Promising Ongoing Frontline Trials

Richard S. Finn, MD: There is a lot of exciting stuff coming down the pike. We’ve talked about the rapidly changing landscape. I’ve been involved in the combination of lenvatinib and pembrolizumab, looking at this combination of IO [immune-oncology] and TKI [tyrosine kinase inhibitor], that is showing response rates of around 36% in a frontline population with Child-Pugh A. That’s moved onto a frontline study of lenvatinib/pembrolizumab vs lenvatinib. That is the LEAP-002 study, which has completed accrual, and we’re waiting for a readout. The safety from that study looks consistent with single-agent lenvatinib or single agent pembrolizumab. Katie, you’re involved in some of the ongoing studies. Can you give us a high-level overview of what we have to look forward to in the coming months?

Katie Kelley, MD: Yes. Following upon the IMbrave150 trial and the success of the combination of antiangiogenic with IO therapy, there is now the approach of combining a TKI with a checkpoint inhibitor as you alluded to: lenvatinib plus pembrolizumab, as well as the cabozantinib plus atezolizumab study, COSMIC-312. Both of these trials are based on the premise that not only is there a potential for additive benefit or synergy when you combine antiangiogenic therapy with IO therapy, but these TKI therapies can also be immunomodulatory in the microenvironment and promote an immune response in other ways by inhibiting other kinase pathway signaling and conferring potential for additive effect, being active drugs in their own right. You mentioned pembrolizumab plus lenvatinib, that’s the LEAP-002 phase 3 trial, which has completed accrual.

The phase 1b data were presented by Andrew Zhu, [MD, PhD,] this year at ASCO 2020 [the American Society of Clinical Oncology annual meeting], and as you alluded to, it had profound results in terms of response rate of about 36% by RECIST 1.1 as well as a very high disease control rate. This again suggests both angiogenic inhibition and the IO benefit, so it’ll be interesting to see how the phase 3 data look compared to the lenvatinib control arm, bearing in mind that the IMbrave150 trial was against sorafenib in the control arm. The COSMIC-312 trial I mentioned is cabozantinib plus atezolizumab, and it is based on early phase 1b data that haven’t been presented yet. It is also based on the rationale that cabozantinib has some interesting tyrosine kinase inhibition that may be immunomodulatory in a different way, and that has shown some promising results in renal cell carcinoma, presented just recently at ESMO [the European Society for Medical Oncology Virtual Congress] 2020 as well.

Those are a different way of combining antiangiogenic therapy with IO. The other family of trials on the horizon are the CTLA-4 inhibition plus PD-1 or PD-L1 inhibition combinations, based, of course, on what we’ve seen in lung cancer and melanoma and other tumor types that show synergy in the immune response. The 2 trials that are in phase 3 and reporting on the horizon are, first, the HIMALAYA trial, which is a study of durvalumab, a PD-L1 inhibitor, plus tremelimumab, with 3 different arms in the final phase 3 design. The first is the standard arm of sorafenib, but the other control arm is durvalumab alone. The combination arm is a little different than the usual CTLA-4 inhibition. It is based on phase 2 data presented at this year’s ASCO, which is looking at a single priming dose of the CTLA-4 inhibitor tremelimumab given on day 1 of treatment, along with maintenance durvalumab monthly.

It is based on some interesting data from melanoma and lung cancer, which were born out in phase 2, and it showed that giving a single priming high dose of tremelimumab achieved a burst of proliferative activated T cells at the beginning of treatment, and it was associated with a higher response rate and lower rates of toxicity than the higher sequential dose of tremelimumab. It could potentially promote efficacy and maybe minimize downstream toxicity with a single priming dose strategy.

The other combination on the horizon is nivolumab plus ipilimumab, which is also based on phase 2 data. That has also led to regulatory approval after sorafenib, in the second-line context, which we’ll talk more about later. That ongoing trial is CheckMate 9DW, and its compared to the control arm of physician’s choice: either sorafenib or lenvatinib. Both of these will be interesting strategies to compare to the TKI or bevacizumab plus checkpoint inhibitor combination.

Richard S. Finn, MD: There are 4 ongoing phase 3 studies in the frontline setting, after the approval for atezolizumab/bevacizumab, which speaks to the fact that there’s been incredible interest and excitement in the liver cancer space. You mentioned some data from ESMO recently. There were also data with lenvatinib/pembrolizumab presented within the melanoma cohort for patients who progressed on prior IO, showing that there was some activity with this multitargeted TKI, sensitizing patients to response after progression on frontline IO. The other thing along those lines from the phase 1b study of atezolizumab/bevacizumab is, there was a single-agent atezolizumab arm and a subset of patients who progressed on single-agent atezolizumab and then had bevacizumab added to the atezolizumab.

If you look at the PFS [progression-free survival] on atezolizumab alone vs the PFS on atezolizumab and bevacizumab, the atezolizumab/bevacizumab at progression had a PFS that was twice as long as the frontline atezolizumab. There is clearly a lot of science that we still need to work out.

Transcript edited for clarity.