Highlights

Oh gosh, everything [is an unmet need]. Everything from adjuvant therapy, we don’t have efficacious enough drugs there to prevent recurrences. You could say neoadjuvant we don’t downstage enough. In advanced metastatic disease, we have poor outcomes. In third line, I mean, we barely even get people to third line. So, if I had to pick one, it’s not necessarily that there’s the greatest unmet need but it’s just where I think we don’t have anything really technically right now, would be like fourth line, but I don’t know if anybody wants to go into fourth line, because the number of patients is pretty small there. But if you fail pembrolizumab in third line, it’s not clear if there’s benefit for fourth line. There might be. We just don’t know.

I would say [the impact of PD-1 inhibitors] has been pretty modest. I mean, they have activity, but the response rate is about 15% even in PD-L1-positive patients and they’re third line. So, about half the people are PD-L1-positive and so of that half, some get responses – and they’re durable responses when they do happen. So, it’s a benefit but a lot of people don’t see it unfortunately… [PD-1 blockade] may be [effective] in some groups but not in others. So, there is that MSI-high subgroup, and other subgroups. There may be other subgroups to discover. There may be people with high tumor mutational burden et cetera. But it’s probably not like renal cell carcinoma, let’s just say that. There aren’t too many people who’d benefit.

It’s possible there could be some activity [in Keytruda] in the first line… But I just don’t see it happening as an approval because the benefits are small, there is an opportunity to get checkpoint blockade later, and so I would be surprised if [Keytruda] gets a first-line approval from KEYNOTE-062… it’s going to need a pivotal trial, another study to show that benefit… There obviously is some activity, so I think there’s a possibility that [KEYNOTE-859] will hit the endpoint. [With KEYNOTE-062] it wasn’t that they were far off. So, yes, I would say that there’s a better chance with KEYNOTE-859, but there’s still going to be a small benefit.

I think the combination [of Opdivo and Yervoy]… I would say looks a little bit more effective [than Keytruda]. So, I think that it does have a chance of crossing the line and being effective, as it has been in say renal cell first-line, some lung first-line data. So, yes, I think the dual checkpoint will be enough, it’s just enough additional benefit… Assuming they don’t uncover any major toxicity challenges, yes, I think it’ll become the standard. And again, that’ll affect later utilization of pembrolizumab and then even if the KEYNOTE trial is positive, you know, you already have had extensive use of nivo/ipi, so I think it’ll make a big difference to pembrolizumab use.

With the ToGA trial, trastuzumab became standard for HER2-amplified gastric cancer with platinumcontaining chemotherapy. So, the outcome for patients with 3+ HER2 amplification is substantially better than chemotherapy alone, so I think it made a big impact. This is only about 20% of the gastric cancer patients, but among those people it’s quite a bit of benefit.

I think the response rates [of Enhertu] were in the 50% or so in the DESTINY trial and in people who already had trastuzumab. I mean… it obviously has activity in later-line pretreated, it would suggest that… it might be better than trastuzumab alone in other scenarios. And I want to point out that… they did not require people to get fresh tissue tested for HER2 positivity. So, in fact there are some people on that study who – by the time they were treated – probably had HER2-negative tumors! …If they restricted it to people with newly tested HER2 positivity, it might actually have even greater activity.