi/nivo combo may be much decreased in the relatlimab/nivo combo.

2.  For reasons we don't fully understand, melanoma responds differently to the same treatment in different folks.  For me, thus far, nivolumab alone was 100% effective.  Obviously that is not the case for most melanoma patients.  So having another effective immunotherapy combination, that may well be far less than 100% effective in all of us, may still be completely effective in some.

And, finally, as ever - the drug company did not see fit to configure the trial such that the new combo went up against the old one directly.  Why not BMS?  Why not????  Why not three arms?  One with nivo alone.  One with the ipi/nivo combo? And the third with relatimab/nivo?  WHY???

5.  We still don't have durability of response data to this combo - but I would presume (given the durability we know about responses to nivo) they would be good.

SOooooooooooooooo - there you have it - a newly FDA approved combo for melanoma dubbed - OPDUALAG!!!!  (Seriously, these names!  My word!)

Now, this:

FDA Approves Relatlimab Plus Nivolumab for Unresectable or Metastatic Melanoma

March 18, 2022  Krista Rosa OncLive

The FDA has approved the fixed-dose combination of relatlimab plus nivolumab (Opdualag) for the treatment of adult and pediatric patients who are 12 years of age or older and who have unresectable or metastatic melanoma.1

The regulatory decision is based on data from the phase 2/3 RELATIVITY-047 trial (NCT03470922), which showed that the doublet (n = 355) resulted in a median progression-free survival (PFS) of 10.1 months vs 4.6 months with single-agent nivolumab (n = 359; P = .0055).

“Since the approval of the first immune checkpoint inhibitor more than 10 years ago, we’ve seen immunotherapy, alone and in combination, revolutionize the treatment of patients with advanced melanoma,” F. Stephen Hodi, MD, director of the Melanoma Center and the Center for Immuno-Oncology at Dana-Farber Cancer Institute, stated in a press release. “Today’s approval is particularly significant, as it introduces an entirely new combination of two immunotherapies that may act together to help improve anti-tumor response by targeting two different immune checkpoints — LAG-3 and PD-1.”

To be eligible for enrollment to RELATIVITY-047, patients had to have previously untreated, unresectable, or metastatic melanoma and an ECOG performance status of 0 or 1.

A total of 714 patients were randomized 1:1 to receive the fixed-dose combination of relatlimab at 160 mg and nivolumab at 480 mg administered every 4 weeks vs single-agent nivolumab at the same dose and schedule.

Patients were stratified by LAG-3 expression on immune cells in the tumor microenvironment, PD-L1 expression on tumor cells, BRAF mutational status, and AJCC v8 M stage.

The primary end point of the trial was PFS per blinded independent central review (BICR). Secondary end points included overall survival (OS) and ORR per BICR. End points were tested in hierarchy, with PFS evaluated first, followed by OS, and then objective response rate (ORR).

Baseline characteristics were well balanced between the arms. The median age of participants was 63 years, 41.7% were female, and 66.9% had an ECOG performance status of 0. The serum lactate dehydrogenase level was above the upper limit of normal in 36.1% of patients.

LAG-3 expression was 1% or higher in 75.2% of patients, and it was lower than 1% in 24.8% of patients. PD-L1 expression was at least 1% in 41.0% of patients, and lower than 1% in 59.0% of patients. Moreover, 38.5% of patients had BRAF-mutated disease, and 61.5% had BRAF wild-type disease. Lastly, 65.7% of patients had AJCC M stage of M0/M1any[0], and 34.3% had M1any[1].

Data presented during the March 2022 ASCO Plenary Series showed that at a median follow-up of 19.3 months, the median OS with the doublet had not yet been reached vs 34.10 months with nivolumab monotherapy.  Although this benefit was not found to be statistically significant, it was considered to be clinically meaningful.

Additional data showed that PFS rates continued to be higher in the doublet arm vs the monotherapy arm. At 12 months, these rates were 48.0%  and 36.9%, respectively; at 24 months, these rates were 38.5% and 29.0%, respectively.

Notably, PFS and OS benefit favored the doublet over the monotherapy across all stratification factors that were assessed.

In the investigative arm, the complete response rate achieved was 16.3%, the partial response rate was 26.8%, and 17.2% of patients experienced stable disease. Additionally, 29.6% of patients in this arm had disease progression.

The median duration of response had not yet been reached in both the relatlimab/nivolumab arm and the control arm. Moreover, the disease control rate achieved with the doublet was 62.8% vs 50.7% with the monotherapy.

Notably, fewer patients who received the doublet went on to receive subsequent therapy vs those who received single-agent nivolumab, at 40.8% and 42.6%, respectively. Specifically, fewer patients in the investigative arm received systemic therapy vs those in the control arm, at 32.7% vs 34.5%, respectively. Additionally, 11.8% of patients who received relatlimab/nivolumab went on to receive PD-L1 and/or CTLA-4 inhibitors vs 15.9% of those who received nivolumab monotherapy.

Specifically, 4.2% of patients on the relatlimab/nivolumab arm went on to recive nivolumab and ipilimumab (Yervoy), 4.2% received nivolumab monotherapy, 3.7% received ipilimumab, 1.7% received pembrolizumab (Keytruda) monotherapy, and no patients received single-agent avelumab (Bavencio); these rates were 6.7%, 5.6%, 5.3%, 2.8%, and 0.3%, respectively.

Additionally, 12.4% of patients on the investigative arm went on to receive BRAF and/or MEK inhibitors vs 14.8% of those on the control arm. Other subsequent treatment was received by 13.8% of those who received the doublet vs 12.3% of those who were given the monotherapy. Slightly more patients on the investigative arm received radiotherapy at 14.6% vs 12.3% on the control arm; however, more patients on the control arm underwent surgery, at 8.1% vs 7.0%, respectively.

The fixed-dose combination is associated with severe and fatal immune-mediated adverse reactions such as pneumonitis, colitis, hepatitis, endocrinopathies, nephritis with renal dysfunction, dermatologic adverse reactions, myocarditis, and other immune-mediated adverse reactions; infusion-related reactions. The doublet is also linked with complications of allogeneic hematopoietic stem cell transplantation and embryo-fetal toxicity.

“While we have made great progress in the treatment of advanced melanoma over the past decade, we are committed to expanding dual immunotherapy treatment options for these patients,” Samit Hirawat, chief medical officer of global drug development at Bristol Myers Squibb, added in the press release. “Inhibiting LAG-3 with relatlimab, in a fixed-dose combination with nivolumab, represents a new treatment approach that builds on our legacy of bringing innovative immunotherapy options to patients. The approval of a new medicine that includes our third distinct checkpoint inhibitor marks an important step forward in giving patients more options beyond monotherapy treatment.”

An updated "Primer of Melanoma Treatments" to be posted soon.  Hang tough, peeps! - c

ASCO 2015: Nivo plus ipi vs ipi alone. Results of the CheckMate 069 melanoma study.

Clinical response, progression-free survival, and safety in patients with advanced melanoma receiving nivolumab combined with ipilimumab vs ipi monotherapy in CheckMate 069 study.  ASCO J Clin Oncol 33, 2015.  Hodi, Postow, Chesney, Pavlick, Robert, Wolchok, et al.

Combined blockade of T cell checkpoints by Nivo and Ipi demonstrate a high objective response rate, promising overall survival, and manageable safety profile in a phase 1 study, based on which an appropriate dose was selected for registrational trials.  142 patients with metastatic and unresectable melanoma, including patients with poor prognostic factors were randomized 2:1 to receive IPI 3 mg/kg combined with either Nivo 1mg/kg or placebo every 3 weeks X 4, followed by Nivo 3mg/kg or placebo every 2 wks until disease progression or unacceptable toxicity.  Results:  In BRAF wild type (n=109) overall response rate was 60% (43/72) for Nivo plus ipi; 11% (4/37) for ipi alone. Complete responses were reported in 12 (17%) for the combo and 0 for ipi alone.  Higher overall response rate was observed for nivo plus ipi vs ipi in predefined subgroups such as:  elevated baseline LDH (53 vs 0%) M1c stage disease (62 vs 25%).  Similar results were found in 33 BRAF mutation positive patients.  Grade 3/4 AE's were reported in 51% of patients given the Nivo/ipi combo vs 20% for ipi alone and was similar across all groups.  Most resolved with immunosuppressive meds (more than 83%) with the exception of endocrinopathies.

Not really news at this point.  The ipi/nivo combo provides better results than ipi alone.  The combo causes more adverse reactions as well....  What'cha gonna do???  Hang in there, ratties!!! - c

How to deal with recurrence on or after anti-PD-1 as adjuvant or treatment for active melanoma disease

Current melanoma treatment options are nothing short of a miracle to those of us who survived the Melanoma Dark Ages when there were literally NO effective treatments available.  Still, melanoma treatment remains far from clear or easy.  Should one who is BRAF positive choose immunotherapy or targeted therapy?  Does one opt for anti-PD-1 as a single agent or combined with anti-CTLA-4 (ipi)?  [Noting that the combo is not yet approved for Stage III patients.] And if those puzzlers are not enough, what do you do if you respond to anti-PD-1 initially, but then progress either while still on it or after having been on it?  Research has been trying to grapple with these questions ~

2018:  Melanoma patients treated beyond progression with anti-PD-1  - with the conclusion that:  "Treatment beyond progression with anti-PD-1 antibody therapy might be appropriate for selected patients with unresectable or metastatic melanoma, identified by specific criteria at the time of progression, based on the potential for late responses in the setting of the known toxicity profile."

2018:  anti-PD-1 after progression - In this report, after progression on stopping anti-PD-1 the authors conclude:  "Our data suggest that anti-PD(L)1 therapy should be resumed if progression occurs after a planned anti-PD(L)1 interruption. Further prospective studies are needed to confirm these results. "

and I note: "Small numbers here and not all are melanoma patients.  But, some responses on the re-do."

A bit of a review in 2019:  Anti-PD-1 results in melanoma patients: outcomes plus responses to retreatment where the new data presented ended up with mixed and unclear results on retreatment.

This post in 2020:  Response after discontinuation of anti-PD-1 in melanoma patients whether due to disease progression, side effects or choice - presents articles that try to address what happens to patients who stop anti-PD-1 therapy.

So, as you can see, many patients and their docs are unclear as to what path is best if a patient progresses or recurs while on or after anti-PD-1 therapy.

Now, there's this:

Management of early melanoma recurrence despite adjuvant anti-PD-1 antibody therapy.  Owen, Shoushtari, Chauhan, et al.   Ann Oncol. 2020 May 6.

BACKGROUND:

Anti-PD-1 antibodies (PD1) prolong recurrence-free survival in high-risk resected melanoma; however, approximately 25-30% of patients recur within one year. This study describes the pattern of recurrence, management and outcomes of patients who recur with adjuvant PD1 therapy.

PATIENTS AND METHODS:

Consecutive patients from 16 centres who recurred having received adjuvant PD1 therapy for resected stage III/IV melanoma were studied. Recurrence characteristics, management and outcomes were examined; patients with mucosal melanoma were analysed separately.

RESULTS:

Melanoma recurrence occurred in 147 (17%) of ∼850 patients treated with adjuvant PD1. In those with cutaneous melanoma (n=136), median time to recurrence was 4.6 months (range 0.3-35.7); 104 (76%) recurred during (ON) adjuvant PD1 after a median 3.2 months, and 32 (24%) following (OFF) treatment cessation after a median 12.5 months, including in 21 (15%) who ceased early for toxicity. Fifty-nine (43%) recurred with locoregional disease only and 77 (57%) with distant disease. Of those who recurred locally, 22/59 (37%) subsequently recurred distantly. Eighty-nine (65%) patients received systemic therapy after recurrence. Of those who recurred ON adjuvant PD1, none (0/6) responded to PD1 alone; 8/33 evaluable patients (24%) responded to ipilimumab (alone or in combination with PD1), and 18/23 (78%) responded to BRAF/MEK inhibitors. Of those who recurred OFF adjuvant PD1, 2/5 (40%) responded to PD1 monotherapy, 2/5 (40%) responded to ipilimumab-based therapy, and 9/10 (90%) responded to BRAF/MEK inhibitors.

CONCLUSIONS:

Most patients who recur early despite adjuvant PD1 develop distant metastases. In those who recur ON adjuvant PD1, there is minimal activity of further PD1 monotherapy, but ipilimumab (alone or in combination with PD1) and BRAF/MEK inhibitors have clinical utility. Retreatment with PD1 may have activity in select patients who recur OFF PD1.

These researchers looked at 850 Stage III and IV melanoma patients who had their disease removed and were treated with anti-PD-1.  17% (136 patients) recurred.  Average time to recurrence was about 5 months.  76% of those patients (104) recurred while they were still taking anti-PD-1 after about 3 months.   24% of that same subgroup (32 patients) recurred in about 12 months after coming off anti-PD-1.  89 patients were given systemic therapy.  Of those who recurred while ON anti-PD-1 ~ none responded to anti-PD-1 as a single agent, 24% responded to ipi alone or in combination with anti-PD-1, and 78% responded to targeted therapy.  Of those who recurred AFTER anti-PD-1 ~ 40% responded to retreatment with anti-PD-1, 40% responded to ipi, and 90% responded to targeted therapy.  Therefore, their conclusion is as noted above.

There is also this:

Ipilimumab (IPI) alone or in combination with anti-PD-1 ((_( + PD1) in patients with metastatic melanoma (MM) resistant to PD1.  Da Silva, Ahmed, Lo, et al.  ASCO Meeting Library, 2020.

PD1 induces long-term responses in approximately 30% of MM pts, however 2/3 are resistant (innate or acquired) and will require further treatment. A subset of these pts will benefit from IPI or IPI+PD1, but these pts are yet to be identified. We sought to determine; i) response rate (RR) and survival to IPI+/-PD1 after PD1 progression, and ii) clinical predictors of response and survival to IPI+/-PD1.

MM pts resistant to PD1 and then treated with IPI+/-PD1 were studied. 

Of 330 MM pts resistant to PD1 (median time to prog 2.9 months [0.5 – 42.3], 12% adjuvant, 88% metastatic; 70% innate, 30% acquired), 161 (49%) had subsequent IPI and 169 (51%) had IPI+PD1. Characteristics at start of IPI+/-PD1 were similar in IPI vs IPI+PD1 groups (stage M1D 27% vs 34%; elevated LDH 38% vs 40%), except IPI group had more ECOG greater than/= to 1 (60% vs 34%) and less BRAF mutation (mut) (21% vs 37%). Median follow-up from start of IPI+/-PD1 was 22.3 months (19.8 - 25.8); RR was 22%, higher in IPI+PD1 (31%) vs IPI (12%). PFS and OS at 1 year were 20% and 48%, respectively; better with IPI+PD1 (27%/57%) vs IPI (13%/38%). PD1 setting (adjuvant/metastatic) and response did not impact response to IPI+/-PD1. Most pts progressing on adjuvant PD1 had IPI+PD1 (88%) and RR was 33%. Neither the interval between PD1 and IPI+/-PD1 nor use of other drugs affected response to IPI+/-PD1. RR was similar in BRAF WT (23%) vs BRAF mut (RR 21%) pts. In BRAF WT pts, RR was higher with IPI+PD1 vs IPI (38% vs 9%), while RR was similar with IPI (24%) or IPI+PD1 (19%) in BRAF mut pts. One third of BRAF mut pts had BRAF inhibitors (BRAFi) prior to IPI+/-PD1 and lower RR (13%) vs those without BRAFi (RR = 25%). High grade (greater than/= to G3) toxicity (tox) was similar with IPI+PD1 (30%) or IPI (34%), and was not associated with response. Stage III/M1A/M1B, normal LDH and treatment with IPI+PD1 were the best predictors of response. These factors, in addition to sex (male), ECOG PS = 0, BRAF mut, progressed/recurred greater than 3 months on PD1, and absence of bone mets were the best predictors of longer OS.

In pts resistant to PD1, IPI+PD1 has higher RR, longer survival, yet similar high grade tox than IPI alone. Predictive models of response & survival will help select pts for IPI+/-PD1 after progressing on PD1.

This study looked at patients who did not attain long term durable response to initial anti-PD-1 therapy - about 70% of patients.  They followed 330 melanoma patients who had progressed on or after anti-PD-1 therapy and were then treated with either ipi alone or ipi combined with anti-PD-1. Overall, patients retreated or changed to the ipi/anti-PD-1 combo had higher response rates and longer survival.

For what it's worth. - c

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 1^stdose 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