If oncology drug development is considered race to the market, the fever around combinations with immune checkpoint inhibitors is turning it into a sprint. The pace at which clinical development is rapidly evolving has rendered the clinical trial landscape—especially for immune checkpoint inhibitors—an important headache that drug developers need addressing.

Since Keytruda’s approval in 2014 for unresectable or metastatic malignant melanoma, PD-1 inhibitors have offered deep and durable responses across many cancer types. The impressive efficacy achieved by PD-1 inhibitors has set the efficacy bar high and oncology R&D has now turned to combination regimens in an effort to achieve more than incremental efficacy gains, a trend that started in malignant melanoma before expanding across a range of malignancies.

Bristol-Myers Squibb and Ono Pharmaceutical’s combination of Opdivo (PD-1 inhibitor) plus Yervoy (CTLA-4 inhibitor) was approved for unresectable or metastatic melanoma in 2015, marking the dawn of a new era for combinations involving immune checkpoint inhibitors. Although the combination offers substantially improved efficacy over the single agents alone, a proportion of patients do not respond and the combination is associated with a high incidence of grade 3/4 adverse events (59% grade 3/4 treatment-related adverse events [Phase III CheckMate-067 trial])1. Much opportunity for developers therefore remains, especially in patients with low levels of PD-1 expression, and indeed, many drug developers are now asking themselves ‘how can we improve responses?’ and ‘what combinations are best to develop?’.

At ASCO 2018, a wealth of the data released has not only offered a fresh look into many of emerging combinations attempting to address these questions, but also offered insight into the current positions in this race.

Warnings from Epacadostat + Keytruda

It is impossible not mention the Incyte’s fallen star, the IDO1 inhibitor epacadostat, and its failure in the Phase III ECHO-301/KEYNOTE-252 trial in combination with Keytruda in malignant melanoma (abstract 108), in the context of combination therapy development. Original hype surrounding the combination stemmed from Phase Ib/II data showing an ORR of 55% and a median PFS of 22.8 months2 rivalling that of Opdivo + Yervoy but without the safety and tolerability issues. The Kaplan–Meier curves for PFS and OS were remarkably identical for the combination and Keytruda plus placebo (median PFS was 4.7 months versus 4.9 months, respectively, with a hazard ratio of 1.00 [0.83-1.21; P=0.517]). With the findings consistent across subgroups, including PD-L1 and BRAF status, there seems little left to be salvaged for the combination in malignant melanoma, despite the announcement that several post hoc analyses (such as IDO-1 mRNA expression, and tumor mutational burden) are being performed.

This shock failure of epacadostat undoubtedly shook the world of drug development and has perhaps served as a reminder for extreme caution needed when making cross trial comparisons, especially using Phase I/II data in low numbers of patients, and not least reiterates the risk of progressing to Phase III development in the absence of randomized Phase II studies.

Can Novel Combinations Give BMS A Boost?

In February 2018, Bristol-Myers Squibb stunned the pharmaceutical sector by announcing a global collaboration with Nektar Therapeutics to evaluate NKTR-214 plus Opdivo in a deal reported to cost an incredible $1.85 billion, comprised of $1 billion cash and an $850 million equity investment, for a share of NKTR-214 profits.

Although this deal might be seen by many as a risky decision by Bristol-Myers Squibb in trying to defend Opdivo from rival PD-1 inhibitor, Keytruda, there is scientific rationale for combining the mechanisms of action of NKTR-214 (a PEGylated IL-2 prodrug) and Opdivo. The combination hopes to complement Opdivo’s mechanism of action by stimulating the production of immune cells that enhance antitumor immune responses, potentially converting ‘cold’ PD-1 non-responders to responders. The updated Phase I/II PIVOT-02 data raise more questions than answers (abstract 3006). Impressive ORR data from the Phase I dose-escalation cohorts were announced in March 2018, albeit in a small number of patients; but, in the ASCO update, more patients were enrolled and yet the ORR dropped (malignant melanoma, 85% to 50%; renal cell carcinoma, 64% to 46%). However, other data presented at the annual meeting suggested that while the tumor response takes time to deepen, both PD-L1 positive and negative patients could receive benefit, where 53% of PD-L1 negative patients were converted to PD-L1 positive by week 3.

With another eagerly anticipated update of the data likely to emerge around ESMO 2018, there is much interest into how the efficacy data matures. The decision to initiate a Phase III trial in malignant melanoma based on pre-specified efficacy criteria being met for ORR in the first part of PIVOT-02 is controversial, especially in light of the ECHO-301/KEYNOTE-252 outcome for epacadostat. All eyes will be on this study.

In addition to NKTR-214, ASCO 2018 also saw the release of Phase I/II data for combinations of JTX-2011 (an ICOS agonist mAb being developed by Jounce Therapeutics) or varlilumab (a CD27 agonist mAb being developed by Celldex therapeutics) with Opdivo in heavily pre-treated patients (abstracts 3000 and 3001, respectively). Although data were for low number of patients and longer follow ups are needed, both combinations might show promise in the future, where JTX-2011 plus Opdivo elicited a response in some patients that had previously failed PD-1 inhibition (especially in patients with high ICOS expression), while varlilumab plus Opdivo could also turn some ‘cold’ tumors ‘hot’, increasing PD-L1 expression.

Playing It Safer in Combinations with Already Approved Targeted Agents

Alongside the combinations involving novel agents above, numerous immune checkpoint inhibitors are being developed in combinations with targeted agents already approved for a specific indication. In this way, developers are hoping to add incremental benefits, where the late-phase pipeline of renal cell carcinoma is a good example with five different immune checkpoint inhibitor plus angiogenesis inhibitor combinations are in Phase III development versus Sutent. Efficacy and safety data on numerous examples of these types of combinations in a range of development phases were presented at ASCO, offering new data into the current state of play in their respective indications. These included:

  • Keytruda plus Lenvima/Kisplyx in metastatic renal cell carcinoma (abstract 4560): A poster showing Phase Ib/II results (including ORR, median PFS, and safety and tolerability) for a combination in Phase III development in first-line advanced renal cell carcinoma.
  • Tecentriq plus Avastin in treatment-naïve metastatic renal cell carcinoma (abstract 4511): An oral presentation showing significantly improved patient reported outcomes from this registrational Phase III trial.
  • Keytruda plus Avastin in metastatic renal cell carcinoma (abstract 4558): A poster showing Phase Ib/II results (including response rates, median PFS, and safety and tolerability) for a combination with a similar mechanism of action to one in Phase III development in first-line advanced renal cell carcinoma (Tecentriq plus Avastin).
  • Opdivo plus Avastin or Yervoy followed by surgery in metastatic renal cell carcinoma (abstract 4520): A poster showing early Phase 1 results (including best overall response and best overall response excluding surgical effect) for a similar mechanism of action to one in Phase III development in first-line advanced renal cell carcinoma (Tecentriq plus Avastin) and one that is already approved (Opdivo plus Yervoy).
  • Keytruda plus Zejula in recurrent ovarian cancer (abstract 106): An oral presentation showing Phase I/II data (including ORR, durability of response, and safety and tolerability) demonstrating activity in a population where Zejula is already approved.
  • Tecentriq plus Alecensa in treatment-naive ALK+ advanced NSCLC (abstract 9009): An oral presentation showing Phase Ib data (including ORR, median PFS, duration of response, and safety and tolerability) demonstrating safety and activity in a population where Alecensa is already approved.
  • Bavencio plus Xalkori or lorlatinib in previously treated advanced/metastatic ALK-negative/wildtype or ALK+ NSCLC (abstract 9008): An oral presentation showing Phase Ib data (including ORR, and safety and tolerability) demonstrating safety and activity in a population where ALK inhibitors are already approved.

This is an exciting time for in an exponentially expanding area of drug development. Keep up-to-date and informed on these developments with solutions from Decision Resources Group that include our Oncology Clinical Trial Monitor, Real World Brand Tracker, and Disease Landscape & Forecast offerings on Malignant melanoma, Renal Cell Carcinoma, Ovarian Cancer, Non-Small Cell Lung Cancer, and more.


  1. Larkin J, et al. Abstract CT075: Overall survival results from a phase III trial of nivolumab combined with ipilimu ab in treatment-naïve patients with advanced melanoma (CheckMate-067). Cancer Res. July 1 2017 (77) (13 Supplement) CT075
  2. Hamid O. et al. Epacadostat plus pembrolizumab in patients with advanced melanoma: Phase 1 and 2 efficacy and safety results from ECHO-202/KEYNOTE-037. Annals of Oncology. 2017;28(5)

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