ASH – A way in for anti-PD-1 therapy in haematology
It was already abundantly clear that the entry of anti-PD-1 therapy into haematological cancers was going to be a major feature at ASH, and sure enough both Merck & Co’s Keytruda and Bristol-Myers Squibb’s Opdivo impressed in early data presented Saturday.
However, a mechanistic subtlety – namely the relevance of the so-called 9p24.1 genetic alteration – could be by far the most relevant point to emerge from the meeting as regards anti-PD1s. This is important because it pinpoints classical Hodgkin’s lymphoma as a logical target, while likely leaving other haematological malignancies outside the scope of checkpoint inhibition.
Both Dr Philippe Armand, of the Dana‐Farber Cancer Institute, and Dr Craig Moskowitz, of the Memorial Sloan Kettering Cancer Center, highlighted the central role of 9p24.1 amplification. They were presenting the first data in heavily pretreated classical Hodgkin’s patients for Opdivo and Keytruda respectively.
This genetic alteration results in overexpression of PD-L1 and PD-L2 on cancer cells, they said, making them particularly apt for PD-1 inhibition.
But the key is that 9p24.1 amplification is frequent only in classical Hodgkin’s and mediastinal large B-cell lymphoma (a rare cancer) – but few other haematological malignancies. This likely explains the positive Hodgkin’s data, as well as the negative Opdivo result in 27 patients with multiple myeloma (ASH preview – Stock-moving for some, damp squib for others, November 28, 2014).
If, as seems likely, there is scientific rationale in this then it suggests that checkpoint inhibition in haematology might be limited to just one or two cancer types, leaving the targeted and small-molecule approaches of the entrenched players intact.
Too close to call
As is to be expected, investors will now try to tease out the differences between the Merck and Bristol drugs, though for now this is too close to call.
Dr Armand said that in the 23 Hodgkin’s patients in the Checkmate 039 study there were 10 who were evaluable for protein expression, and all were found to harbour genetic abnormalities at 9p24.1 leading to over‐expression of PD-1 ligands. The overall response rate to Opdivo in the full 23-patient group was 87%.
Dr Moskowitz provided a similar analysis of Keytruda’s Keynote-013 study in 29 Hodgkin’s patients. He said PD-L1 expression was observed in 100% of evaluable tumour samples; 21% of patients had complete remission, while the ORR was lower than with Opdivo, at 66%.
While the obvious interpretation is that Opdivo has beaten Keytruda here in efficacy terms, both medics cautioned against jumping to such a conclusion, stressing significant heterogeneity between the two patient groups.
One obvious difference is that the Opdivo group had some slightly less advanced patients, 78% of them having failed Seattle Genetics’ Adcetris. In contrast, Keynote-013 exclusively recruited Adcetris failures.
Another point that has yet to play out, of course, is the question of retreating with Adcetris the patients who have already failed on it. Indeed, one study showed that 30% of Adcetris failures retreated with the Seattle antibody-drug conjugate achieved complete remission.
Regarding the Merck versus Bristol battle specifically, Dr Armand said extreme care had to be taken in making any cross-study comparisons given that the two trials were so small.
Dr Moskowitz agreed, stating: “You can’t draw a distinction. They’re basically similar.”