Sunday, May 22, 2016

ASCO 2016...Let the Games Begin!! Pembro: alone, with ipi, and OS

Pembrolizumab (Keytruda) has better response rates than ipi and has fewer side effects...not really news...but still good to know! In this study, Pembro had response rates of about 36% no matter the dosing frequency, while ipi only reached 13%.  Interestingly, responders without further progression was higher with ipi, though by a small margin, at 75% vs 72 and 69% for pembro.

Pembrolizumab versus ipilimumab for advanced melanoma: Final overall survival analysis of KEYNOTE-006.  ASCO 2016. #9504.  J Clin Oncol 2016.  Scachter, Ribas, Long, et al.

Background: In the phase III KEYNOTE-006 study (NCT01866319), pembro (anti–PD-1) provided superior OS and PFS and a lower incidence of grade 3-5 treatment-related AEs compared with ipi (anti–CTLA-4) in patients (pts) with advanced melanoma and ≤ 1 prior therapy. Here, we present the final OS analysis. Methods: 834 pts were randomized 1:1:1 to 24 mo of pembro 10 mg/kg Q3W or Q2W or to 4 doses of ipi 3 mg/kg Q3W. Clinically stable pts with radiologic progression could receive treatment until confirmed progression. Response was assessed per RECIST v1.1 by central review at wk 12, every 6 wk until wk 48, then every 12 wk thereafter. Survival follow-up was every 12 wk. Final OS analysis occurred after all pts were followed for ≥ 21 mo. Differences in OS were assessed in the intention-to-treat population using the stratified log-rank test with the Hochberg procedure. Results: As of Dec 3, 2015, median follow-up duration was 22.9 mo and 383 pts had died. Pembro continued to provide superior OS, PFS, and ORR over ipi, with no difference between pembro schedules (Table). Median OS was not reached for pembro vs 16.0 mo with ipi; estimated 24-mo OS rates were 55% and 43%, respectively. The PFS KM curves appeared to flatten after ~20 mo for all arms, with estimated 24-mo rates of ~30% for pembro and 14% for ipi. KM estimates suggest ~70% of responding pts have a response lasting greater than or equal to 72 wk. There was 1 treatment-related death (sepsis in the pembro Q2W arm). The safety profile was consistent with that previously reported. Conclusions: With an additional 9 mo of follow-up, median OS was not reached for pembro, and the superiority of pembro over ipi for advanced melanoma was confirmed. Coupled with the durability of response and manageable safety profile, these data support pembro as a standard of care for advanced melanoma. Clinical trial information: NCT01866319

Pembro 10 Q2W
N = 279
Pembro 10 Q3W
N = 277
N = 278
OS, median, mo
Median, mo
24-mo rate, %
HRa (95% CI)
0.68 (0.53-0.87)
0.68 (0.53-0.86)
PFS, median, mo
Median, mo
24-mo rate, %
HRa (95% CI)
0.61 (0.50-0.75)
0.61 (0.50-0.75)
ORR, %
Responders without further progression, %

Pembrolizumab (pembro) plus ipilimumab (ipi) for advanced melanoma: Results of the KEYNOTE-029 expansion cohort.  ASCO 2016. #9506.  J Clin Oncol 2016.  Long, Atkinson, Cebon, et al.

Background: Pembro (MK-3475), an anti–PD-1 antibody that prevents PD-1 from binding to its ligands, PD-L1 and PD-L2, is approved in several countries for treating advanced melanoma. In KEYNOTE-006, pembro showed superior OS over the anti–CTLA-4 inhibitor ipi. In a phase 3 trial, combination therapy with reduced-dose nivolumab (anti–PD-1) and standard-dose ipi showed higher ORR and longer PFS than either checkpoint inhibitor alone but was associated with increased toxicity. Preliminary data from the phase 1 KEYNOTE-029 study (NCT02089685) suggested that standard-dose pembro + reduced-dose ipi was safe and provided robust antitumor activity. Here, we present data from a larger population of patients (pts) treated with pembro + ipi in the KEYNOTE-029 expansion cohort. Methods: Eligible pts had advanced melanoma, ECOG PS 0-1, no active brain metastases, and no prior immune checkpoint inhibitor therapy. Pts received pembro 2 mg/kg Q3W + ipi 1 mg/kg Q3W for 4 doses, then pembro 2 mg/kg Q3W until intolerable toxicity, progression, or 2 y. Response was assessed by RECIST v1.1 at wk 12, every 6 wk until wk 30, then every 12 wk thereafter. Results: Of 153 pts enrolled in the expansion, 107 had greater than or = to, 18 wk of follow-up (median 6.4 mo, range 4.3-9.4) by the Oct 26, 2015, data cutoff and were eligible for analysis. 18% of pts had elevated LDH, 55% had stage M1c disease, 36% were BRAFV600mutant, 13% received greater than or = to, 1 prior therapy, and 12% received a prior BRAF ± MEK inhibitor; 84% had PD-L1–positive tumors (ie, greater than 1% staining in tumor and adjacent immune cells). 79 pts (74%) received all 4 ipi doses; 73 pts (68%) remained on pembro. 41 pts (38%) had ≥1 grade 3-4 drug-related AE (DRAE); 68% of these DRAEs resolved by data cutoff. DRAEs led to discontinuation of pembro and ipi in 9 pts (8%), ipi alone in 11 (10%), and pembro alone in 4 (4%); there were no treatment-related deaths. Immune-mediated AEs of any grade and grade 3-4 severity occurred in 57 (53%) and 21 (20%) pts. ORR by investigator review was 57%, with 5 (5%) CR and 56 (52%) PR; by central review, ORR was 51%, with 9% CR and 42% PR. Conclusions: Pembro 2 mg/kg in combination with 4 doses of ipi 1 mg/kg has a manageable toxicity profile and provides robust antitumor activity in pts with advanced melanoma. Clinical trial information: NCT02089685

The following has been beat to death by the media and Merck...but still pretty damn good.....  Interesting that the OS data at 36 months was NO different for the ipi treated and ipi naive patients.
Three-year overall survival for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001.  ASCO 2016. #9503.  J Clin Oncol 2016.  Robert, Tibas, Hamid, Daud, Wolchok, Weber, et al.

Background: The anti–PD-1 antibody pembro (pembro; MK-3475) prevents PD-1 from binding to its ligands, PD-L1 and PD-L2, and is approved for treating advanced melanoma at a dose of 2 mg/kg every 3 wk (Q3W). Pembro demonstrated superior PFS over chemotherapy for ipilimumab (ipi)-refractory melanoma (KEYNOTE-002) and superior OS and PFS over ipi for advanced melanoma (KEYNOTE-006). We present 3-year OS data for all patients (pts) with melanoma enrolled in the phase 1b KEYNOTE-001 study (NCT01295827). Methods: Pts were enrolled in ipi-naive and ipi-treated cohorts and received pembro 2 or 10 mg/kg Q3W or 10 mg/kg Q2W until intolerable toxicity, progression, or investigator decision. Clinically stable pts with radiographic progression could remain on pembro until progression was confirmed. Response was assessed by RECIST v1.1 every 12 wk. After pembro discontinuation, pts were contacted to assess survival every 3 mo. OS was estimated using the Kaplan-Meier method. Results: Of the 655 pts enrolled, 24% had BRAFV600mutation, 78% had stage M1c disease, 38% had elevated LDH, 75% had greater than or = to, 1 prior therapy, and 52% had prior ipi. As of the Sep 18, 2015, data cutoff date, median follow-up duration was 32 mo (range 24-46) and 358 (55%) pts had died. The 36-mo OS rate was 40% and median OS was 23.8 mo, with similar results for each dose. 36-mo OS rates were 41% in both ipi-treated and ipi-naive pts and 45% in treatment-naive pts. Examination of the OS curve suggests a long-term OS benefit for a fraction of pts treated with pembro. Additional data, including PFS, ORR, duration of response, and safety, will be available for presentation. Conclusions: Pembro provides long-term survival benefit in pts with ipi-naive and ipi-treated advanced melanoma, with 40% of pts alive at 3 years. These data support the use of pembrolizumab in pts with advanced melanoma regardless of prior treatment. Clinical trial information: NCT01295827

Median OS
(95% CI), mo
24-mo OS Rate, %
36-mo OS Rate, %
Pembro 2 Q3W
23.5 (18.3-35.0)
Pembro 10 Q3W
22.9 (18.5-31.1)
Pembro 10 Q2W
25.9 (18.9-41.8)
Ipi treated
20.0 (17.8-27.1)
Ipi naive
28.8 (23.1-32.2)
Treatment naive*
32.0 (27.1-NR)

So the games have begun.  I will group and report out data as best I can. My thoughts, or data I feel hits the crux of the matter, will be in red.  Otherwise...the abstracts are presented as is.  Roll on ratties....roll on!!!! - c