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

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