One more time....better responses when radiation is combined with immunotherapy

While we've learned that radiation alone doesn't help that much in melanoma patients:

Radiation alone, not such a good idea in melanoma!!!

Radiation of lymph node basin: not so helpful if that is all that is done...

We have also learned that radiation COMBINED with immunotherapy can make a real difference!!!

Brain mets in Melanoma - don't wait to add immunotherapy after SRS!

Nivo (Opdivo) with radiation = better for melanoma patients with brain mets

And finally....this link....that contains several more links within:  Review of abscopal responses after radiotherapy in melanoma patients

Now there is this:

A Prospective Clinical Trial Combining Radiation Therapy With Systemic Immunotherapy in Metastatic Melanoma.  Hiniker, Reddy, Maecker, et al.  Int J Radiat Oncol Biol Phys. 2016 Nov 16.  

Local radiation therapy (RT) combined with systemic anti-cytotoxic T-lymphocyte-associated protein-4 immunotherapy may enhance induction of systemic antimelanoma immune responses. The primary objective of the present trial was to assess the safety and efficacy of combining ipilimumab with RT in patients with stage IV melanoma. The secondary objectives included laboratory assessment of induction of antimelanoma immune responses.  In our prospective clinical trial, 22 patients with stage IV melanoma were treated with palliative RT and ipilimumab for 4 cycles. RT to 1 to 2 disease sites was initiated within 5 days after starting ipilimumab. Patients had greater or equal to1 nonirradiated metastasis measuring greater or equal to 1.5 cm available for response assessment. Tumor imaging studies were obtained at baseline, 2 to 4 weeks after cycle 4 of ipilimumab, and every 3 months until progression. Laboratory immune response parameters were measured before and during treatment.  Combination therapy was well-tolerated without unexpected toxicities. Eleven patients (50.0%) experienced clinical benefit from therapy, including complete and partial responses and stable disease at median follow-up of 55 weeks. Three patients (27.3%) achieved an ongoing systemic complete response at a median follow-up of 55 weeks (range 32-65), and 3 (27.3%) had an initial partial response for a median of 40 weeks. Analysis of immune response data suggested a relationship between elevated CD8-activated T-cells and response.  This is the second prospective clinical trial of treatment of metastatic melanoma using the combination of RT and systemic immunotherapy and the first using this sequence of therapy. The results from the present trial demonstrate that a subset of patients may benefit from combination therapy, arguing for continued clinical investigation of the use of RT combined with immunotherapy, including programmed cell death 1 inhibitors, which might have the potential to be even more effective in combination with RT.

We still have folks being told by oncologists that they can't combine SRS and immunotherapy or can't have one after the other "too soon" due to some sort of bad effect.  Now, while there may be a few exceptions where that reasoning may apply, it is not where the data is leading us!!!  Think Jimmy Carter.  Cut out the liver met, zap the brain tumor, start anti-PD1....zip, zap, boom.  He's already off meds and latest report says melanoma free!!!

Hang tough ratties!  Take reports to your docs as needed!!! Wishing you well. - c

2 year survival outcomes for ipi/nivo combo. Ipi/nivo does better than ipi alone.

No real surprises here!!!

Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial.  Hodi, Chesney, Pavlick, McDermott, Agarwala, Wolchok, Postow, et al.  Lancet Oncol. 2016 Sep 9.

Results from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged progression-free survival with the combination of nivolumab (an anti-PD-1 antibody) plus ipilimumab (an anti-CTLA-4 antibody) compared with ipilimumab alone. We report 2-year overall survival data from a randomised controlled trial assessing this treatment in previously untreated advanced melanoma.

In this multicentre, double-blind, randomised, controlled, phase 2 trial (CheckMate 069) we recruited patients from 19 specialist cancer centres in two countries (France and the USA). Eligible patients were aged 18 years or older with previously untreated, unresectable stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 2:1 to receive an intravenous infusion of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or ipilimumab 3 mg/kg plus placebo, every 3 weeks for four doses. Subsequently, patients assigned to nivolumab plus ipilimumab received nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity, whereas patients allocated to ipilimumab alone received placebo every 2 weeks during this phase. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by BRAF mutation status. The study funder, patients, investigators, and study site staff were masked to treatment assignment. The primary endpoint, which has been reported previously, was the proportion of patients with BRAFV600 wild-type melanoma achieving an investigator-assessed objective response. Overall survival was an exploratory endpoint and is reported in this Article. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all treated patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01927419, and is ongoing but no longer enrolling patients. 

Between Sept 16, 2013, and Feb 6, 2014, we screened 179 patients and enrolled 142, randomly assigning 95 patients to nivolumab plus ipilimumab and 47 to ipilimumab alone. In each treatment group, one patient no longer met the study criteria following randomisation and thus did not receive study drug. At a median follow-up of 24·5 months, 2-year overall survival was 63·8% for those assigned to nivolumab plus ipilimumab and 53·6%  for those assigned to ipilimumab alone; median overall survival had not been reached in either group. Treatment-related grade 3-4 adverse events were reported in 51 (54%) of 94 patients who received nivolumab plus ipilimumab compared with nine (20%) of 46 patients who received ipilimumab alone. The most common treatment-related grade 3-4 adverse events were colitis (12 [13%] of 94 patients) and increased alanine aminotransferase (ten [11%]) in the combination group and diarrhoea (five [11%] of 46 patients) and hypophysitis (two [4%]) in the ipilimumab alone group. Serious grade 3-4 treatment-related adverse events were reported in 34 (36%) of 94 patients who received nivolumab plus ipilimumab (including colitis in ten [11%] of 94 patients, and diarrhoea in five [5%]) compared with four (9%) of 46 patients who received ipilimumab alone (including diarrhoea in two [4%] of 46 patients, colitis in one [2%], and hypophysitis in one [2%]). No new types of treatment-related adverse events or treatment-related deaths occurred in this updated analysis.   

Although follow-up of the patients in this study is ongoing, the results of this analysis suggest that the combination of first-line nivolumab plus ipilimumab might lead to improved outcomes compared with first-line ipilimumab alone in patients with advanced melanoma. The results suggest encouraging survival outcomes with immunotherapy in this population of patients.

Good to see durable responses.  Good to see no new side effects presented. Cause Lord knows we got enough of those already!!!!  See the latest listing I put together here:   Side effects to immunotherapy: Part 5

 - c

Travel Chaotically: Chicago - through an artist's eye!

B's pics are lovely, no??? - c

Prolonged survival in Stage III melanoma treated with ipi as adjuvant!!!

Having developed brain and lung mets in 2010, I was unceremoniously thrust from my 2003 Stage 3b melanoma diagnosis to Stage IV!  I got busy ~ zapping the brain met and removing the upper lobe of my lung to rid myself of the melanoma there.  Then...nothing.  There were no FDA approved drugs for melanoma available (other than interferon...so, yeah.  Nothing.).  No BRAFi, ipi, much less anti-PD1.  Trials were practically nonexistent, because, as I quickly discovered, almost all of them required "measurable disease", something I had just gone to a great deal of trouble to rid myself of!!!!  Through perseverance, almost endless computer searches and phone calls bordering on the level of insanity, B did find one trial for which I qualified - the NED arm of a Phase 1 Nivo/vaccine trial at Moffit.  (This was back when Nivolumab, now Opdivo, was known as MDX1106 and I was certain melanoma was going to kill me!!)  Despite how well I and my fellow ratties have done for the most part (blessings and sorrow for those who did not fare as well) adjuvant treatments for melanoma patients are still hard to find.  It should not be this way!!!  

Here is one recent post addressing "progress" for NED melanoma patients as well as a link to the results of my NED/nivo study:  Surgical management and adjuvant therapy for high risk melanoma - still waiting for answers!!

The only FDA approved treatments for NED patients currently, are interferon (Crazy, right????) and ipi. Now there is this report:

Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy.  Eggermont, Chiarion-Sileni, Grob, Dummer, Wolchok, Schmidt, Hamid, Robert, Ascierto, Richards, Lebbé, Ferraresi, Smylie, Weber, ... , Hodi , et al.  N Engl J Med. 2016 Oct 7. 

On the basis of data from a phase 2 trial that compared the checkpoint inhibitor ipilimumab at doses of 0.3 mg, 3 mg, and 10 mg per kilogram of body weight in patients with advanced melanoma, this phase 3 trial evaluated ipilimumab at a dose of 10 mg per kilogram in patients who had undergone complete resection of stage III melanoma. After patients had undergone complete resection of stage III cutaneous melanoma, we randomly assigned them to receive ipilimumab at a dose of 10 mg per kilogram (475 patients) or placebo (476) every 3 weeks for four doses, then every 3 months for up to 3 years or until disease recurrence or an unacceptable level of toxic effects occurred. Recurrence-free survival was the primary end point. Secondary end points included overall survival, distant metastasis-free survival, and safety. At a median follow-up of 5.3 years, the 5-year rate of recurrence-free survival was 40.8% in the ipilimumab group, as compared with 30.3% in the placebo group. The rate of overall survival at 5 years was 65.4% in the ipilimumab group, as compared with 54.4% in the placebo group. The rate of distant metastasis-free survival at 5 years was 48.3% in the ipilimumab group, as compared with 38.9% in the placebo group. Adverse events of grade 3 or 4 occurred in 54.1% of the patients in the ipilimumab group and in 26.2% of those in the placebo group. Immune-related adverse events of grade 3 or 4 occurred in 41.6% of the patients in the ipilimumab group and in 2.7% of those in the placebo group. In the ipilimumab group, 5 patients (1.1%) died owing to immune-related adverse events.  As adjuvant therapy for high-risk stage III melanoma, ipilimumab at a dose of 10 mg per kilogram resulted in significantly higher rates of recurrence-free survival, overall survival, and distant metastasis-free survival than placebo. There were more immune-related adverse events with ipilimumab than with placebo. 

Not surprisingly, Stage III, NED folks treated with ipi did much better than those without treatment in recurrence-free survival, overall survival, and in their rate of distant metastasis.  Also, not surprisingly, they developed more side effects from ipi than did the folks who did not get it!!!  All of this is good news. (Well...not the side effects!!!)  Hopefully, the folks who responded will remain melanoma free forever.  BUT! This is not enough.  Anti-PD1 remains off limits for these same patients....even though we KNOW that these drugs have a better response rate, fewer side effects, AND when taken BEFORE ipi - a much higher response rate than when taken after!!!  Check out this link - to the tune of... Sequential nivo then ipi = ORR of 41%. Ipi followed by nivo = ORR of 20%!!!! FDA! Are you listening??????? 

While I am thrilled that Stage III/IV NED melanoma patients DO have ipi available to them and that this report confirms its value ~ and while I would have jumped at the chance to take ipi back in 2010 ~ we can do better.  These folks deserve better.  And no, I will not stop saying it!!!!! - c

Stopping BRAF/MEKi after a complete response? Case study of 12 melanoma patients...

A question I know many BRAFi patients have....

Cessation of targeted therapy after a complete response in BRAF-mutant advanced melanoma: a case series.  Carlino, Vanella, Girgis, ... Ascierto.  Br J Cancer. 2016 Oct 6. 

It is unknown whether melanoma patients achieving complete response (CR) with targeted therapy can safely discontinue treatment.  All patients treated with BRAF/MEK inhibitors achieving CR and ceasing treatment before progression were identified. Clinical data at treatment initiation, cessation and progression were examined.  A total of 12 eligible patients were identified, with median follow-up of 16 months, of whom 6 (50%) recurred at a median of 6.6 months after treatment cessation. One patient lost to follow-up until presentation with symptomatic recurrence was the only relapser to die. At relapse, the remaining five patients had an LDH less than 1.2 times ULN, four were ECOG 0 and one ECOG 1. Baseline characteristics and time to CR and to discontinuation did not influence the rate of relapse. A large proportion of patients achieving CR with BRAF/MEK inhibitors relapse after treatment cessation. The optimal treatment duration in such patients is unclear, particularly where alternative treatments are available. 

Hmmm... Well that didn't work out so well for these 12 patients.  Perhaps...though small numbers with limited ability to extrapolate from....BRAFi patients with a complete response should switch quickly to immunotherapy before time runs out????? - Just thinking out loud.  My best to you all. - c

For Josh and John - use of interleukin-2....today....

As I've spoken about before, my very first oncologist looked at me 13 years ago with tears in his eyes and said, "Renal cell carcinoma and melanoma are the cancers I hate most."  As disconcerting as it was to hear, he had good reason for that opinion!  Until recently, patients with these cancers had very few effective treatment options.  Now, however, we are learning that immunotherapy can shine a light of hope for both.  My dear John being one of these peeps in urothelial cancer wold!!!  And as Joshie has experienced first hand...twice...IL-2 is an older drug in melanoma world that can provide durable responses, albeit for a small number of treated patients.  Now there is this:

Contemporary experience with high-dose interleukin-2 therapy and impact on survival in patients with metastatic melanoma and metastatic renal cell carcinoma.  Alva, Daniels, Wong, ... McDermott, Agarwala et al.  Cancer Immunol Immunother. 2016 Oct 6. 

High-dose interleukin-2 (HD IL-2) was approved for treatment of metastatic renal cell carcinoma (mRCC) in 1992 and for metastatic melanoma (mM) in 1998, in an era predating targeted therapies and immune checkpoint inhibitors. The PROCLAIM^SM registry was established to collect and analyze data for patients treated with HD IL-2 in the current era. This analysis includes 170 patients with mM and 192 patients with mRCC treated between 2005 and 2012 with survival data current as of July 27, 2015. For patients with mM, complete response (CR) was observed in 5 %, partial response (PR) in 10 %, stable disease (SD) in 22 %, and 63 % had progressive disease (PD). The median overall survival (mOS) for these patients was 19.6 months, with a median follow-up of 43.1 months. The mOS was not reached for patients achieving CR or PR, and was 33.4 months for patients with SD. For patients with mRCC, 6 % achieved CR, 9 % had PR, 22 % had SD, and 62 % had PD. The mOS was 41 months, with a median follow-up of 46.6 months. The mOS for patients who had CR and PR was not reached and was 49.6 months for patients with SD. There were no treatment-related deaths among 362 patients. The duration of mOS for patients with mM and mRCC is longer than historically reported. These data support a continued role for IL-2 in the treatment of eligible patients with mM or mRCC and warrant further evaluation of HD IL-2 in combination or sequence with other therapeutic agents.

My hope is that IL-2 can be made much more useful when combined with TIL and/or immunotherapy as is already underway in current studies.  Hang in there ratties...of all stripes!!! love, c

I KNOW ~ but: LIVE!!!!

Just like everybody else, I have worries, anxieties, irritations, frustrations, conflicts...as well as joy, happiness and love in my life.  I am lucky - in many ways.  Others have experienced, and are currently facing, challenges, losses, and struggles that I can only imagine.  Some are only just now embarking on the frightening and complex melanoma journey I, along with many others, have been living for over 13 years.

But, that's the thing, isn't it?  LIVING!!!!  No matter how sucky and miserable and painful your day may be - it is a day.  And we are not blessed with that many...no matter who we are. So, the advice I give myself is:  LIVE!!!

"Begin doing what you want to do now.  We are not living in eternity.  We have only the moment.  Sparkling like a star in our hand - and melting like a snowflake."  ~  Francis Bacon, Sr.

Blessings and love to you all.  LIVE! - c