With the publicity of Merck's expanded access program (Hopefully they will actually TREAT a patient SOON!) for their anti-PD1 product, and the buzz around anti-PD1 generally...there have been many questions posed on the various forums about anti-PD1 lately. Having had anti-PD1 (in the form of Nivolumab, BMS' product) as an ever present part of my world since December of 2010, I forget some folks don't know what it does and how. I even looked back on my blog, and realized I hadn't posted many of the latest official results and info...so...here you go:
What is anti-PD1? In the simplest possible terms: Anti-PD1 drugs are antibodies that block the switch on white cells so that they can now attack melanoma cells. Specifically, programmed death ligand-1 [PD-L1] is produced by the surface of melanoma tumors. That ligand binds to the infiltrating T-cells, down-regulating them. Basically, turning those cells "OFF" to melanoma. ANTI-PD1 blocks that potential interaction, so that the T-cells can now attack melanoma cells.
How is it given? In your vein through an IV or port.
At what dose? They are still checking the results of various Nivolumab doses: 1, 3, or 10mg/kg. I was given 1mg/kg. If I had to guess, the FDA approved dose will probably be 3. Positive effects against melanoma have been seen at all dosage levels.
What are the side effects?
Fatigue - very common.
Arthralgias - joint pain is frequently reported. Inflammation triggered by the immune response does not make joints happy.
Mucositis - irritation of the mucus membranes, from
redness and tenderness to pain and lesions. (The gut is just one long
tube that starts in the mouth after all....see Colitis below.)
Hypothyroidism - not as common, but certainly has
happened. Often treatable with thyroid hormone in pill form, synthroid.
Colitis - irritation and inflammation in the bowel that
can cause diarrhea and bleeding. Sometimes, causing dehydration and the
need for hospitalization, fluids, discontinuation of the drug for a
time or permanently, and at times prednisone to stop the progression.
This is a fairly common cause of patients being taken off ipi and
Pneumonitis - significant inflammation in the lungs that
may be treated as noted above and has even been a cause of death for
patients on ipi and anti-PD1, and obviously removal from a trial or
Pituitary failure and vision problems related to the optic nerve, as well as retinitis, have occurred but are not reported as common events.
Vitiligo - the depigmentation of the skin (and/or hair),
leaving white patches. Thought to occur because of the shared antigens
located on melanoma cells and normal pigment cells. It is considered a
good prognostic sign that the drug is working against melanoma and
occurs in 5-9% of patients on ipi or anti-PD1.
Survival, Durable Tumor Remission, and Long-Term Safety in Patients with Advanced Melanoma Receiving Nivolumab Topalian, Sznol, Sosman, Hodi, et al. Journal Of Clinical Oncology. March 3, 2014
107 patients with "advanced melanoma [out of 306 patients with various cancer types], enrolled between 2008 and 2012, received intravenous nivolumab in an outpatient setting every 2 weeks for up to 96 weeks and were observed for overall survival, long-term safety, and response duration after treatment discontinuation."
In the 107 melanoma patients: Median survival was 16.8 months. 1 year survival = 62%. 2 year survival = 43%. In 33 patients with objective tumor regression, estimated median response duration was 2 years. Toxicities in all 306 patients were similar to those previously reported.
Conclusion: Overall survival following nivolumab treatment in patients with advanced treatment-refractory melanoma compares favorably with that in literature studies of similar patient populations. Responses were durable and persisted after drug discontinuation. Long-term safety was acceptable.
NOTE: The above trial is the one that Dr. Weber was comparing the Moffitt trial results to on my last visit. Link to the results we discussed: discussion of my anti-PD1 trial results
The report below is from the sister arm, of NON-resected patients, from my anti-PD1 trial, though I am in the NED arm. Also keep in mind, that when I started, folks who had been given ipi were not allowed in, but later arms were created that allowed patients who had failed ipi to participate. Additionally, those of us originally enrolled in all arms were given vaccines, but since they were found to have no positive effect, later arms did not take them. This report addresses all those arms EXCEPT mine, the NED cohort.
Safety, Efficacy, and Biomarkers of Nivolumab with Vaccine in Ipilimumab-Refractory or -Naive Melanoma. Weber, et al. Journal of Clinical Oncology. December 1, 2013.
"We report the results of treatment of patients with unresectable metastatic melanoma who were ipilimumab naive (34 patients) or refractory (56 patients) and received nivolumab at 1, 3, or 10mg/kg. Some patients also received an HLA-A 0201-restricted multipeptide vaccine."
"90 patients were enrolled at Moffitt Cancer Center between August 2010 and December 2012. 87 were evaluated for response, and three were too early for response evaluation. 74 patients had primary cutaneous melanoma. 8 had ocular mel. 8 had an unknown primary. 3 patients experienced progression on BRAF-i before enrollment. 10 had radiated brain mets. 5 patients in cohort 6 had untreated brain mets."
"Most common adverse event = fatigue. One patient experienced grade 3 bilateral optic neuritis, one had fevers, 2 others had pneumonitis...all resolved with steroids over 4 weeks to 4 months and discontinuation of treatment. Colitis was not seen in this trial. Rashes were common, 1 required prednisone. No treatment related deaths were observed."
"Median follow-up times were 20.3 months for patients in cohorts 1-3, 6.8 months for cohorts 4-6, and 8.1 months for all patients. In ipi naive patients (n=34): 2 patients had a complete response, 6 had partial response, 7 had stable disease at 24 weeks, and 19 had progressive disease. Disease control rate = 45%. In responders, median follow-up of 21.2 months, median duration of response was not reached. In ipi refractory patients (n=53): 14 patients had partial response, 11 had stable disease at 24 weeks, 28 experienced progression. Disease control rate = 47%. In responders, median follow-up of 8.4 months, median duration of response was not reached. For all 87 evaluable patients (ipi refractory and naive) the response rate was 25%, with a disease control rate of 46%. Median duration of response was not reached at a median of 8.1 months. PD-L1 tumor staining was associated with responses to Nivolumab, but negative staining did not rule out a response."
NOTE: "12 of the 18 non-responders in cohorts 1-3 subsequently received ipi at 3mg/kg for a planned 4 doses. 2 patients had partial response. 2 had mixed response. 8 had progressive disease. 2 required steroids and infliximab for dose limiting colitis with ipi. But, it demonstrates that patients who progress on Nivo can respond to ipi."
Hope that helps. Wishing each of you my best. - c