Immunology update/webinar for melanoma by Dr. Weber with a look forward...

Check out the link below for a webinar with slides presented by Jeffrey S. Weber, MD, PhD now of the Laura and Isaac Perlmutter Cancer Center at NYU.  Just click the 'view activity' button at the bottom.  I have included some info off the slides as well as my report of Dr. Weber's applicable comments in red below.  (Sorry for the strange lay out...best I could do without retyping everything!)

Immuno-Oncology 2016 update by Dr. Weber

What’s New in Melanoma 2016?

 Combination immunotherapies and targeted therapies

 Overcoming BRAF resistance

 New immune agonistic molecules

 Novel cytokines and fusion molecules

 Chemokine antibodies

 Bispecific T-cell engaging molecules

 Adoptive cell therapy

 Targeted therapy and immunotherapy

 Masked antibodies

Vemurafenib Plus Atezolizumab in BRAF-Mutant Melanoma—Trial Design

Patients with untreated BRAFV600-mutant unresectable or metastatic melanoma (N = 17)  
Cohorts: 1- atezo and vemurafenib together   2- vemurafenib X 56 days followed by atezo
3- vemurafenib X 28 days  followed by Atezo.  Atezolizumab (an anti PD-L1 anti-body) was given IV q 3 wk at 20 or 15 mg/kg and Vemurafenib was BID at 960 mg during run in, then decreased to 720mg bid.
Confirmed overall response rate:  Cohort 1 - 33%, Cohort 2 - 75 %, Cohort 3 - 100%.  Overall 76% response rate.  Median of 12.2 months.  AE's were manageable with no grade 4.  Additive activity with excellent level of response.  You will hear much more about this combo in the future.

 MASTERKEY-265: A Phase Ib/III Study of T-VEC + Pembrolizumab (NCT02263508)

        Phase Ib:Enrollment from December 2014 to March 2015  (n = 21 ) N = 21 patients, Unresectable stage III or IV melanoma, treatment naive, injectable lesions, no clinically active brain mets, no active herpetic skin lesions or prior complications from herpetic infection.  TVEC intralesional 4ml/treatment was given with pembro 200 mg IV q2wk.  Mild side effects.

Complete response - 12.5%, Partial response - 43.8%. ORR - 56.3%.  Additive effects, may even be better.  Phase 3 study is ongoing.   
           

Epacadostat (an IDO inhibitor) + Pembrolizumab:Preliminary Results

                61 patients were enrolled by September 2, 2015  Safety data on 46 patients (19 melanoma, 7 RCC, 7 NSCLC, 5 transitional cell carcinoma, 4 endometrial adenocarcinoma). Most common all-grade treatment-related AEs were rash (22%), fatigue (17%), nausea (11%), and pruritus (11%).    Grade 3/4 treatment-related AEs occurred in 13% of patients (rash, 7%).   One patient discontinued for a treatment-related AE.  IDO inhibitor did not seem to increase side effects.  Melanoma patients only (n - 18) - 56% ORR.  Melanoma treatment naive patients (n - 16) - 63% ORR.  Weber found these results very promising and comparable to the ipi/nivo combo in regard to response rates but with much milder side effects!!!

 

KEYNOTE-029: Pembrolizumab + Low-Dose Ipilimumab for Advanced Melanoma
 Pembrolizumab 2 mg/kg + ipilimumab 1 mg/kg.  72% received all 4 ipilimumab doses.  36% incidence of grade 3-4 treatment-related AEs.  54% incidence of immune-mediated AEs (17% grade 3/4).   Pembrolizumab 2 mg/kg + ipilimumab 1 mg/kg provided an ORR of 56%, comparable to that previously reported for nivo 1 mg/kg + ipilimumab 3 mg/kg.   Efficacy, safety, and biomarkers to be further analyzed in the full expansion cohort of 153 patients.  So far, the side effects appear to be decreased by decreasing the ipi dose...while response rates remain good.

                 

                        CheckMate 064: Study Design:  Cohort A - nivo 3mg/kg q2wk X6, then ipi 3mg/kg 1 3wk X4.  Cohort B - ipi 3mg/kg 1 3wk X4, then nivo 3mg/kg q2wk X6. Both cohorts were followed with nivo, 3mg/kg q2wk until progression, toxicity, or withdrawal of consent. Toxicities were no different between arms.  Significant difference in response rates due to sequence of drugs.  Nivo followed by ipi gave better results. "A real surprise."
I already had a rant on this one:  Sequential nivo then ipi orr of 41%!

Efficacy Summary Week 13				Week 25
NIVOàIPI (n = 68)		IPIàNIVO (n = 770)		NIVOàIPI (n = 68)		IPIàNIVO (n = 70)
Confirmed ORR, %	--		--		41.2		20.0
Complete response, n	0		0		0		0
Partial response, n	24		7		28		14
Conventional ORR, %	35.3		10.0		47.7		22.6
Progression rate, %	38.2 (26.7–50.8)		61.4 (49.0–72.8)		38.2 (26.7–50.8)		60.0 (47.6–71.5)

Intralesional Immunotherapy With Oncolytic Coxsackievirus A21 (CVA21) 
 Final response and safety data of the open-label, multicenter phaseII CALM (CAVATAK in Late-stageMelanoma) study of intratumoral CVA21 in 57 patients with unresectable stage IIIC/IV melanoma.    The study met its primary endpoint.  22 of 57 (38.6%) evaluable patients with PFS at 6 months.    Median PFS of 4.2 mos.   ORR 28.1%; median TTR 2.8 mos.  1-year survival rate 75.4%.  Median OS and median DOR not reached (16.5 mos follow-up).  Most common AEs were grade 1 fatigue, chills, fever, and injection site reactions; no grade 3/4 AEs observed.  Looks like another promising intralesional therapy.  Will soon have phase 3 study.

Radiotherapy in Combination With Anti-PD-1 Antibodies: Safety and Efficacy

    Retroactively evaluated all patients at Melanoma Institute Australia and Westmead Hospital who had received either pembrolizumab or nivolumab for unresectable stage III/IV melanoma who had sequential or concurrent radiotherapy.     In 32 evaluable patients, 9 (28%) PR and 5 (16%) stable disease.     In 25 patients who had progressed on PD-1 at the start of RT, 7 (28%) subsequent PRs and 3 (12%) CRs, while 5 (20%) continued progressing.    Survival Brain metastases: PFS 2.5 mos, OS 6.8 mos.  Which I think is excellent.   No brain metastases: PFS 4.1 mos, OS 16.4 mos.   

No excess RT toxicity observed except cerebral radionecrosis in 1 patient 3 months after SRS; potential delayed neurotoxicity in 1 patient with multiple small asymptomatic BMs; disproportionate cerebral edema in 1 patient with rapidly progressive BMs.  So, yes, you can deliver radiation to the brain, or elsewhere, safely...there is no excess toxicity if radiation is given with either nivo or pembro.

Clinical Activity To Date: BRAF + MEK + PD-L1 ab MEDI 4736

 Response-evaluable population includes all patients dosed ≥16 weeks prior to the cut-off date with measurable disease at baseline and ≥1 f/u scan (or discontinuation due to death or PD prior to 1st scan).  Dabrafenib (BRAFi) and Trametinib (MEKi) and MEDI 4736 (PD-L1 antibody) were given in various regimens.   Median duration of response has not yet been reached for Cohorts A and B.             *Shorter follow up in Cohort C, with 5 additional patients ongoing with best response of unconfirmed PR.

Clinical activity	Cohort A(n = 26)		Cohort B(n = 19)		Cohort C*(n = 15)
	D + T + M	T + M		T /M (sequential)
ORR, n (%)	18 (69)		4 (21)		2a(13)
DCR (CR + PR + SD), n (%)	26 (100)		15 (79)		12 (80)
SD ≥12 weeks, n (%)b	4 (15)		10 (53)		6 (40)
Ongoing responders, n/N (%)	16/18 (89%)		4/4 (100%)		1/2 (50%)
Range of duration of ongoing response, wks	7.7+ –50.6+		7.9+ –24.7+		7.0+

Very interesting study.  I like this a lot.  Large influx of T-cells with the trio, converting a cold tumor to a hot tumor, leading to an augmentation of T-cell function.  The trio with its 69% response rate, at least gave additive efficacy, if not synergistic, without increased side effects.

Innovative Ideas: Targeted Therapies 

                           Immunotherapy with targeted therapies:

 BRAF + MEK + pembro,  atezo, IPI + HDAC inhibitor, Ipi + nivo + HDAC inhibitor

              Overcoming BRAF resistance by combining with:
Hsp90 inhibitors,   HDAC inhibitors,   PI3 kinase/AKT inhibitors,   ERK inhibitors,   ERBb3 inhibitors
  

Innovative Ideas: Immunotherapy

 “Masked antibodies” have a peptide linker that “masks” the antigen-binding region of antibodies unless it is cleaved by proteases within the tumor (This is the same as the ADC's - antibody drug conjugates.  Post here:  Another antibody drug conjugate)

 IL-12 has been linked to a tumor-targeting antibody

 IL-15/IL-15 receptor alpha fusion proteins to augment binding to effector T cells but not T regulatory cells

 TGF-beta receptor antibody has been linked to a PD-L1 antibody

 Neoantigen-specific T cells can be expanded from tumor-infiltrating lymphocytes and adoptively transferred

 Bispecific T-cell engagers link CD3 and tumor-associated antigens

Prime Points:  Melanoma Immunotherapy

IDO plus pembro trial will have mature data at ASCO
Survival f/u from sequential BMS-064 trial of nivo then ipi vs nivo then ipi

Nivo + CD137 antibody phase I-II trial
LAG-3 antibody + nivo phase I-II trial
OX- 40 antibody phase I trial
IL-15/IL-15 receptor complex phase I trial
Coxsackievirus + pembro phase I-II trial
Ipi + high dose IL=2


Synopsis of final thoughts by Dr. Weber:

"I think we will all agree that it is a very bright era for immunotherapy in melanoma and immunotherapy for cancer in general.  Ipi is a very impressive drug that is more like a shotgun, while anti-PD1 is like a sniper rifle.  Ipi has the capacity to expand a lot of different antigen specific cells whether they are tumor specific or not, and therefore, combining anything with ipi will expand the side effects.  If you look at survival, the plateau on the curve, for melanoma over the last decade it's about 10%.  Long term results from the early ipi trials, 2010 - 2011, we got up to 20% and that was progress.  If you look at the plateau with the PD-1 trials, we're probably at about 30%, which could be construed as a cure...something we now tell our patients for the first time...but I am absolutely not satisfied with a 30% rate of plateau .  So, we may be looking at triple drug therapy or quadruple drug therapy...and tailoring the therapy to the individual patient.  In patients with slow growing, low burden disease with a normal LDH, it's ok to start with immunotherapy before targeted therapy, since the targeted therapy appears to work just as well whether it is given before or after the immunotherapy.  I think most of us agree that in a BRAF mutated patient with high disease burden, that's symptomatic, rapidly progressing with a high LDH, we would all go with BRAF plus MEK.   If BRAF mutated with low disease burden...that's a tough one.   Interestingly, you might argue that you could go either way because BRAF plus MEK drugs work best with a low LDH, with a low tumor burden, while ipi plus nivo works very well with a high LDH or not...so you might counter argue that you might go with the BRAF/MEK for a finite period of time and then come in with the immunotherapy."

More to come it seems!!!  Thanks, ratties. - c