Kelly Davio

In subset findings from the LOXO-TRK-14001 (NCT02122913) and NAVIGATE (NCT02576431) studies presented during the 2019 European Lung Cancer Congress (ELCC), larotrectinib (Vitrakvi) demonstrated an&nbsp;overall response rate (ORR) of 71% in patients with nonsmall cell lung cancer (NSCLC) harboring

The TRK inhibitor was approved by the FDA in November 2018 based on data from these 2 trials. The agent is indicated for the treatment of adult and pediatric patients with solid tumors that have an

gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative therapies or that have progressed following treatment.

Results from the studies showed, of 7 patients with metastatic lung adenocarcinoma who were evaluable for larotrectinib response, there was 1 complete response (CR), 4 partial responses (PRs), and 2 patients with stable disease. Additionally, the median time to response was 1.8 months, and the median duration of response (DOR) was not reached.

Additionally, an integrated analysis of the ALKA-372-001, STARTRK-1 and STARTRK-2 trials evaluated the activity of entrectinib in patients with locally advanced or metastatic

fusionpositive NSCLC, which was also presented at the 2019 ELCC. Results showed that the multikinase inhibitor is highly active and well tolerated in this patient population, including those who have CNS metastases.

Based on these findings, the FDA granted a priority review designation to a new drug application for entrectinib as a treatment for select adult and pediatric patients with

fusionpositive locally advanced or metastatic solid tumors, as well as those with metastatic

&ldquo;The takeaway message is that entrectinib is an active drug for

fusionpositive lung cancers. The hope is that at some point in the future, maybe we&rsquo;ll get the drug approved for this subset of patients. The question then becomes, &ldquo;When do I use entrectinib versus crizotinib (Xalkori)?,&rdquo; said Alexander Drilon, MD, clinical director, Early Drug Development Service, associate professor of thoracic oncology service, Memorial Sloan Kettering Cancer Center.

during the 2019 ELCC, Drilon discussed these findings with larotrectinib in

fusionpositive tumors and entrectinib in

Could you give some background to TRK inhibition and the findings presented at this year&rsquo;s meeting?

fusions are a bona fide driver of both lung cancers and many other different cancers. In fact, larotrectinib was approved late last year, in November 2018, for any

fusionpositive cancer, regardless of what the cancer looks like under the microscope. That was really a landmark approval, because it was the first targeted therapeutic that was approved for a genomic signature and really agnostic of tumor type.

At the 2019 ELCC, we specifically pulled out the outcomes of NSCLC patients who harbor

fusion in their cancers, and there were 11 patients who were part of the larotrectinib series, and we found that there was a high response rate to therapy. It was a 71% ORR, considering that the denominator isn&rsquo;t large. We saw a disease reduction in all patients who had therapy, there were deep responses to treatment, and 1 had a CR to larotrectinib.

In terms of durability, the median DOR was actually not reached yet. Most patients who received larotrectinib for their

fusionpositive lung cancers remain on therapy. The patient who had been on [treatment] the longest is already pushing 2.5 years.

The last thing we featured was the intracranial activity of larotrectinibrecognizing that there were 3 out of 11 patients who had brain metastases on this trial. This has been a question that&rsquo;s come up for the

field in general, on whether or not these drugs have substantial activity in the CNS. What we saw was that patients had global overall disease control, meaning that patients had disease regression both extracranially and intracranially.

Thus far, we weren&rsquo;t able to calculate intracranial response rate, but we featured a case of an older woman in her mid-70s who was found to have a

fusion in her stage IV lung cancer. She, unfortunately, had multiple asymptomatic brain metastases, and she refused standard-of-care platinum-doublet therapy after hearing the phenomenal results that we&rsquo;ve achieved with larotrectinib across different cancers. She had a confirmed PR to therapy with a near complete intracranial response. By volumetric analysis, this was almost a 95% reduction in her tumor burden in the CNS.

The punchline here is that larotrectinib is not only an active drug if you have a lung cancer that harbors a

fusion, but also if you have brain metastasesthis can be a very active therapy. The corollary to that, hopefully, is that it also helps prevent the acquisition of CNS disease.

How do these findings affect screening decisions?

The take-home message is that you should screen for

fusions. Coming from a lung cancer paradigm where we&rsquo;re screening for many other drivers, you just need to be cognizant of whether you&rsquo;re using an assay that meaningfully looks for these

Diagnostically, this can be a little bit more challenging than detecting other fusions, such as

, because we found that the best way to look for a

fusion is to do next-generation sequencing (NGS), preferably with a hybrid capture-based platform. Also, we found that even when you use a very good DNA-based NGS test, you can still miss some of these

fusions. That&rsquo;s due to the length of the introns, for example; it&rsquo;s hard to find these fusions.

The punchline here is that, if you&rsquo;re looking at an assay, it might be best to look for an assay that has RNA on top of DNA in order to maximize the likelihood of picking up these fusions. In our experience with using an RNA-based assay, such as anchored multiplex PCRfollowing a good DNA-based NGA assay&mdash;is that you miss a driver 15% of the time, even when you do a good DNA test, that&rsquo;s subsequently picked up by an RNA assay.

What are the most pressing research questions that remain to be answered about larotrectinib in this setting?

Now that the drug is FDA approved, we would obviously like to see how the &ldquo;chips fall&rdquo; in terms of long-term tolerability. Thankfully, we&rsquo;ve seen that with the safety data presented so far; there is a very good tolerability profile. The rate of dose reductions was very lowit was 9%&mdash;of the more than 120 patients who received larotrectinib, only 1 discontinued for a drug-related adverse event. However, it would be nice to see how things march out when patients are on this therapy for a very long time&mdash;knowing that they could be on this for years given the durability of disease control.

The second major challenge would be helping to characterize the profile of resistance to larotrectinib. We know that some of these cancers can acquire on-target resistance, meaning the cancers are still reliant on the

Usually, when you see a report, when you re-sequence these cancers or do a plasma test, you find a kinase-domain. Thankfully, we now have next-generation TRK inhibitors, such as repotrectinib, formerly known as TPX-0005, and LOXO-195. These are drugs that that have been designed to address these resistance mutations. There are ongoing phase I trials for both agents. Therefore, if you have a patient who progresses on a first-generation TRK inhibitor like larotrectinib, [these options] would be available for patients. There have been data presented that we can reestablish disease control with a second pill after an earlier-generation pill fails.

You are also an author on an integrated analysis of ALKA-372-001, STARTRK-1, and STARTRK-2, which looked at entrectinib in locally advanced or metastatic

fusionpositive NSCLC. What did your analysis find?

We know that crizotinib (Xalkori) is already approved by 1 or more regulatory agencies for the treatment of

fusionpositive lung cancers. The question then becomes, &ldquo;Are there agents that are able to improve outcomes for patients in this setting?&rdquo; Entrectinib is a very potent ROS1 inhibitor that was designed to cross the blood-brain barrier. The question is, &ldquo;Are we able to use a CNS-active agent in the first-line setting and hopefully improve outcomes for patients?&rdquo; We know that crizotinib, while it can get into the CNS and we can see CNS responses, there can be a high failure rate in the CNS; about half of patient with

will have some type of failure intracranially when they progress on crizotinib.

The entrectinib trial took ROS1 TKI-na&iuml;ve patients. This is mainly because we know that, with our early patients on entrectinib who received prior ROS1-targeted therapies, we did not see any responses in that group. Therefore, the first important point is that entrectinib is not only a CNS-active agent, but it is really considered more of an early-generation ROS1 inhibitor.

fusionpositive lung cancers, this was a data set that had north of 50 patients, all of whom obviously had a

fusion that was detected by a local platform. Some did fluorescence in situ hybridization (FISH), some did NGS, but what we saw in the topline results in terms of activity was that the ORR was high at 77%this is something that you like to see with a targeted therapy that&rsquo;s highly active, with a very nice waterfall. The majority of patients had disease regression with entrectinib, and certainly there were deep and durable responses to therapy.

The data set is notable, in that entrectinib actually achieved the longest median duration of response of any ROS1 TKI at approximately 25 months. That, to me, is a meaningful endpoint. If you have almost 80% of patients responding to therapy, it&rsquo;s comforting to know that these responses can go on for a very long period of time. In terms of other endpoints, the median progression-free survival for the data set was around 19 months.

What should community oncologists take away from these findings?

Certainly, if you had a patient with brain metastases, given the substantial number of patients with brain metastases on the entrectinib series, I would feel very comfortable giving the drug to those patients. We&rsquo;re not only seeing an ORR of approaching 80%, but there&rsquo;s also an intracranial response rate that was north of 50% in the entrectinib data set.

Corollary to that, if you assume that if the drug has meaningful penetration of the blood-brain barrier, then even in patients who do not have CNS metastases, you hope that with the use of entrectinib, you might prevent the emergence of brain metastases.

Drilon A, Kummar S, Moreno V, et al. Activity of larotrectinib in TRK fusion lung cancer. Presented at: 2019 European Lung Cancer Congress; April 11 to 13, 2019; Geneva, Switzerland. Abstract 111O.

Barlesi F, Drilon A, De Braud F, et al. Entrectinib in locally advanced or metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC): integrated analysis of ALKA-372-001, STARTRK-1 and STARTRK-2. Presented at: 2019 European Lung Cancer Congress; April 11 to 13, 2019; Geneva, Switzerland. Abstract 109O.

Articles

Alexander Drilon, MD,&nbsp;discussed updated findings with larotrectinib in NTRK fusion&ndash;positive tumors and entrectinib in ROS1 fusion&ndash;positive NSCLC. 
&nbsp;

Updated Data Support Efficacy of Larotrectinib, Entrectinib in NSCLC

The investigational agent avapritinib demonstrated encouraging response rates in patients with advanced gastrointestinal stromal tumors (GIST) and PDGFR&alpha; D842V-driven GIST, according to findings presented during the 2018 Annual Meeting of the Connective Tissue Oncology Society in Rome, Italy.

Findings from the phase I NAVIGATOR study (NCT02508532) showed an overall response rate (ORR) of 84% in patients with PDGFR&alpha; D842V-driven GIST and a 20% ORR fourth-line or later GIST. Additionally, 98% of patients with PDGFR&alpha; D842V GIST and 60% of patients in fourth-line or later experienced tumor reduction.

Lead study author Michael C. Heinrich, MD, of the Oregon Health and Science University&rsquo;s Knight Cancer Institute in Portland, Oregon, presented the findings during the meeting.

, Heinrich discussed the NAVIGATOR study, the next steps for avapritinib&rsquo;s development, and how this therapy could deliver on the promise of precision medicine for patients with this malignancy.

What are the key findings from the NAVIGATOR study in patients with GIST?

The key finding is that it endorses our vision of precision medicine for all of oncology, but particularly in GIST, which is knowing particular types of mutations in different types of GIST and rationally designing drugs that would be most beneficial in terms of effectiveness and also safety.

That also builds upon existing drugs that have some benefit, particularly in the first-line, not so much in the second- and third-line, but we&rsquo;ve come to learn that there are particular reasons for drugs not working.

Avapritinib builds upon all that 15 years of knowledge that there are particular mutations that existing drugs don&rsquo;t work against, and making a better drug to target those secondary mutations will lead to better results. What the results show is that in patients with

-mutant GIST &shy;&shy; which is a less common type of GIST but a GIST that doesn&rsquo;t respond to any available therapy &ndash; 98% of patients treated with avapritinib had tumor shrinkage. This is truly amazing for any disease, and any drug, let alone this disease where we&rsquo;d expect a response rate of close to 0% for anything else we could do.

We also found that, consistent with how the drug was developed and what it was designed to do, in patients with 1 to 6 prior lines of therapy, that they also would respond to avapritinib.

Going forward, we can move from a static view of the patient&rsquo;s tumorwhich is their biopsy from 10 years ago of their original tumor&mdash;to understanding, at the time when we need to switch therapies, what&rsquo;s going on with their tumors based on sampling their blood. We could select or deselect populations who would greatly or less greatly benefit from avapritinib. Moving forward, we&rsquo;d like to explore that in a prospective study where patients are randomized based on what&rsquo;s going on with their mutations in their blood.

What are the next steps in development of avapritinib, and do you foresee an FDA submission on the horizon?

We believe that the results are very promising for

-mutant GIST, which has no effective treatment, and for patients with fourth-line or later-treated GIST, who have no treatment at all. Our data are compelling enough that a new drug application would be filed next year in those indications.

There&rsquo;s an ongoing randomized phase III study of avapritinib versus the current standard third-line treatment, which is regorafenib. We hope in the next year to complete enrollment of that study to see the results, but based on our preliminary results from our phase I, we would be optimistic that avapritinib would be superior to regorafenib in that setting. More excitingor less developed right now&mdash;is the idea of moving avapritinib into the second-line, but rather than basing it on line of therapy, selecting patients based on mutational status. If they have the type of circulating tumor DNA profile that predicts optimally for avapritinib response, they would be randomized versus sunitinib, which is the current therapy, to see the outcome.

We would predict that in the optimally selected or deselected population, that that would increase efficacy in the second-line. Conversely, we feel that sunitinib patients could also benefit, because patients who would benefit the most from sunitinib would be given sunitinib rather than enter this randomized study. We feel it has the potential to increase the second-line outcomes both for patients favored for avapritinib and for sunitinib.

How well tolerated is avapritinib so far?

I think it&rsquo;s generally well-tolerated. Less than 9% of people discontinued the drug due to adverse events, which is a low rate for many TKIs. We felt that the side effects were consistent with inhibiting KIT in PDGFRA, which is the target. If we hit the target, there are certain side effects that we&rsquo;re going to expect, and we see them.

Compared to second- and third-line agents, I feel the side effect profile is much better. Many patients would endorse that. I&rsquo;ve had patients say, &ldquo;I haven&rsquo;t felt this well in years,&rdquo; which is partly because the drug is working, and partly because it has fewer side effects than what they were on previously.

-mutant GIST, it would be approved and would be the first-line therapy for those patients. We feel that in the fourth-line and later patients, there&rsquo;s no therapy that has efficacy and has been approved. Avapritinib has strong activity for those patients.

As the third-line randomized studies go on, we predict it would eventually become the third-line agent and potentially the second-line agent for patients with certain genotypes. Optimistically, it probably would be the best agent for frontline therapy, but imatinib has really good results for efficacy and safety, so that would be a much bigger venture to try to move into frontline therapy.

Can you say a bit about the ongoing VOYAGER trial?

It&rsquo;s a randomized study for patients in the third-line or fourth-line who have never received regorafenib, the standard treatment. Patients are randomized to regorafenib or avapritinib. If patients receive regorafenib first and get progression, then they can receive avapritinib, so everybody has the opportunity to get avapritinib either first or second.

How do you characterize the treatment landscape for GIST, and what are some open research questions?

There&rsquo;s another agent in development, DCC-2618, that had results presented at this meeting by Dr Suzanne George, which also shows promising activity.

Both were rationally designed. So, what is avapritinib going to be approved for? What could DCC-2618 be approved for?

A number of different studies here have looked at circulating tumor DNA, so there is some value to that: how do we use it, what type of decisions do we make based on the results, when should we even do it? These are open questions, but that&rsquo;s exciting. Knowing what was wrong in a patient&rsquo;s tumor, having a drug that would fix that which was wrong, and doing so is a much better approach than saying &ldquo;We use this first, we use this second, we use this third, we don&rsquo;t really care about your tumor, we don&rsquo;t care about anything individual about you, these are the ways we do things.&rdquo; In a disease that is heterogenous, diverse, and different patient have different mutations, that doesn&rsquo;t make sense anymore.

The idea of precision oncology is to take an understanding of the biology of the diseasewhat&rsquo;s broken&mdash;and apply, in the most precise way possible, the fix to it. We&rsquo;re moving from the world of radiation and chemotherapy, which are effective for many cancers&mdash;but they&rsquo;re kind of blunt instruments, they&rsquo;re not individualized, they&rsquo;re not precision, it&rsquo;s the same for everybody.

We believe that, in the future, for any patient, rather than saying, &ldquo;You have disease X,&rdquo; it&rsquo;d be better to say, &ldquo;You have disease X with the following abnormalities, which would be sensitive to the following drugs,&rdquo; and choose a therapy based on that.

Heinrich M, von Mehren M, Jones RL, et al. Avapritinib is highly active and well-tolerated in patients (PTS) with advanced GIST driven by diverse variety of oncogenic mutations in KIT and PDGFRA. Paper 012 #3027631. Presented at the 2018 Annual Meeting of the Connective Tissue Oncology Society, November 14-17, 2018; Rome, Italy.

George S, Heinrich M, Chi P, et al. Initial results of phase 1 study of DCC-2618, a broad-spectrum KIT and PDGFRA inhibitor, in patients (PTS) with gastrointestinal stromal tumor (GIST) by number of prior regimens. Paper 013 #3033840. Presented at the 2018 Annual Meeting of the Connective Tissue Oncology Society, November 14-17, 2018; Rome, Italy.

The investigational agent avapritinib demonstrated encouraging response rates in patients with advanced gastrointestinal stromal tumors and PDGFR&alpha; D842V-driven GIST, according to findings presented during the 2018 Annual Meeting of the Connective Tissue Oncology Society in Rome, Italy.

Avapritinib Could Deliver Precision Medicine to Patients With GIST, Says Heinrich

In findings presented during the 2018 Annual Meeting of the Connective Tissue Oncology Society, the ALK inhibitor crizotinib (Xalkori) showed promise for the treatment of inflammatory myofibroblastic tumor (IMFT), a rare soft tissue sarcoma that usually occurs in children and young adults.

Results from the CREATE trial, a phase II study of crizotinib in advanced inoperable IMFT, were presented by lead study author Patrick Sch&ouml;ffski, MD, MPH. Findings from the study showed a 50% objective response rate in this patient population (95% CI, 21.1%-78.9%).

The study enrolled 35 patients across 13 sites in 8 European countries. Of those patients, 20 had centrally confirmed IMFT and were treated with crizotinib. Among 12 evaluable patients with ALK+ disease, 6 patients achieved a confirmed partial response (PR) or complete response, 1 achieved a non-confirmed PR and 5 had stable disease as best response.

, Sch&ouml;ffski, of the Catholic University of Leuven, in Leuven, Belgium, discussed the key findings of the trial, the next steps for research into IMFT, and the regulatory challenges for approval of drugs for rare cancers.

: What are the key findings from your study of crizotinib in patients with inoperable IMFT?

In our CREATE trial, we wanted to assess the activity of an oral targeted agent called crizotinib in patients with a very rare disease called IMFT. We documented a high objective response rate in patients with this disease characterized by positivity for an ALK rearrangement. Fifty percent of our patients had an objective response to crizotinib.

: Do these results point to a new standard of care in

: This disease is so extremely rare that it is impossible to run big, randomized prospective trials. Actually, the study I am presenting here is the very first prospective phase II trial ever performed in this disease. All other data in the literature come from dose-finding studies in adult patients or pediatric patients from a mixed population of cancer patients with ALK-positivity of their tumors, so this is the very first attempt to study the activity in a rigorous way. It is impossible to do bigger, more definitive trials, so I strongly believe that the data we provide here should serve as the reference and should be the basis for using crizotinib in clinical routine.

: Interestingly, we allowed the entry of both

-negative patients in this trial. We believe this was ethical because there is no standard of care for both subsets of this disease.

negative subset of patients, we treated and evaluated 7 patients exposed to crizotinib, and interestingly, 3 of these 7 patients had shrinkage of their target lesions according to the standards that we used in this trial; 1 of these patients even had an objective partial response.

: What are the next steps in your research?

: Well first of all, this was a cohort of a multitumor study. I managed over the past year to publish 5 full papers related to this trial, so we put data into the literature for 5 very rare diseases, all coming from the same study with the same study design, and all patients treated with the same agent.

The next step has to be to work further on the biology of the tumors that we treated in this trial. When I wrote the protocol several years ago, I decided to collect tissue blocks from every tumor that was included in this trial. We have these tumor blocks, which Is a wonderful resource for doing translational research. We have built what we call tissue microarrays; we have put tiny little pieces of tumor from every patient in this trial in 1 paraffin block, which allows us to studyin a very rapid way&mdash;the biology, the expression of certain molecular targets, for example, in all patients simultaneously by just doing 1 staining.

This is something that&rsquo;s currently ongoing. We are trying to understand what might be prognostic or predictive factors for response to crizotinib. Furthermore, we are trying to understand the difference between

-negative cases. Of course, we are very interested in looking at the

-negative patients who had some shrinkage of the target lesions or even a sporadic response, so we are doing a lot of tissue-based work at this time.

Furthermore, we have not only collected tissue blocks, but also scans from all of these patients, from the start of treatment until the end of treatment. I&rsquo;m currently stimulating a number of radiology substudies. These diseases are so rare that even the radiological presentation of these tumors has not been described very well in the literature, so there is still a lot that can be done with materials collected in this study.

Futhermore, [in] the cohort that I&rsquo;m presenting today, the myofibroblastic patients, about a third of these patients were still receiving active treatment when I first published data from this trial. Of course, we are still following them. We are still updating our database. We know at this point that the response rate will ultimately be even higher than what I&rsquo;m reporting here today because we have seen some patients who had only stable disease on the treatment, converting to partial responses later on. It&rsquo;s very likely that the objective response rate that I&rsquo;m reporting as the primary endpoint will even increase over time.

: Given the rarity of this cancer, what are some of the unmet research needs in IMFT?

: It&rsquo;s very difficult to perform research if you only have a sporadic case to perform some translational work. The beauty of our trial is that we did not only use it for establishing the response rate for a given treatment but to collect material in a prospective way, which is really a goldmine for further research.

Apart from the promising efficacy findings in this trail, further papers that will come out of this trial will teach us a lot about the biology about the spontaneous course of this disease, the natural evolution of the disease, and even survival.

If you look at the data that I&rsquo;m presenting here, you will see that we provide very mature overall survival data. There is no data in the literature on how long a patient can actually live with advanced IMFT. We are providing data in a prospective way from a well-done, investigator-initiated academic trial.

: Are there challenges related to approval of a drug for a rare indication in which a large, randomized study is not feasible?

: The problem in rare diseases such as IMFT or the other cancers that we have treated in this prospective trial is that we will never generate the randomized level of evidence that is routinely required to get drugs approved by regulatory bodies. So far, with a tumor like IMFT, we have to be very creativeand regulators have to be very flexible&mdash;to broaden the label of such a drug in this disease.

Crizotinib is approved for NSCLC, which is a very common malignancy, as you know, but only for a tiny little subset of NSCLC patients, the ALK- and

-positive patients. Still, this is a considerable number of patients to do a more definitive study. In a disease like IMFT, it would be impossible.

We need a lot of flexibility on the side of regulators to bring the drug to the patients in need of such agents. At this point, we have already 3 generations of ALK inhibitors on the market for other indications. Critozinib was the prototype agent, and we need a way to bring this drug to the patients outside of clinical trials.

Sch&ouml;ffski P, Sufliarsky J, Gelderblom H, et al. Prospective trial of crizotinib (C) in patients (PTS) with advanced, inoperable inflammatory myofibroblastic tumor (IMFT) with and without ALK alterations: EORTC phase II study 90101 &ldquo;CREATE.&rdquo; Paper 017#3016595. Presented at the 2018 Annual Meeting of the Connective Tissue Oncology Society, November 14-17, 2018; Rome, Italy.

Patrick Sch&ouml;ffski, MD, MPH,&nbsp;discussed the key findings from the CREATE trial, the next steps for research into inflammatory myofibroblastic tumor, and the regulatory challenges for approval of drugs for rare cancers.

Crizotinib Holds Promise for Treating IMFT, Says Schoffski

The treatment paradigm for hepatocellular carcinoma (HCC) has advanced in recent years, however, the disease remains a challenging one to treat.

Research trends are now pointing to immune checkpoint inhibitors both alone and in combination as a promising new direction of for the treatment of HCC, explained Bruno Sangro, MD, during a presentation at the 12th International Liver Cancer Association (ILCA) Annual Conference, held in London, United Kingdom. The key will be determining which patients will be likely to benefit from this class of agents, he added.

At the meeting, Sangro, director of the liver unit and codirector of the hepatobiliary oncology area at Clínica Universidad de Navarra in Pamplona, Spain, discussed immunotherapy and immune-based biomarkers in liver cancer.

Immunotherapy has already entered the landscape. In September 2017, the FDA granted an accelerated approval to nivolumab (Opdivo) for the treatment of patients with HCC following prior sorafenib (Nexavar), regardless of PD-L1 status.

The approval is based on 154 patients enrolled in the phase I/II CheckMate-040 trial, in which the overall response rate by blinded independent central review was 18.2% per mRECIST criteria for those who had previously been treated with sorafenib. Now, the community is eagerly awaiting the results of the phase III CheckMate-459 trial (NCT02576509), which is comparing nivolumab with sorafenib in the frontline setting for patients with advanced HCC. Additionally, the randomized, multicenter, phase III HIMALAYA trial (NCT03298451) is looking at 4 treatment arms for patients with previously untreated, unresectable HCC with 2 regimens of durvalumab (Imfinzi) plus tremelimumab, durvalumab monotherapy, and sorafenib alone.

, Sangro discussed the current landscape for systemic therapies, new directions with immunotherapy, and the need for greater research into combination therapies for HCC.

Please provide an overview of your presentation on immunotherapy and immune-based biomarkers in HCC.

What we know is that, if you treat patients at the most advanced stages of the disease after sorafenib, the results in single-arm trials show thatcompared with the behavior you would expect from placebo-treated patients&mdash;immunotherapy-treated patients survive much longer. That was the basis on which the FDA and other regulatory agencies worldwide have accepted nivolumab, which is an antiPD-1 therapy, for the treatment of patients with advanced-stage HCC in the second-line setting.

Based on those results and the data we earlier produced with another antiCTLA-4 inhibitor, tremelimumab, [which showed] in a much smaller trial that there was some activity there, the field has evolved to large phase III trials. [The results] in the first- and second-line settings for advanced disease have been challenging the standard of care, which is sorafenib for the first-line setting and best supportive care for the second-line setting. We are awaiting the results of these trials, which will be hopefully less than 1 year from now.

Eventually, this will change the treatment paradigm if these studies are positive. Even if they&rsquo;re not, the knowledge of the activity of these agents in liver cancer has promoted the clinical development of combinations of immunotherapies and agents that we already know are active, such as sorafenib, lenvatinib (Lenvima), cabozantinib (Cabometyx), regorafenib (Stivarga), or ramucirumab (Cyramza).

The early things we know about some of these combinations are that they may be highly active. This has changed the whole spectrum of clinical development pathways. Now immunotherapy is not only tested in combination with the advanced patients, they are also tested as adjuvant therapies in those who have been resected or treated with percutaneous ablation and have a high chance of having recurrent disease, as they have different factors of poor prognosis.

Immunotherapy is now challenging the whole spectrum of stages in patients with HCC. The issue is, we know that there is a fraction of patients who respond very well, and these patients survive for a very long time. However, there is also a fraction of patients who seem to have no effect at all, and others in which the effect is difficult to illustrate or capture. Now, with 4 or 5 different drugs soon to be available, there is an absolute need to have markers that could identify patients who would benefit most from one therapy or another.

Unfortunately, we lack biomarkers for the available drugs&hellip;and biomarkers have produced conflicting results in other tumor types. What do we know now in HCC? We know very little, because only a fraction of information has been reported so far. The only thing we certainly know is that the presence of PD-L1 in the tumor cells does not correlate with better activity of the drug in patients who have such expression. In future clinical trials, we have to gather the samples that will allow us to learn and identify biomarkers that could help us in selecting patients for these kind of therapies.

What other areas of research would you like to see conducted?

Of course, we always need more and more therapies. However, the most unmet needs now are more potent systemic therapies. The pathway to go is very likely combination therapies. We are there; the programs have started. It&rsquo;s just a matter of time, but we will find more active combinations that will improve the patient benefit.

The second unmet need is [improving] the results of patients with earlier-staged disease, and there are also efforts to have combination therapies with locoregional treatments and adjuvant postresection or ablation.

The third unmet need is a method of selecting patients who are fit for one or another therapy, so the decision is evidence-basednot just the perception of a certain physician or the preference of a certain patient.

In looking at the current systemic therapeutic options, how do you choose a frontline treatment for patients with advanced HCC?

The situation is very clear. We do have sorafenib. We&rsquo;ve been using this drug that has very consistently shown to prolong survival in patients with advanced tumors. We are familiar with the way the drug has to be handled, and this is the standard of care worldwide. Now we have lenvatinib, which has been proven to be noninferior, and has as distinct profile, but it is not too different from what we are used to with sorafenib.

The problem with lenvatinib is that we don&rsquo;t have trials showing the efficacy of drugs following it. We cannot extrapolate the results from post-sorafenib treatments to post-lenvatinib situations, because lenvatinib has a unique tyrosine kinase inhibitor profile, and therefore the extrapolation cannot be made in a very straightforward manner.

Therefore, for first-line treatment: sorafenib. Lenvatinib can be an option, but one has to think [about] what will happen after the patient progresses through one drug or the other and put in some thought in advance.

What else is being explored in this landscape?

The most relevant trend is expansion of the systemic therapy into stages other than the most advanced disease. We have to go back and see why that was the case. Thirty years ago, HCC tumors were either resectable or unresectable; most of them were unresectable. The evidence showed that a small faction of unresectable tumors benefited from locoregional therapies. However, because there was nothing therebecause cytotoxic chemotherapy doesn&rsquo;t work in HCC&mdash;these locoregional therapies were used for patients with tumor stages different from those in which the evidence was produced.

This space now is not empty. We have information about the benefit of treating patients with systemic therapy in the advanced setting. Now we have to rethink the limits. What is the border between patients who would benefit from locoregional therapy and those who would benefit from systemic therapy?

Are there ongoing studies that you are eagerly awaiting results of?

Everyone is eagerly awaiting the results of CheckMate-459, which is comparing nivolumab and sorafenib as the first-line option for patients in the advanced stage, because that will be a major change if the trial results are positive.

It would certainly be a change anyway. If it&rsquo;s negative, we will probably have an idea of what patients could benefit [from immunotherapy], and this will be the basis for future clinical development.

Crocenzi TS, El-Khoueiry AB, Yau T, et al. Nivolumab (nivo) in sorafenib (sor)-naive and -experienced pts with advanced hepatocellular carcinoma (HCC): CheckMate 040 study.

Bruno Sangro, MD,&nbsp;discusses the current landscape for systemic therapies, new directions with immunotherapy, and the need for greater research into combination therapies for HCC.

Kelly Davio | Authors

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