Sunday, 27 March 2016

Good summary of relevant findings from ASCO 2015

A summary of the most relevant findings from ASCO 2015-

worth watching!

Sunday, 31 May 2015

Interesting- who responds to PD1- to be followed up

Observation to be followed up systematically-

Response to PD1 antibody seems to depend on T-cells being present in the tumour, with patients with more T-cells responding better than the ones without.

Interesting, with CTL4 and PD1, it doesn't seem to matter as CTL4 drives T-cells into the tumour

Yesterday, A. Ribas suggested in a session a future model where treatment choices are based on the amount of T-cells present in the tumor-

patients with a lot of T-cells could just get PD1 - and less toxicity.

CheckMate 067- Ipi/Nivo versus Ipi versus Nivo

Efficacy and safety results from a phase III trial of nivolumab (NIVO) alone or combined with ipilimumab (IPI) versus IPI alone in treatment-naive patients (pts) with advanced melanoma (MEL) (CheckMate 067).

Find the original abstract-

presented by Wolchok

Background: The results of a phase I study in MEL suggested complementary clinical activity with NIVO (a PD-1 checkpoint inhibitor) plus IPI (a CTLA-4 checkpoint inhibitor). Here, we report the results of a randomized, double-blind, phase III trial designed to evaluate NIVO combined with IPI or NIVO alone vs IPI alone in MEL. Methods: Treatment-naïve pts (N = 945) were randomized 1:1:1 to NIVO 1 mg/kg Q2W + IPI 3 mg/kg Q3W for 4 doses followed by NIVO 3 mg/kg Q2W, NIVO 3 mg/kg Q2W + placebo, or IPI 3 mg/kg Q3W for 4 doses + placebo, until progression or unacceptable toxicity. Pts were stratified by PD-L1 status, BRAF mutation status, and M-stage. Co-primary endpoints are progression-free survival (PFS) (reported here) and overall survival (pts continue to be followed). Secondary endpoints include objective response rate (ORR) by RECIST v1.1 and safety. Results: At a minimum follow-up of 9 months, NIVO + IPI and NIVO alone significantly improved PFS and ORR vs IPI (Table). Grade 3-4 drug-related adverse events (AEs) occurred in 55.0%, 16.3%, and 27.3% of pts in the NIVO + IPI, NIVO, and IPI arms, respectively (most commonly diarrhea [9.3%, 2.2%, 6.1%], increased lipase [8.6%, 3.5%, 3.9%], increased alanine aminotransferase [8.3%, 1.3%, 1.6%], and colitis [7.7%, 0.6%, 8.7%]). Drug-related AEs led to discontinuation in 36.4%, 7.7%, and 14.8% of pts in the NIVO + IPI, NIVO, and IPI arms, with 0, 1, and 1 drug-related deaths, respectively. Efficacy outcomes by PD-L1 status will also be presented. Conclusions: NIVO + IPI and NIVO alone had superior clinical activity vs IPI alone. The results with NIVO + IPI and NIVO alone further suggest complementary activity of the two agents. There were no new safety signals or drug-related deaths observed with the combination. Clinical trial information: NCT01844505
NIVO + IPI (N = 314)NIVO (N = 316)IPI (N = 315)
Median PFS,
months (95% CI)
11.5 (8.9–16.7)6.9 (4.3–9.5)2.9 (2.8–3.4)
HR (95% CI)
vs IPI
0.42 (0.31–0.57)*0.57 (0.43–0.76)*--
HR (95% CI)
0.74 (0.60–0.92)**----
ORR (95% CI)57.6% (52.0–63.2)*43.7% (38.1–49.3)*19.0% (14.9–23.8)
CR rate11.5%8.9%2.2%

*< 0.00001 vs IPI. **Study not statistically powered for this comparison.


PFS by PDL1 expression (5% PDL1 expression)

interesting : patients with PDL1 > 5% respond equally well to combo as well as to Nivo alone. HOWEVER, with PDL1 < 5%, patients responded much better to the combo than Nivo alone.

please not that PDL1 expression means different things in different studies- some are > 1%, this is >5% 

and again- response after stopping treatment

67.5% of patients (81/120) who discontinued the combo due to AEs had a response- and half of these occurred AFTER the treatment had ended.

No treatment-related deaths with the combo in this study  (and 1 each for Nivo and Ipi) which shows that safety management is getting better!

Pembro update

Long-term efficacy of pembrolizumab (pembro; MK-3475) in a pooled analysis of 655 patients (pts) with advanced melanoma (MEL) enrolled in KEYNOTE-001.


Read abstract
Background: The anti–PD-1 antibody pembro is approved in the US for treating unresectable or metastatic MEL that progressed following ipilimumab (IPI) and, if BRAFV600 mutant, a BRAF inhibitor. Pembro has demonstrated robust antitumor activity and manageable toxicity in IPI- treated (IPI-T) and naive (IPI-N) pts. In KEYNOTE-002, pembro significantly prolonged PFS over chemotherapy in IPI-refractory MEL. Here we present long-term follow-up data for all pts with MEL enrolled in KEYNOTE-001 (NCT01295827).  Methods: IPI-T and IPI-N pts received pembro 2 mg/kg every 3 weeks (Q3W), 10 mg/kg Q3W, or 10 mg/kg Q2W until unacceptable toxicity, disease progression, or investigator decision. Treatment could continue beyond initial radiographic progression in eligible pts. Response was assessed every 12 wks. Pts were followed for survival every 3 mo after discontinuation. Primary end point was ORR per RECIST v1.1 by central review; secondary end points included PFS, OS, and duration of response (DOR).  Results: 655 pts enrolled: 342 IPI-T, 313 IPI-N. Medianfollow-up duration was 14.8 mo (range, 7.5-29). Median duration of exposure was 5.6 mo (range, 0.03-28.3). At the time of analysis, 217 (33%) pts remained on therapy. ORR was 34% (29% IPI-T, 38% IPI-N), with a 6% CR rate. Median time to response was 2.8 mo (range, 1.6-19.3). 80% of responses were ongoing at the time of analysis, and median DOR was not reached (range, 6+ to 98+ wk). Median PFS was 5.2 mo (95% CI 3.6-5.5) (IPI-T, 4.9 mo [3.0-5.5]; IPI-N, 5.4 mo [3.1-6.9]). PFS rates at 6 and 12 mo were 44% and 34% (41% and 32% IPI-T, 47% and 36% IPI-N). The 1-y OS rate was 67% (63% IPI-T, 71% IPI-N); the rate at 2 y was 50% (46% IPI-T, 53% IPI-N). Overall, 14% of pts experienced grade 3-4 treatment-related AEs, and there were no treatment-related deaths. In randomized cohorts, there were no significant differences in efficacy and safety between doses/schedules.  Conclusions: Pembro provides robust and durable antitumor activity, promising long-term survival data, and a manageable safety profile in pts with IPI-T and IPI-N metastatic MEL. These results support the approved indication for pembro and its further exploration in other MEL populations. Clinical trial information: NCT01295827


Over several trials, in total over 2000 patients evaluated- this is good as at least we'll know more about the drug. While you can see large effects in small trial populations, that unfortunately doesn't hold true for adverse events- rarer events you only pick up with you have seen enough patients.

This is an analysis based on 655 patients- oct 18th- predominantly WT (75%), so this is not necessarily representative of Melanoma in total where the ratio is closer to 50/50.

24% BRAF
75% WT

Take home message-

49% alive after 2 years second-line (and more)
60% alive after 2 years as first-line

most common adverse event:

Hypothyroidism 49%
Hyperthyroidism 15%

ORR - check out plot looking at the different subgroups will post once I found it

M1b higher response compared to M1c so treating earlier in the disease also better here

BRAF mutant slightly higher response than BRAF WT this I think is interesting as BRAF mutant often considered to be more aggressive

first-line patients
patients without progression 86%
CR 13.5%
ORR 45.1

Please disregard until now as I need to verify the details:

Median PFS 13.8 months
Median OS 31.1 months

PDL1 membrane staining

Yet again: Nivo plus Ipi better than Ipi alone- CheckMate 069

Clinical response, progression-free survival (PFS), and safety in patients (pts) with advanced melanoma (MEL) receiving nivolumab (NIVO) combined with ipilimumab (IPI) vs IPI monotherapy in CheckMate 069 study. NCT01927419

This is a randomised Phase 2 study of Ipi + Nivo versus Ipi alone- please check the scheme in the abstract below- Ipi + Nivo had already 88%  2 year OS in the Phase 1 study.

An update of this trial was already posted at AACR earlier this year.

This trial was for treatment- naive patients, stratified by BRAF status.

Read the abstract here

Background: Combined blockade of T-cell checkpoints by NIVO and IPI demonstrated a high objective response rate (ORR), promising overall survival (OS), and a manageable safety profile in pts with advanced MEL in a phase I study, based on which an appropriate dose was selected for registrational trials. We report efficacy and safety of the NIVO + IPI combination vs IPI alone in treatment-naïve pts with advanced MEL, including pts with poor prognostic factors, in a phase II study.  Methods: Pts (N = 142) with metastatic or unresectable MEL were randomized 2:1 to receive IPI 3 mg/kg combined with either NIVO 1 mg/kg or placebo Q3W × 4, followed by NIVO 3 mg/kg or placebo Q2W until disease progression or unacceptable toxicity. The primary endpoint was ORR in BRAF wild-type (WT) pts. Secondary and exploratory objectives included PFS in BRAF WT pts, ORR and PFS in BRAF V600 mutation-positive (MT) pts, and safety.  Results: In BRAF WT pts (n = 109), ORR was 60% (43/72) for NIVO + IPI; 11% (4/37) for IPI alone (P < 0.0001); complete responses were reported in 12 (17%) and 0 pts, respectively. Median PFS was 8.9 months for the combination vs 4.7 months for IPI alone (= 0.0012). Higher ORR was observed for NIVO + IPI vs IPI in predefined pt subgroups with poor prognostic factors, such as elevated baseline LDH (53% vs 0%) and M1c stage disease (62% vs 25%). Similar ORR and PFS results were observed in 33 BRAF MT pts. Grade 3–4 drug-related adverse events (AEs) were reported in 51% of pts receiving NIVO + IPI vs 20% for IPI alone. The safety profile of NIVO + IPI was similar across pt subgroups, including age. Select AEs related to the combination regimen were consistent with phase I reports and most resolved with immunosuppressive medication ( > 83% across organ categories) with the exception of endocrinopathies. Updated results from a planned data analysis in March 2015 will be presented. Conclusions: NIVO + IPI significantly improved ORR and PFS compared with IPI alone and had a manageable safety profile. The efficacy and safety of the combination was similar across pt subgroups and provided a favorable risk-benefit ratio in treatment-naïve pts with advanced MEL. Clinical trial information: NCT01927419

To note-

objective response rates- 

59% Combo Ipi/ Nivo
11% Ipi

Median PFS was 8.9 months for the combination vs 4.7 months for IPI alone 

median time to response

2.8 months combo
2.7 months Ipi 

This is kind of interesting as it is often said the PD1 works faster than Ipi...

68% of the patients who discontinued because of side effects got a CR or PR!!!

So it continues to work despite people no longer being on the treatment. Actually a very good comment during a different session was that treatment schemes are often not scientifically motivated (it was the scheme tested in a clinical trial, it worked, so we stick with it- the speaker referred to 4 doses of Ipi), so that there would be a point of re-assessing whether different schemes were equally effective but less toxic.

From a patient perspective
while the result is hopeful- more patients will live thanks to the combination Ipi + Nivo- the design of this clinical trial is disappointing as to the comparator as well as the placebo is certainly not used to control for psychological effects (I have seen no evidence into a psychological effects of any kind affecting ORR in Melanoma in the magnitude of 50% difference).

What about Nivo single agent as comparator, e.g. stratified by PDL-1 expression, and trying to figure out which patients already respond to Nivo alone and don't need the more toxic combination??

Please note- 

As we know, EAP available- check on the BMS website- worth checking whether anything outside the US finally coming along.

Saturday, 30 May 2015

Should be update the Melanoma guidelines now?

Sitting in an exciting Melanoma session at ASCO- the discussion is Ipi versus PD1 first-line.

'Ipi is no longer to be considered 1st line treatment'

' it has been superseded by PD1'

'we should update the Melanoma guidelines after this ASCO'

Things are moving fast and the PD1 data and the Ipi/ Nivo combo are great news for us!

Reducing toxicity on Ipi

A very good comment from the audience in the Melanoma session-

How to reduce toxicity on Ipi: 4 doses of Ipi are not scientifically justified, it's just what we are currently using, so maybe fewer doses would be equally effective with less toxicity.