More and more clarifying data have researchers convinced that abscopal effects and better patient outcomes when radiation is combined with a variety therapies are very real. Now they are working to figure out HOW it happens, so that it can happen for more people. Here's a roundup of some of the latest research:
Here's a link to a post from an article that speaks to the benefit of combining SRS with PD1 blockade: srs-combined-with-anti-pd1-makes-things-better! (for mice at least)
Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. Deng, Liang, Burnette, et al. The Journal of Clinical Investigation, Feb. 2014.
High dose...radiation results in direct tumor cell death...augments tumor-specific immunity, which enhances tumor control...locally and distantly. Unfortunately, local relapses often occur [after radiation] indicating that [radiation] induced responses are inadequate to maintain antitumor immunity. Therapeutic blockade of the T cell negative regulator PD-L1 can enhance T cell effector function when PD-L1 is expressed in chronically inflamed tissues and tumors. [These researchers] demonstrate that PD-L1 was upregulated [around the tumor] after radiation. Concomitant with tumor regression from radiation, they noted that radiation and anti-PD-L1 worked together to reduce the local accumulation of tumor-inflitrating myeloid-derived suppressor cells (MDSCs)... {Note: Remember, these are the bad guys that block your T cells. In my study, the folks with high levels of MDSCs did least well, while those with the lowest levels did better. That's why, some researchers, like Weber, are talking about depleting these cells in patients FIRST...then administering anti-PD1 or other immunotherapies!!} So...the data acquired in this study demonstrated evidence of the interaction between radiation and T cells....and a basis for the rational design of combination therapy with immune modulators and radiotherapy.
Radiotherapy and Immunogenic Cell Death. Golden and Apetoh. Seminars in Radiation Oncology, Jan 2015.
In their review of radiotherapy induced immunogenic cell death....these peeps noted: Advances in understanding the mechanisms that underlie the interplay between radiation-invoked immune responses and tumor regression are underway. ... The dispersion of radiotherapy-induced immune-stimulating tumor antigens released from dying tumor cells into the surround milieu is one such exploitable process that contributes to the propagation of antitumor immunity. Downstream components of the immune system may suppress, promote or ambiguously affect antitumoral responses.
Combination of Radiotherapy and Immune Checkpoint Inhibitors. Pilones, Vanpoiulle-Box, and Demaria. Seminars in Radiation Oncology. Jan 2015
...only recently [the ability of radiation to cause cell death and inflammatory reactions] has attracted the attention of immunologists seeking to induce or improve antitumor immunity. As immune checkpoint inhibitors are becoming mainstream cancer treatments, radiation oncologists have begun to observe unexpected out-of-the-field (abscopal) responses in patients receiving radiation therapy during immunotherapy. These unexpected responses were predicted by experimental work in preclinical tumor models and have clear biological bases. ....evidence that radiation induces an immunogenic cell death and promotes recruitment and function of T cells within the tumor microenvironment supports the hypothesis that radiation can convert the tumor into an in situ individualized vaccine. This property of radiation is key to its synergy with immune checkpoint inhibitors, antibodies targeting inhibitory receptors on T cells such as cytotoxic T lymphocyte antigen-4 and programmed death 1. By removing obstacles hindering the activation and function of antitumor T cells, these agents benefit patients with pre-existing antitumor immunity but are ineffective in patients lacking these spontaneous responses. Radiation induces antitumor T cells complementing the activity of immune checkpoint inhibitors.
Stereotactic Radiosurgery for Melanoma Brain Metastasis in Patients Receiving Ipilimumab: Safety Profile and Efficacy of Combined Treatment. Kiess, Wolchok, Baker, et al. Int J Radiat Oncol Biol Phys. 2015 March.
Ipi is a monoclonoal antibody against cytotoxic T-lymphocyte antigen-4, and has been shown to improve survival in patients with metastatic melanoma. From 2005 - 2011, 46 patients with melanoma were given ipi and SRS for brain mets. Radiation was a single dose. Ipi was given at 3 or 10 mg/kg for 4 doses. 15 patients had SRS during ipi. 19 had SRS before ipi. 12 had SRs after ipi. Patients treated with SRS during or before ipi had better overall survival and less regional recurrence. (1 year OS = 65% vs 56% vs 40%. 1 year regional recurrence = 69% vs 64% vs 92%) On MRI, an increase in BM diameter up to more than 150% was seen in 50% of patients treated during or before ipi, but in only 13% of patients treated after ipi. Overall, ipi and SRS were well tolerated and concurrent delivery of ipi and SRS is associated with favorable locoregional control and possibly longer survival. It may also cause a temporary increase in tumor size, possibly because of an enhanced immunomodulatory effect.
Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Victor, Rech, Maity, Rengan, et al. Nature. March 2015.
Immune checkpoint inhibitors result in impressive clinical responses, but optimal results will require combination with each other and other therapies....Here we report major tumor regressions in a subset of patients with metastatic melanoma treated with [ipi] and radiation, and reproduced this effect in mouse models. Although combined treatment improved responses in irradiated and unirradiated tumors, resistance was common....analysis of mice revealed that resistance was due to upregulation of PD-L1 on melanoma cells and associated with T cell exhaustion. ...Ipi (anti-CTLA4) inhibits T reg cells, thereby increasing the CD8 T cell to T reg ration. Radiation enhances the diversity of the T cell receptor repertoire of intratumoral T cells. Addition of PD-L1 blockade reverses T cell exhaustion to mitigate depression in the CD8/Treg ratio and further encourages ....T cell expansion. Like the mice, patients on our clinical trial with melanoma showing high PD-L1 did not respond to radiation plus anti-CTLA4, demonstrated persistent T cell exhaustion, and rapidly progressed. Thus, PD-L1 on melanoma cells allows tumors to escape anti-CTLA4 based therapy, and the combination of radiation, anti-CTLA4 and anti-PD-L1 promotes response and immunity through distinct mechanisms.
From mice to ratties and back to mice again. Thanks to both, the mechanism and chain of events stimulated by radiation is becoming clear. It certainly seems that one should get your radiation BEFORE or DURING ipi (and probably other immunotherapies as well). While radiation kills some tumor cells directly, perhaps more importantly, it sets off an immune response caused by an influx of tumor cell antigens. When that response is aided by either anti-PD1, anti-CTLA-4 or both, T reg suppressor cells can be blocked, CD8 fighter T cells are increased, T cell exhaustion can be reversed and the invisible shroud in which melanoma cells like to hide, evaporates. Despite the incredulity that must be swallowed to acknowledge that a somewhat mystical, minute, but deadly cellular war is being waged within my own body.....it sounds good to me!!! - c
Sunday, March 29, 2015
Friday, March 27, 2015
NEW ipi vs nivo trial for resected melanoma patients!!!!!!!!!!!!!!!!!!!!!!!!
With all the advancements (ie new drugs) that have occurred over the past 4 years in the treatment of melanoma, several large HICCUPS remain for many, many patients.
But first....a quick review:
Ipi (Ipilimumab or Yervoy) - a CTLA-4 checkpoint inhibitor (immunotherapy). FDA approved for patients with Stage IV metastatic melanoma. Response rate = 15-20% for those patients.
BRAF inhibitors (Dabrafenib [Tafinlar] and Vemurafenib [Zelboraf]) - work only in patients with the BRAF mutation. FDA approved for metastatic melanoma. Response rate = 50-80% (depending on the group and study you look at - most researchers have now agreed upon 70% as the response rate). Big problem with these drugs, apart from their effectiveness being limited to patients with the mutation, is that the duration of their effectiveness has been documented to be only 3-7 months. However, with the addition of MEK inhibitors (Trametinib, Cobimetinib, Binimetinib, Selumetinib, and a few others) taken simultaneously, duration of effect has been lengthened and side effects have been diminished.
Anti-PD1 drugs (Nivolumab [Opdivo] and Pembrolizumab [Keytruda]) - Both are FDA approved for patients with Stage IV metastatic melanoma AFTER having failed ipi and BRAFi (if BRAF positive). Have about a 40% response rate.
Have you guessed the HICCUPS yet? Well, the first and most obvious one....is that the two drugs with the BEST RESPONSE RATES, given duration of effect and side effect profile, are FDA approved (read: that's how insurance will pay for them!!!) only AFTER patients have failed to respond to ipi and BRAFi. I could go on and on about that...but here is the other HICCUP....
I have had melanoma skin lesions, brain mets, a lung met and a tonsilar met. I was also lucky enough to participate in a nivo trial for resected patients in 2010, took the drug for 2 1/2 years...and have been NED ever since. BUT!!! WHAT if? What if I get a met, that I would be lucky enough to have surgically removed (because that....after all...is still what helps patients survive melanoma the most!!!)? What treatment would I, a Stage IV melanoma patient with multiple recurrences, have access to after I removed the new met? ONLY ONE!!!!!!!!!!!!
Interferon!! An ancient immunotherapy that was offered to me when I was first diagnosed. It makes patients so sick that few are able to complete the year that is recommended and has a response rate of MAYBE 10% with very little impact on overall survival.
STILL!!!! After all this time. After all the ratties who like me....are doing well after resection and ANY of the drugs listed above. After study after study has PROVEN that all of these drugs work best when the patient has the lowest disease burden possible. That's it. If you have Stage III/IV melanoma and have surgery to remove your tumor....the only option you have for treatment without being in a trial...is interferon. (Even IL2 is not used in an adjuvant setting....and I'm not sure it should be since it is such a tough therapy that 2-3% of patients can die from the drug alone and that risk may not be a wise balance when you are resected.)
So...if you have resected melanoma with a high risk of recurrence here are your options:
Adjuvant trials currently being offered include -Vitamin supplements, various vaccines, quality of life and family hx with observation measurements, nifty tests to ID tumor markers, radiation, electroporated autologous dendritic cells, IL 2 vs Dacarbazine, Ipi vs high dose interferon, Tamimogene Lakerparevec and surgery vs surgery alone, Vemurafenib vs placebo, Dabrafenib with trametinib, and though not yet recruiting - Pembrolizumab vs placebo.
That's it. Those are the trial options for resected patients. The drugs with the most effect are often placed up against placebo. But....there is a new trial option just starting....
IPI vs NIVO for Stage IIIb/c or Stage IV melanoma after complete resection
Dr. Weber spoke to us about it on our last visit, but it has only just been posted to the ClinicalTrials.gov site. It is not yet recruiting, but will be soon. I don't know of locations other than Tampa yet. Complete resection is required. No previous cancer treatments are allowed. Patients with ocular and uveal melanoma are excluded.
So...there's the info. It is certainly a trial I would have signed up for had it been available in 2010. I hope it helps many. Here's to the ratties....who someday will convince the powers that be, that folks with resected melanoma need better REAL treatment options!!! - c
But first....a quick review:
Ipi (Ipilimumab or Yervoy) - a CTLA-4 checkpoint inhibitor (immunotherapy). FDA approved for patients with Stage IV metastatic melanoma. Response rate = 15-20% for those patients.
BRAF inhibitors (Dabrafenib [Tafinlar] and Vemurafenib [Zelboraf]) - work only in patients with the BRAF mutation. FDA approved for metastatic melanoma. Response rate = 50-80% (depending on the group and study you look at - most researchers have now agreed upon 70% as the response rate). Big problem with these drugs, apart from their effectiveness being limited to patients with the mutation, is that the duration of their effectiveness has been documented to be only 3-7 months. However, with the addition of MEK inhibitors (Trametinib, Cobimetinib, Binimetinib, Selumetinib, and a few others) taken simultaneously, duration of effect has been lengthened and side effects have been diminished.
Anti-PD1 drugs (Nivolumab [Opdivo] and Pembrolizumab [Keytruda]) - Both are FDA approved for patients with Stage IV metastatic melanoma AFTER having failed ipi and BRAFi (if BRAF positive). Have about a 40% response rate.
Have you guessed the HICCUPS yet? Well, the first and most obvious one....is that the two drugs with the BEST RESPONSE RATES, given duration of effect and side effect profile, are FDA approved (read: that's how insurance will pay for them!!!) only AFTER patients have failed to respond to ipi and BRAFi. I could go on and on about that...but here is the other HICCUP....
I have had melanoma skin lesions, brain mets, a lung met and a tonsilar met. I was also lucky enough to participate in a nivo trial for resected patients in 2010, took the drug for 2 1/2 years...and have been NED ever since. BUT!!! WHAT if? What if I get a met, that I would be lucky enough to have surgically removed (because that....after all...is still what helps patients survive melanoma the most!!!)? What treatment would I, a Stage IV melanoma patient with multiple recurrences, have access to after I removed the new met? ONLY ONE!!!!!!!!!!!!
Interferon!! An ancient immunotherapy that was offered to me when I was first diagnosed. It makes patients so sick that few are able to complete the year that is recommended and has a response rate of MAYBE 10% with very little impact on overall survival.
STILL!!!! After all this time. After all the ratties who like me....are doing well after resection and ANY of the drugs listed above. After study after study has PROVEN that all of these drugs work best when the patient has the lowest disease burden possible. That's it. If you have Stage III/IV melanoma and have surgery to remove your tumor....the only option you have for treatment without being in a trial...is interferon. (Even IL2 is not used in an adjuvant setting....and I'm not sure it should be since it is such a tough therapy that 2-3% of patients can die from the drug alone and that risk may not be a wise balance when you are resected.)
So...if you have resected melanoma with a high risk of recurrence here are your options:
Adjuvant trials currently being offered include -Vitamin supplements, various vaccines, quality of life and family hx with observation measurements, nifty tests to ID tumor markers, radiation, electroporated autologous dendritic cells, IL 2 vs Dacarbazine, Ipi vs high dose interferon, Tamimogene Lakerparevec and surgery vs surgery alone, Vemurafenib vs placebo, Dabrafenib with trametinib, and though not yet recruiting - Pembrolizumab vs placebo.
That's it. Those are the trial options for resected patients. The drugs with the most effect are often placed up against placebo. But....there is a new trial option just starting....
IPI vs NIVO for Stage IIIb/c or Stage IV melanoma after complete resection
Dr. Weber spoke to us about it on our last visit, but it has only just been posted to the ClinicalTrials.gov site. It is not yet recruiting, but will be soon. I don't know of locations other than Tampa yet. Complete resection is required. No previous cancer treatments are allowed. Patients with ocular and uveal melanoma are excluded.
So...there's the info. It is certainly a trial I would have signed up for had it been available in 2010. I hope it helps many. Here's to the ratties....who someday will convince the powers that be, that folks with resected melanoma need better REAL treatment options!!! - c
Monday, March 23, 2015
Fault lines and the Hypnotic Eye....
Put this on and listen while you read!!!!
Tom Petty's Fault Lines
See those fault lines
Laid out like land mines,
It's hard to relax.
A promise broken, the ground breaks open
Love falls through the cracks.
And I got a few of my own
I got a few of my own fault lines.
Running under my life
Running under my life.
I'm alone here
I play the odds dear
I go where I please.
Down below the man I know,
Might not be me.
And I got a few of my own
I got a few of my own fault lines.
Running under my life
Running under my life.
On the high wire
Above the wild fire
An old acrobat, on faulty cable
Still he's able....not to fall flat.
And I got a few of my own
I got a few of my own fault lines.
Running under my life
Running under my life.
___________________________________________________
Awesome, no???? B brought Tom Petty, Joni Mitchell, Star Wars (even though I'd played the soundtrack a million times in high school band productions), Leo Kottke, flamenco and many other things art and musical to my life. While all of the songs are now imbedded in MY brain, and he will not remember them tomorrow, he is very good at picking what I like. He is also, FAIRLY good, at having the patience to listen, as best as I can share, to what things sound like in MY head. So....a few bars in....he had to listen to this...(Music HE should know...but does not...while I've known the entire album since early childhood!!!!)....
The Ventures - Tequila
Can you hear it???? The multiple syncopated guitar lines? The steady snare back beat? The minor chords? Maybe it's just me....
Petty's has much better recording equipment. Better lyrics. The entire album is really good...and I rarely say that. Blues, country rock, jazzy soft melodies....and the lyrics....
"How am I gonna tell her that I love her? When words don't mean a thing. And I'm a full grown boy."
"Now you see him against the sky. Believing in his own lies, and he's power drunk..."
"I feel like a four letter word. I know what few can know. How angry words can pierce the heart. How a soul can sink so low..."
"When the past gets up in your face. Memories slide out of place. All those things that were hidden away, ain't so bad in the light of day. You say you love me, wish you liked me more. I'm no angel that's for sure. Said you forgave me each time I was caught. But you still paint me as something I'm not. Oh, let me tell you the truth. I love you more, than the sins of my youth."
Don't know about you...but I've got a few fault lines.....running under my life!!!! - c
Tom Petty's Fault Lines
See those fault lines
Laid out like land mines,
It's hard to relax.
A promise broken, the ground breaks open
Love falls through the cracks.
And I got a few of my own
I got a few of my own fault lines.
Running under my life
Running under my life.
I'm alone here
I play the odds dear
I go where I please.
Down below the man I know,
Might not be me.
And I got a few of my own
I got a few of my own fault lines.
Running under my life
Running under my life.
On the high wire
Above the wild fire
An old acrobat, on faulty cable
Still he's able....not to fall flat.
And I got a few of my own
I got a few of my own fault lines.
Running under my life
Running under my life.
___________________________________________________
Awesome, no???? B brought Tom Petty, Joni Mitchell, Star Wars (even though I'd played the soundtrack a million times in high school band productions), Leo Kottke, flamenco and many other things art and musical to my life. While all of the songs are now imbedded in MY brain, and he will not remember them tomorrow, he is very good at picking what I like. He is also, FAIRLY good, at having the patience to listen, as best as I can share, to what things sound like in MY head. So....a few bars in....he had to listen to this...(Music HE should know...but does not...while I've known the entire album since early childhood!!!!)....
The Ventures - Tequila
Can you hear it???? The multiple syncopated guitar lines? The steady snare back beat? The minor chords? Maybe it's just me....
Petty's has much better recording equipment. Better lyrics. The entire album is really good...and I rarely say that. Blues, country rock, jazzy soft melodies....and the lyrics....
"How am I gonna tell her that I love her? When words don't mean a thing. And I'm a full grown boy."
"Now you see him against the sky. Believing in his own lies, and he's power drunk..."
"I feel like a four letter word. I know what few can know. How angry words can pierce the heart. How a soul can sink so low..."
"When the past gets up in your face. Memories slide out of place. All those things that were hidden away, ain't so bad in the light of day. You say you love me, wish you liked me more. I'm no angel that's for sure. Said you forgave me each time I was caught. But you still paint me as something I'm not. Oh, let me tell you the truth. I love you more, than the sins of my youth."
Don't know about you...but I've got a few fault lines.....running under my life!!!! - c
Friday, March 20, 2015
Nivo (Opdivo) effectiveness in melanoma - NO BRAF positive status needed
When ipi naive melanoma patients are given Nivolumab (or Pembrolizumab for that matter), there is roughly a 40% response rate in patients irregardless of BRAF status.
This was reported at ASCO, June 2014:
Survival, response duration, and activity by BRAF mutation status of nivolumab (anti-PD1, BMS-936588) and ipilimumab concurrent therapy in advanced melanoma
Abstract LBA9003, Sznol, Kluger, Kirkwood, Wolchok, et al
53 melanoma patients were enrolled from 2009-2012 and were given ipi and nivo concurrently, then followed by nivo alone (with a variety of dosing patterns). Patients with and without BRAF had similar response.
Nivolumab in previously untreated melanoma without BRAF mutation. Robert, Long, Brady, et al. N Engl J Med, November 2014.
418 previously untreated patients without the BRAF mutation were randomly assigned to Nivolumab (Opdivo) at 3mg/kg every 2 weeks or dacarbazine every three weeks. At 1 year, the overall survival rate was 72.9% in the nivo group vs 42% in the dacarbazine group. Median progression free survival was 5.1 months for the nivo group vs 2.2 months for dacarbazine. Objective response was 40% for nivo vs 13.9% for dacarbazine.
Good enough. BRAF status makes no difference in your response rate to Nivo. Now STOP giving people dacarbazine!!!!! They really are people...not just ratties!! - c
This was reported at ASCO, June 2014:
Survival, response duration, and activity by BRAF mutation status of nivolumab (anti-PD1, BMS-936588) and ipilimumab concurrent therapy in advanced melanoma
Abstract LBA9003, Sznol, Kluger, Kirkwood, Wolchok, et al
53 melanoma patients were enrolled from 2009-2012 and were given ipi and nivo concurrently, then followed by nivo alone (with a variety of dosing patterns). Patients with and without BRAF had similar response.
Nivolumab in previously untreated melanoma without BRAF mutation. Robert, Long, Brady, et al. N Engl J Med, November 2014.
418 previously untreated patients without the BRAF mutation were randomly assigned to Nivolumab (Opdivo) at 3mg/kg every 2 weeks or dacarbazine every three weeks. At 1 year, the overall survival rate was 72.9% in the nivo group vs 42% in the dacarbazine group. Median progression free survival was 5.1 months for the nivo group vs 2.2 months for dacarbazine. Objective response was 40% for nivo vs 13.9% for dacarbazine.
Good enough. BRAF status makes no difference in your response rate to Nivo. Now STOP giving people dacarbazine!!!!! They really are people...not just ratties!! - c
Tuesday, March 17, 2015
Ipi for melanoma...the data keeps pouring in...and it's pretty good!
Since the FDA in all its wisdom has required ipi failure (given ipi's response rate of 10-20%) as a prerequisite to the use of anti-PD1 drugs (with their 40% response rate), we need all the data we can get on ipi. Here's some of the latest...and it's not too bad! Especially when looking at some of the durability numbers.....
Efficacy and safety of ipilimumab in elderly patients with pretreated advanced melanoma treated at Italian centres through the expanded access programme. Chiarion, Pigozzo, Ascierto, et al. J Exp Clin Cancer Res. April 2014.
Elderly patients with metastatic melanoma have different disease characteristics and a poorer prognosis than younger patients. However, data suggest ipi confers a consistent survival benefit and has a similar safety profile. Patients older than 70 years with pretreated melanoma were given ipi 3mg/kg every 3 weeks for 4 doses. Immune related disease control rate (usually referred to as 'clinical benefit') among 188 patients was 38%, with 4 patients with an immune-related complete response, 24 with an immune-related partial response, and 44 with immune-related stable disease. Median progression-free survival was 4 months and the 1 and 2 year progression free survival rates were 21% and 12% respectively. Median overall survival rates was 8.9 months. 1 and 2 year overall survival rates were 38% and 22% respectively. Adverse effects generally resolved within a median of 2 weeks. Ipi was generally well tolerated and resulted in clinical benefit and extended survival in elderly patients treated in Italy.
Three year follow-up of advanced melanoma patients who received ipilimumab plus fotemustine in the Italian Network for Tumor Biotherapy, Phase II study. Di Giamcomo, Ascierto, Queirolo, et al. Ann Oncol. Dec. 2014.
Ipi and fotemustine (an old time typical chemo) was given to patients with metastatic melanoma, with or without brain mets. 86 patients, including 20 with asymptomatic brain mets,...pre-treated with radiotherapy in 7 subjects, were enrolled. With a median follow-up of 39.9 months, median OS and 3 year survival rates were 12.9 months and 28.5% for the whole study population, and 12.7 months and 27.8% for patients with brain mets, respectively. BRAF status did not correlate with outcome.
Survivorship in immune therapy: assessing chronic immune toxicities, health outcomes, functional status among long-term ipilimumab survivors at a single referral center. Johnson, Friedman, Berry, et al. Cancer Immunol Red. Feb. 2015.
Ipi is associated with long-term survival in more than 20% of advanced melanoma patients and is being evaluated in the adjuvant setting. Vanderbilt researchers looked at 90 patients given ipi for metastatic melanoma or as adjuvant therapy between Jan 2006 and September 2012. 33 patients survived more than 2 years with a median survival of 60.1 months. Of these, 24 were alive at last follow-up (73%) with 14 patients free of disease (42%). GI and derm adverse events were frequent but largely transient. Hypophysitis universally required ongoing corticosteroids although largely remained asymptomatic with appropriate hormone replacement. Surviving patients had excellent performance status. Chronic neuro toxicities caused problems for 2 patients who received whole brain radiotherapy more than 5 years before analysis and in one patient with chronic, painful peripheral neuropathy. No previously undescribed cardiac, pulmonary, gi, hematologic, or neoplastic safety signals were id'd. Ipi was associated with excellent functional outcomes among long-term survivors.
Pooled analysis of long-term survival data from phase II and phaseIII trials of ipilimumab in unresectable or metastatic melanoma. Schadendorf, Hodi, Robert, Weber, Hamid, Chen, Wolchek, et al. J Clin Oncol. Feb. 2015.
This primary analysis pooled OS data for 1, 861 patients from 10 prospective and 2 retrospective studies of ipi. Patients were previously treated (n=1,257) or treatment naive (n=604) and the majority of patients were given ipi 3mg/kg or 10 mg/kg. We also conducted a secondary analysis of OS data with an additional 2,985 patients from an expanded access program.
Among 1,861 patients, median OS was 11.4 months, which included 254 patients with at least 3 years survival follow-up. The survival curve began to plateau around year 3, with follow-up of up to 10 years. 3 year survival rates were 22%, 26%, and 20% for: all patients, treatment naive patients, and previously treated patients, respectively. Including data from the EAP, median OS was 9.5 months, with a plateau at 21% in the survival curve beginning around year 3. These data add to the evidence supporting the durability of long-term survival in ipi-treated patients with advanced melanoma.
Gauging the long-term benefits of ipilimumab in melanoma. Ribas, Flaherty. J Clin Oncol. 2015.
....interest in cancer immunotherapy is based on the premise that it could provide responses with long duration that may translate into true cures... ...high-dose IL-2 [was FDA approved] on the basis of a 6% durable complete response rate. [The usefulness of this] is limited to relatively young patients who could endure the severe physiologic stress induced by this therapy. By using IL-2 in asymptomatic patients with limited disease burden of metastatic disease, the fraction of responding patients can be increased but not the absolute number of long-term survivors.
Anticytotoxic T-lymphocyte-associated antigen 4 antibody (ipilimumab) .... studies [have] response rates...in the range of 10-15% and are typically manifested only after 3 months or more...from initiation of therapy. The progression free and overall survival curves separated after several months and stayed separated by approximately 10% beyond 2 years. In [the Schadendorf article noted above] the authors document a plateau in the survival curve at 21% starting at 3 years and maintained thereafter, suggesting that patients...treated with ipi who survive to 3 years are highly likely to have a good long-term outcome.
While pooled analysis of large numbers of patients treated with a single agent...[is helpful]...inclusion of patients on uncontrolled trials loses benefit...Schadendorf et al do not provide info on long-term outcomes in control arms... Patients who participated [in these trials were] unlikely to have had access to new...targeted and second-generation immunologic therapies. Therefore, it is reasonable to consider that [outcomes of control arm patients were the same] as cohorts from the preceding era. [A review of stage IIIc/IV overall survival Kaplan-Meier curves in 2009] suggest that these curves may have a plateau in patients not treated with ipi, but [it occurs beyond 8 years]. The updated data...provides survival rates at 19%, 13%, and 9% at 3, 5, and 10 years, respectively for stage IV melanoma. Therefore, [this suggests] the long-term benefit of ipi at 3 years may not be too different from what could be expected, but...it improves by 10% over the [treatments offered at the time] these studies were conducted. Notably, this difference aligns with the percentage of patients who achieve objective responses.
....It is notoriously difficult to assess response rate and progression-free survival in patients treated with ipi because there are well-documented instances of patients who meet the criteria for disease progression early [on] but...go on to have a durable tumor response. ...it would have been useful to query this large database of patients...to determine how many of the patients in the 21% plateau after 3 years were disease-free or stably maintaining response at that time. This would represent firmer evidence of the long-term benefits of ipi, even if it did overestimate the small percentage of patients who may have benefited from subsequent therapy.
...despite the generalized belief that ipi is highly toxic, the great majority of patients have no serious adverse effects with [ipi]... However, 10-15% had grade 3/4 adverse effects that may require hospitalization to manage, leading to a 2.1% of deaths as a result of toxicity.
Since 2011...5 additional agents have been approved in the US...for patients with advanced melanoma...BRAF-mutated patients can derive benefit from the use of BRAF and MEK inhibitors. Because of the frequent development of acquired resistance within months and relatively shorter follow-up available for these agents compared to ipi, it is less clear that BRAF inhibitor based therapies will have a tail in the survival curve that can be maintained for years. Though on the basis of a small fraction of patients now beyond 3 years from the initiation of single-agent BRAF inhibitors and improved...outcomes with combined BRAF/MEK, it is certainly possible... Anti-PD-1 antibodies [have proven] to improve overall survival compared to dacarbazine and...[extend responses in patients] previously progressed on ipi...[and the fact that] anti-PD-1 and anti-PD-L1...are being tested in...combination therapies...[their] impact on outcomes may be far greater.
Despite...exciting developments...we are still far from the goal of benefiting most patients over the long term. ... Ipi was the first agent to demonstrate overall survival, a benefit that we now know can be sustained even when measured in years. We look forward to...continuing improvement in long-term outcomes of patients with advanced melanoma.
Thought it was a little interesting that 2 melanoma big dogs NOT included in the pooled analysis by Schadendorf put together a response gunning for the ones who collected and put out the data...though they make a couple of reasonable points. It seems we've finally discovered most all the side effects ipi can cause...and pretty good ways of dealing with them. Thanks, ratties!!! Older patients can tolerate ipi and attain benefit. These articles reiterate the ability of some patients to attain durable responses to immunotherapy generally, and ipi specifically. Remember the data already posted here: Review of immunotherapy and durable benefit in melanoma!!! As noted we know there have been complete and durable responses to IL2. It is looking as though ipi can do the same, for some. And while similar time frames have not passed since the utilization of anti-PD1 products, durable effects look possible there as well. It will be interesting to see if there is a difference in the duration of response among immunotherapies. Will durable response be proportional to the percentage of initial responses across all drugs? Time will tell, ratties. Time will tell. - c
Efficacy and safety of ipilimumab in elderly patients with pretreated advanced melanoma treated at Italian centres through the expanded access programme. Chiarion, Pigozzo, Ascierto, et al. J Exp Clin Cancer Res. April 2014.
Elderly patients with metastatic melanoma have different disease characteristics and a poorer prognosis than younger patients. However, data suggest ipi confers a consistent survival benefit and has a similar safety profile. Patients older than 70 years with pretreated melanoma were given ipi 3mg/kg every 3 weeks for 4 doses. Immune related disease control rate (usually referred to as 'clinical benefit') among 188 patients was 38%, with 4 patients with an immune-related complete response, 24 with an immune-related partial response, and 44 with immune-related stable disease. Median progression-free survival was 4 months and the 1 and 2 year progression free survival rates were 21% and 12% respectively. Median overall survival rates was 8.9 months. 1 and 2 year overall survival rates were 38% and 22% respectively. Adverse effects generally resolved within a median of 2 weeks. Ipi was generally well tolerated and resulted in clinical benefit and extended survival in elderly patients treated in Italy.
Three year follow-up of advanced melanoma patients who received ipilimumab plus fotemustine in the Italian Network for Tumor Biotherapy, Phase II study. Di Giamcomo, Ascierto, Queirolo, et al. Ann Oncol. Dec. 2014.
Ipi and fotemustine (an old time typical chemo) was given to patients with metastatic melanoma, with or without brain mets. 86 patients, including 20 with asymptomatic brain mets,...pre-treated with radiotherapy in 7 subjects, were enrolled. With a median follow-up of 39.9 months, median OS and 3 year survival rates were 12.9 months and 28.5% for the whole study population, and 12.7 months and 27.8% for patients with brain mets, respectively. BRAF status did not correlate with outcome.
Survivorship in immune therapy: assessing chronic immune toxicities, health outcomes, functional status among long-term ipilimumab survivors at a single referral center. Johnson, Friedman, Berry, et al. Cancer Immunol Red. Feb. 2015.
Ipi is associated with long-term survival in more than 20% of advanced melanoma patients and is being evaluated in the adjuvant setting. Vanderbilt researchers looked at 90 patients given ipi for metastatic melanoma or as adjuvant therapy between Jan 2006 and September 2012. 33 patients survived more than 2 years with a median survival of 60.1 months. Of these, 24 were alive at last follow-up (73%) with 14 patients free of disease (42%). GI and derm adverse events were frequent but largely transient. Hypophysitis universally required ongoing corticosteroids although largely remained asymptomatic with appropriate hormone replacement. Surviving patients had excellent performance status. Chronic neuro toxicities caused problems for 2 patients who received whole brain radiotherapy more than 5 years before analysis and in one patient with chronic, painful peripheral neuropathy. No previously undescribed cardiac, pulmonary, gi, hematologic, or neoplastic safety signals were id'd. Ipi was associated with excellent functional outcomes among long-term survivors.
Pooled analysis of long-term survival data from phase II and phaseIII trials of ipilimumab in unresectable or metastatic melanoma. Schadendorf, Hodi, Robert, Weber, Hamid, Chen, Wolchek, et al. J Clin Oncol. Feb. 2015.
This primary analysis pooled OS data for 1, 861 patients from 10 prospective and 2 retrospective studies of ipi. Patients were previously treated (n=1,257) or treatment naive (n=604) and the majority of patients were given ipi 3mg/kg or 10 mg/kg. We also conducted a secondary analysis of OS data with an additional 2,985 patients from an expanded access program.
Among 1,861 patients, median OS was 11.4 months, which included 254 patients with at least 3 years survival follow-up. The survival curve began to plateau around year 3, with follow-up of up to 10 years. 3 year survival rates were 22%, 26%, and 20% for: all patients, treatment naive patients, and previously treated patients, respectively. Including data from the EAP, median OS was 9.5 months, with a plateau at 21% in the survival curve beginning around year 3. These data add to the evidence supporting the durability of long-term survival in ipi-treated patients with advanced melanoma.
Gauging the long-term benefits of ipilimumab in melanoma. Ribas, Flaherty. J Clin Oncol. 2015.
....interest in cancer immunotherapy is based on the premise that it could provide responses with long duration that may translate into true cures... ...high-dose IL-2 [was FDA approved] on the basis of a 6% durable complete response rate. [The usefulness of this] is limited to relatively young patients who could endure the severe physiologic stress induced by this therapy. By using IL-2 in asymptomatic patients with limited disease burden of metastatic disease, the fraction of responding patients can be increased but not the absolute number of long-term survivors.
Anticytotoxic T-lymphocyte-associated antigen 4 antibody (ipilimumab) .... studies [have] response rates...in the range of 10-15% and are typically manifested only after 3 months or more...from initiation of therapy. The progression free and overall survival curves separated after several months and stayed separated by approximately 10% beyond 2 years. In [the Schadendorf article noted above] the authors document a plateau in the survival curve at 21% starting at 3 years and maintained thereafter, suggesting that patients...treated with ipi who survive to 3 years are highly likely to have a good long-term outcome.
While pooled analysis of large numbers of patients treated with a single agent...[is helpful]...inclusion of patients on uncontrolled trials loses benefit...Schadendorf et al do not provide info on long-term outcomes in control arms... Patients who participated [in these trials were] unlikely to have had access to new...targeted and second-generation immunologic therapies. Therefore, it is reasonable to consider that [outcomes of control arm patients were the same] as cohorts from the preceding era. [A review of stage IIIc/IV overall survival Kaplan-Meier curves in 2009] suggest that these curves may have a plateau in patients not treated with ipi, but [it occurs beyond 8 years]. The updated data...provides survival rates at 19%, 13%, and 9% at 3, 5, and 10 years, respectively for stage IV melanoma. Therefore, [this suggests] the long-term benefit of ipi at 3 years may not be too different from what could be expected, but...it improves by 10% over the [treatments offered at the time] these studies were conducted. Notably, this difference aligns with the percentage of patients who achieve objective responses.
....It is notoriously difficult to assess response rate and progression-free survival in patients treated with ipi because there are well-documented instances of patients who meet the criteria for disease progression early [on] but...go on to have a durable tumor response. ...it would have been useful to query this large database of patients...to determine how many of the patients in the 21% plateau after 3 years were disease-free or stably maintaining response at that time. This would represent firmer evidence of the long-term benefits of ipi, even if it did overestimate the small percentage of patients who may have benefited from subsequent therapy.
...despite the generalized belief that ipi is highly toxic, the great majority of patients have no serious adverse effects with [ipi]... However, 10-15% had grade 3/4 adverse effects that may require hospitalization to manage, leading to a 2.1% of deaths as a result of toxicity.
Since 2011...5 additional agents have been approved in the US...for patients with advanced melanoma...BRAF-mutated patients can derive benefit from the use of BRAF and MEK inhibitors. Because of the frequent development of acquired resistance within months and relatively shorter follow-up available for these agents compared to ipi, it is less clear that BRAF inhibitor based therapies will have a tail in the survival curve that can be maintained for years. Though on the basis of a small fraction of patients now beyond 3 years from the initiation of single-agent BRAF inhibitors and improved...outcomes with combined BRAF/MEK, it is certainly possible... Anti-PD-1 antibodies [have proven] to improve overall survival compared to dacarbazine and...[extend responses in patients] previously progressed on ipi...[and the fact that] anti-PD-1 and anti-PD-L1...are being tested in...combination therapies...[their] impact on outcomes may be far greater.
Despite...exciting developments...we are still far from the goal of benefiting most patients over the long term. ... Ipi was the first agent to demonstrate overall survival, a benefit that we now know can be sustained even when measured in years. We look forward to...continuing improvement in long-term outcomes of patients with advanced melanoma.
Thought it was a little interesting that 2 melanoma big dogs NOT included in the pooled analysis by Schadendorf put together a response gunning for the ones who collected and put out the data...though they make a couple of reasonable points. It seems we've finally discovered most all the side effects ipi can cause...and pretty good ways of dealing with them. Thanks, ratties!!! Older patients can tolerate ipi and attain benefit. These articles reiterate the ability of some patients to attain durable responses to immunotherapy generally, and ipi specifically. Remember the data already posted here: Review of immunotherapy and durable benefit in melanoma!!! As noted we know there have been complete and durable responses to IL2. It is looking as though ipi can do the same, for some. And while similar time frames have not passed since the utilization of anti-PD1 products, durable effects look possible there as well. It will be interesting to see if there is a difference in the duration of response among immunotherapies. Will durable response be proportional to the percentage of initial responses across all drugs? Time will tell, ratties. Time will tell. - c
Saturday, March 14, 2015
3-14-15 = Happy Pi Day!!!!
3.1415!!! The best pi day in a hundred years, so I'm told by nerds I love!!! Perhaps March 14th of 1592 may have been better, but we weren't around for that one and I'm not sure pi was either!!! So, what does one do on and around the best pi day in a lifetime??????
Trim roses. Pull weeds and newly hatching acorns from various beds to ready them for spring planting. Add soil to said beds as needed. Create a new bed....just wait til you see the hostas and ferns that will be so beautiful there, Bentie!!! Finish a special dress for a purple durple:
Learn that double yolk eggs can hatch into two normal chicks. That shamrocks grow from a rhizome like affair. Can be planted outside, but should be taken up in the winter (at least where I live). And if you keep them inside, they need a couple of periods of dormancy in a cool dark place with little water a couple of times a year.
That the White Wine for Dummies book is a good way to learn about wines. While Wine for Dummies, Chardonnay is....surprise, surprise....for DUMMIES!!!
Study radiation combined with immunotherapies...and why the combo is more effective than radiation alone in melanoma. (More on that later.) Learn the geography and history of Chechnya. It's a wonder that any humans live there. How is it that Putin is still a free man? Finished "A Constellation of Vital Phenomena" by Anthony Marra. A most horrible and wonderful book.
Create a really delicious and amazing goat stew. Yep, goat stew. 1 pound goat pieces hacked up as they do at DeKalb. Sprinkle with curry, cayenne, coriander, cumin, ginger, cinnamon, salt and pepper. Marinate in fridge about 12 hours. Sear pieces in olive oil. Add chopped onions. Cook until a bit softened. Add a splash of red wine, canned tomatoes, and beef stock to pan. Place covered, in low oven (around 250) for as many hours as you have...at least 4. Roast carrots and potatoes sprinkled with peri peri pepper, lime juice and olive oil til almost tender....whenever in this process you prefer. Add to the roasting goat about an hour before serving. Add a little water or chicken stock at this point if it is looking dry. Serve and enjoy!!! It really is good!
And of course, there was PIE!
A constellation of vital phenomena.....is there any better definition of life? Well....maybe it SHOULD include an option for some of the NON-vital components. Cause that's sometimes the stuff that makes mine complete. Love to you all! Happy Pi day!! - c
Thursday, March 12, 2015
Doctor. Writer. Father. Cancer patient. Passes. Life Begins.
There are no words. He said them best. I can only say...I, too, have lived on both sides of the aisle. It is strange. One does think, "I can't go on." Yet, "I will go on." Please read his words. Live them. For him. For me. For yourself.
How long have I got left?
Before I go....
Paul Kalanithi, neurosurgeon/writer/father/man
Though the origin of this quote is argued....its truth is not...
"We do not inherit the earth from our ancestors, we borrow it from our children." Paul Kalanithi knew this well. If we live as he did, we will not go wrong. - for Fred and Rose...not because I created what you are, but because you are the best of me.
How long have I got left?
Before I go....
Paul Kalanithi, neurosurgeon/writer/father/man
Though the origin of this quote is argued....its truth is not...
"We do not inherit the earth from our ancestors, we borrow it from our children." Paul Kalanithi knew this well. If we live as he did, we will not go wrong. - for Fred and Rose...not because I created what you are, but because you are the best of me.
Sunday, March 8, 2015
One more Tampa trip! Update on 33 Melanoma Ratties' Nivo/Opdivo trial....
As I noted on a prior post from our published study: "33 patients were enrolled. 10/33 patients relapsed. Of the 10 relapsed patients, five died due to metastatic melanoma; three were rendered free of disease surgically and remain disease-free at 2, 27 and 54 weeks after relapse. One patient had spontaneous regression... and has been free of disease for over 3 years. One additional relapsed patient is alive and on active therapy with dabrafenib plus trametinib." Those facts need only a small adjustment as we confirmed that the status of those relapsed patients is unchanged. It remains important to remember that only 2 of the 10 of us with prior brain mets relapsed...one early on with undetected disease at admission to the study that was quite progressed and another not that long ago with a lung met that was resected, rendering them NED. On a less favorable note, one patient (with no prior brain mets) is under current evaluation for possible relapse. It sounded as though he had, with fairly extensive disease. That may put the number relapsed to 11, but the final testing and diagnosis had not been officially made. Fingers crossed for you, dear rattie!
Again, as previously noted from the published report:
RELAPSE FREE SURVIVAL:
"A retrospective study....showed a median overall survival of 12 months in stage IV melanoma patients undergoing metastasectomy." Yet, my ratties and I have demonstrated an "impressive relapse-free survival...of 47.1 months and a median overall survival not yet reached with over 32 months of follow-up." Obviously, we are all further along as each day passes.
For me, I am now:
138 months post melanoma diagnosis
58 months post Stage IV melanoma
52 months NED
50 months post start of nivo/Opdivo trial
20 months post my last infusion
Wednesday, March 4, 2015
Long term melanoma survivors....MARCH FORTH!!!!!
It is strangely disconcerting to consider that you may LIVE after being flat out told you weren't going to...or at least no longer than a few months! I was informed of that very thing several times. B and I were just remembering what the oncology radiologist who provided SRS to my brain met said at my last appointment with him... He would - "see [me] back in a few months and 'we' would do whole brain radiation then!" On leaving, I told B that unbeknownst to that fat little turd, it REALLY was my discharge appointment. I would NOT be back to see HIM!!!! He was a jerk who clearly had no knowledge about how he SHOULD be treating patients ethically nor any comprehension of appropriate radiation care for melanoma! You most certainly can, and should, use SRS multiple times if necessary before jumping to whole brain radiation in melanoma!!! But, I digress...I hold no animosity to other docs who gave me the same limited life expectancy. They were telling me the data that was the REALITY of the time! There was no ipi, anti-PD1, BRAFi!!! Options were few and far between and 6 months or so was EXACTLY the planet time most folks like me had to look forward to....then. When you add to that rather scaring experience the fact that melanoma doesn't play like other cancers....it can be hard for patients who are doing well, to go back to "normal" indeed!
Depression, Anxiety and Quality of Life in Long-Term Survivors of Malignant Melanoma: A Register-Based Cohort Study. Beutel, Fishchbeck, Binder, et al. PLoS One. 2015, January.
Via a state cancer registry in Germany a cohort of survivors of malignant melanoma were contacted. Of 1302 contactable patients, 689 completed a questionnaire that addressed anxiety, depression, and quality of life. Results were statistically analyzed and compared to surveys from the general adult population.
At an average of 8.4 years (5.7-12.2) after diagnosis distress was higher in women than in men. There was a decline of functioning and increase of symptoms across the age range of both genders. Compared to the general population there was slightly increased depression in the female melanoma survivors, but no impaired quality of life. "Yet, survivors evidenced functional decline and more physical symptoms. Distress and reduced quality of life were consistently predicted by lack of social support, fear of recurrence, pessimism and self-blame."
"Overall, long-term survivors have adjusted well achieving a global quality of life comparable to the general population. Yet, compromised functional dimensions, physical symptoms and distress indicate the need for integrating psycho-oncological screening into oncological follow-up..."
Not sure what to make of all that. Women are wimpier than men? Maybe....or perhaps they are more willing to admit their fears on paper? Are cancer patients routinely offered psychological support? I have never been. And if I had, I doubt it would have been covered by my insurance. It was certainly not offered as part of my clinical trial.
Sometimes I do think folks who have been through what I have also shared are incredibly focused on this pain or that sensation. "Could it be melanoma again?" "My treatments have made me forgetful!" "Ever since I had ____________ I just can't work!" Then again, I have known the healthiest of folks to be absolutely certain they have this dread disease or the other because they had a headache, a simple procedure, or a hang nail. I wonder, "Do I do this? Do I over analyze each sensation or event? OR...Do I refuse to address the things I should?"
It is hard to know what is in the heart of a man...or sometimes even your own. I figure we all must do the best we can. I don't think I ignore or am unduly focused on my personal state. But, I may not be the best judge. Finding balance is not easy for anyone. I hope that I simply embrace all the moments I can, today and always!!! So....MARCH FORTH....on this, my favorite day!!! Love, c
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