The 2015 ASCO annual meeting promised to be packed with new and exciting data on cancer immunotherapies, including immune checkpoint inhibitors, therapeutic vaccines, and T-cell therapies (to name a few examples). The meeting has certainly lived up to our expectations, with a few surprises along the way. Our NSCLC expert delves into the Phase III data for Opdivo (nivolumab; Bristol-Myers Squibb/Ono Pharmaceutical) in that indication in a separate article. Here, I will focus more specifically on combinatorial approaches involving immune checkpoint inhibitors in oncology.

Opdivo plus Yervoy in malignant melanoma

The much anticipated results from the Phase III (CheckMate-067) trial of Opdivo plus Yervoy (ipilimumab; Bristol-Myers Squibb/Ono Pharmaceutical) in malignant melanoma took center stage at the meeting's plenary session on Sunday. In this study, nearly 1,000 patients were randomized 1:1:1 to receive Opdivo plus Yervoy, Opdivo alone, or Yervoy alone. In summary, the Phase III data for the combination confirm the exciting Phase II (CheckMate-069) data that were unveiled at the 2015 AACR meeting only a few weeks ago.

  • In Checkmate-067, Opdivo plus Yervoy demonstrated a statistically significant 8.6-month improvement in median PFS (a co-primary end point of the study) compared with Yervoy alone, and a much higher overall response rate (ORR; 58%) than Yervoy (19%). Single-agent Opdivo also significantly improved efficacy outcomes compared with single-agent Yervoy (ORR: 44% vs 19%; median PFS: 6.9 months vs. 2.3 months).
  • While it is tempting to conclude that the combination is more efficacious than Opdivo alone based on numerically better efficacy outcomes, it should be stressed that the Phase III trial was not designed to compare these two arms statistically, and that overall survival (not yet mature) and durability of response data (not reached in any arm in this first analysis of the trial) will be required before drawing any clinically meaningful conclusions.

The efficacy outcomes of Opdivo plus Yervoy are clearly remarkable given the current therapy landscape in first-line unresectable or metastatic malignant melanoma, but they come at the cost of significant toxicities, as was reported in earlier-phase studies. The combination was associated with a higher incidence of grade 3/4 adverse events (55%) that either Yervoy alone (27%) or Opdivo alone (16%), and with a higher number of drug-related treatment discontinuations than either single-agent therapies. Nevertheless, these data are somewhat balanced by the fact that nearly 70% of the patients who stopped combination therapy due to treatment-related toxicity experienced a response, and that a number of grade 3/4 adverse events were manageable with appropriate co-medication. In the absence of OS data, the toxicity profile of the combination will likely complicate treatment decisions for clinicians when trying to balance efficacy and safety.

As we had anticipated in our Cancer Immunotherapies Special Report (which published just before the ASCO meeting), Bristol-Myers Squibb filed the combination for approval based on Phase II (CheckMate-069) data; the sBLA will be reviewed under priority review and the PDUFA date is September 30, 2015. Indeed, we believe that gaining approval of the combination is a top priority for Bristol-Myers Squibb, especially now that OS data are available for its competitor Keytruda (pembrolizumab; Merck & Co.). It is likely that the company will wait for the all-important OS outcomes from the CheckMate-067 trial before sharing Phase III data will regulatory authorities. If approved, Opdivo plus Yervoy will be the first combination therapy based on dual immune checkpoint blockade to be approved for any oncology indication. However, the cost of the combination will be another key variable that will color clinicians, treatment choices for previously untreated patients, notably in the BRAF-mutation-positive setting. We will explore these aspects in our primary research with surveyed clinicians and payers in the upcoming Physician and Payer Forum report  entitled: Immune Checkpoint Inhibitors in Oncology (due to publish in November 2015).

At this point, given the toxicity profile of the combination and the absence of OS data, it is perhaps too early to conclude that Opdivo plus Yervoy should be preferred over single-agent anti-PD-1 therapy in previously untreated unresectable or metastatic patients.

Different indications, different outcomes

Numerous regimens that combine two immune checkpoint inhibitors are in clinical development, and new data were presented for several of these combinations at the ASCO meeting:

  • Opdivo plus Yervoy in glioblastoma multiforme (GBM) : abstract 3010. Preliminary results from the lead-in phase of the CheckMate-143 study showed that 4 of 10 patients treated with the combination discontinued study treatment due to treatment-related toxicity before receiving four doses of the regimen. The combination was not selected for further clinical development; indeed, the Phase III portion of the study will randomize patients between Opdivo alone and Avastin (bevacizumab; Roche/Genentech/Chugai).
  • Opdivo plus Yervoy in small-cell lung cancer (SCLC) : abstract 7503. In the randomized Phase I/II (CheckMate-032) trial conducted in recurrent SCLC, the ORR outcomes were similar for Opdivo plus Yervoy (17%) and Opdivo alone (18%), but the combination doubled MOS compared with Opdivo alone (8.2 months vs. 4.4 months). These results are encouraging given the dearth of effective therapies to treat this subtype of lung cancer.
  • Keytruda plus Yervoy in NSCLC : abstract 8011. Preliminary data from the Phase I (KEYNOTE-021) study showed an ORR of 33% in previously treated advanced or metastatic patients, at the dose selected for further clinical trials (2 mg/kg Keytruda and 1 mg/kg Yervoy).
  • MEDI-4736 plus tremelimumab in NSCLC : abstract 3014. In a Phase Ib study in advanced NSCLC, across all dose cohorts, the ORR for the combination was 27% and the rate of grade 3/4 toxicities was 40%.

These data are still preliminary but it is interesting to note that in some indications, combining two immune checkpoint inhibitors may not necessarily lead to considerably better ORR outcomes than single checkpoint blockade. As stated previously, durability of response and OS data will be even more crucial than ORR to ascertain whether dual immune checkpoint blockade is indeed ready for prime time across oncology. It also remains to be determined what impact a less-than-favorable toxicity profile and inevitable high cost will have on the uptake of combination therapies. While Decision Resources Group anticipates that regulatory approval for the combined use of Opdivo and Yervoy will be key to build and cement their franchise position in the malignant melanoma market, questions still remain over how this combination therapy will fit into the treatment paradigm and fend off competitors.

We will certainly continue to follow developments for Opdivo and Yervoy combination therapy and the raft of other combination approaches that developers are employing with great interest throughout the year, so stay tuned for more insight from our team of experts!

Khurram Nawaz, M.Sc., is a principal business insights analyst on the Oncology team at Decision Resources Group.

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