Bekaii-Saab Considers TKI Therapy to Treat Patients With Advanced GI Cancers


During a recent&nbsp;<em>Targeted Oncology&nbsp;</em>live case-based peer perspectives presentation, Tanios Bekaii-Saab, MD, discussed with a group of physicians the treatment options for patients with gastrointestinal cancers and the characteristics that influence his decision making. Bekaii-Saab explained his clinical decisions based on the case scenario of one patient with colorectal cancer and one with hepatocellular carcinoma.

Tanios Bekaii-Saab, MD

Tanios Bekaii-Saab, MD

Tanios Bekaii-Saab, MD

During a recentTargeted Oncologylive case-based peer perspectives presentation, Tanios Bekaii-Saab, MD, discussed with a group of physicians the treatment options for patients with gastrointestinal cancers and the characteristics that influence his decision making. Bekaii-Saab, a professor of medicine, Mayo Clinic College of Medicine and Science, and the leader of the Gastrointestinal Cancer Program at Mayo Clinic Cancer Center, explained his clinical decisions based on the case scenario of one patient with colorectal cancer (CRC) and one with hepatocellular carcinoma (HCC).

Case 1

A 53-year-old Caucasian man without a previous colonoscopy presented to his primary care physician, complaining of rectal bleeding and abdominal tenderness. He had a medical history of hypertension, which was well controlled on a beta-blocker. His mother had died from complications of breast cancer.

He underwent a colonoscopy with biopsy which revealed an ulcerated nonobstructive mass was noted in the descending colon. Pathology results confirmed poorly differentiated adenocarcinoma. Limited molecular testing suggestedRASwild-type,BRAFV600E—mutated disease.HER2status was not available and he also had microsatellite-stable disease. A CT of the abdomen, pelvis, and chest showed multiple liver lesions and a large nodule in the right lower pulmonary lobe. He was diagnosed with metastatic adenocarcinoma of the right colon; T4N0M1.

The patient was started on FOLFOXIRI (irinotecan, fluorouracil, folinic acid, and oxaliplatin) and bevacizumab (Avastin); therapy was well tolerated after management of grade 2 neutropenia.

Two months later, a follow-up scan showed a 35% decrease in his liver lesions and the lung lesion. He continued on FOLFOXIRI plus bevacizumab for 4 months and then developed grade 1 neuropathy. Eventually, he was switched to FOLFIRI (irinotecan, fluorouracil, and folinic acid) plus bevacizumab.

He did well until 4 months later, when he developed more fatigue and started losing weight. Imaging showed a new 2-cm lung lesion on the left side with pleural expansion and associated pleural effusion. He had an ECOG performance status of 1.

Targeted OncologyTM: What are your initial impressions of this patient?

Bekaii-Saab:This patient had limited genomic analysis. Most patients coming to your clinic probably do not have the basic information such asRASandBRAF.

The suggestion initially was that you still get some benefit from the EGFR inhibitors, but when you look at the cumulative data, they suggest thatBRAFmutations probably should exclude patients from receiving EGFR inhibitors.

Targeted Oncology:So, what treatment should the patient get, based on the presence of aBRAFV600E mutation?

Bekaii-Saab:At this point in time, it doesn&rsquo;t seem to matter for first-line therapy. Where it seems to matter—and you will see more of this coming out this year&mdash;is [with] specific targeted therapies that will likely be approved for theBRAF-mutated colon cancers.

In this situation, because of theBRAFmutation, the patient started on FOLFOXIRI and bevacizumab. For those patients withBRAF-mutated colorectal cancers [CRCs], it appears that the triplet therapy, when indicated, has a much better outcome than [it does for] patients receiving just a doublet like FOLFIRI [irinotecan, fluorouracil, and folinic acid] or FOLFOX [oxaliplatin, fluorouracil, and folinic acid], plus or minus bevacizumab. Bevacizumab enters into the equation just because this was how the study was performed. We don&rsquo;t know if that adds value or not, but overall, those patients, if eligible, have theBRAFV600E [mutation]. If you look at the data with the doublets, it becomes very apparent that those patients have very poor response rates. In fact, most of these patients have an average survival of 9 to 11 months with doublet therapy. As we said, they don&rsquo;t respond to EGFR inhibitors, so triplet therapy with bevacizumab seems to be a better standard.

This patient received FOLFOXIRI and bevacizumab, then had scans showing a 55% decrease in the liver lesions and the lung lesions, so the patient was doing well—not a lot of toxicities. As you know, these triplet therapies are hit and miss in terms of toxicities. Some [patients] end up with horrendous toxicities, and some, surprisingly, end up with almost no toxicities.

The patient continued with FOLFOXIRI/bevacizumab for 4 months and then got grade 1 neuropathy. The oxaliplatin neuropathy stepped in again at that point, so you decided to drop the oxaliplatin and just continue with FOLFIRI and bevacizumab. This patient did well for another 4 months and then started getting more fatigue, losing more weight, and then&hellip;had a lung lesion but also started developing pleural effusions. There&rsquo;s definitely progression, and the ECOG performance status is now 1. This is a patient that had FOLFOXIRI plus bevacizumab, went to FOLFIRI/bevacizumab, went for 8 months, which most of these patients have a tough time even getting to, with a decent response, and now is progressing again.

Targeted Oncology:What would be the treatment options at this point?

Bekaii-Saab:In the National Comprehensive Cancer Network [NCCN] guidelines,1there is actually a study from SWOG that led to an indication, which included vemurafenib [Zelboraf] plus cetuximab plus irinotecan as an option; a BRAF inhibitor, an anti-EGFR antibody, plus chemotherapy.2That you can get reimbursed for, because it&rsquo;s on the NCCN guidelines. This study essentially randomized patients to vemurafenib/rituximab/irinotecan versus irinotecan and cetuximab. It showed a slight OS advantage, which led to that indication going on the guideline.

The phase III BEACON study reported the [safety lead-in phase] of the trial, which is now published in theJournal of Clinical Oncology.3And that includes a BRAF inhibitor, a MEK inhibitor, and an anti-EGFR antibody, cetuximab. So, it&rsquo;s encorafenib [Braftovi], binimetinib [Mektovi], and cetuximab. The thought is, unlike with melanoma where you target tumor with a BRAF inhibitor and you can get a response, albeit a short-lived response, in CRC, the response rate with single-agent BRAF inhibition is close to 5% or less and the progression-free survival [PFS] is about 2 months. It seems that as you block BRAF and you block MEK even underneath, EGFR essentially becomes a primary drug for colon cancer, and that&rsquo;s why it makes sense at that point in time to introduce the EGFR inhibitors.

Interim study results from the BEACON trial were published in a press release. In data from 665 patients, the median overall survival [OS] was 9.0 months versus 5.4 months, [HR 0.52, 95% CI, (0.39-0.70);P<.0001]; and out of 331 patients, the objective response rate was 26.1% versus 1.9% [P<.0001] for the triplet and the control arms, respectively.4

That is likely going to become our standard, probably in the next year or so, after they go through all the commotion. The press release that published these data declared the results to be positive.4

[The SWOG 1406 trial] is now part of the NCCN guidelines, so today this is probably what you have to refer to, because that is what [oncologists can] get reimbursed for, and that&rsquo;s vemurafenib/cetuximab/irinotecan. This was a phase II randomized study of about 100 patients. The hazard ratio is about 0.48. Some groups of patients do extremely badly, regardless of how you treat them, but this is the group that seems to do the best.

The BEACON study randomized patients to triplet encorafenib/binimetinib/cetuximab, and the control was FOLFIRI/cetuximab. The problem with the study is that it accrued very poorly in the United States, because most patients would have had access to a BRAF inhibitor from the NCCN guideline indication. This study completed, actually, and the results will be presented soon and will make their way to the FDA. [In data from] the first 30 patients, the median overall survival [OS] was not yet reached—it&rsquo;s probably going to be about 16-plus months&mdash;and the response rate was 48%.

TheBRAFmutation is in about 6% to 7% of all patients with left-sided tumors. If you take all patients with colon cancer [and] look at the literature, it suggests it&rsquo;s anywhere between 6% and 10%. The reality is, if you take all patients with CRC, it&rsquo;s about 3% to 4%, but for the left-sided tumors, it&rsquo;s about 6%.

These are not common, but they&rsquo;re not uncommon. If you see enough patients with CRC, you&rsquo;re going to see a bunch ofBRAF[mutations]. These patients do incredibly badly. With this doublet and this triplet that I think is coming through BEACON, you&rsquo;re going to change for at least half of the patients the natural history of the cancer. Some of these patients actually are surviving for more than a year or 2.

Typically, for a target to be relevant, you can&rsquo;t have 2 alterations in the same pathway, otherwise it would be a random alteration that the cancer itself doesn&rsquo;t depend on. Those alterations and 1 element of the pathway that is likely to be a driver, likeBRAForKRAS, notBRAFandKRAS, make it a relevant pathway.

In this case, because of the fact that right now you can only have access to vemurafenib, you can certainly change cetuximab for panitumumab [Vectibix] and get about the same [results] with irinotecan. The patient ended up with a good response, then progressed, and now has multiple new lesions. Performance status remains at 1.

Targeted Oncology:What do you do with this patient after progression on second-line treatment?

Bekaii-Saab:Let&rsquo;s say you don&rsquo;t have a clinical trial. Regorafenib [Stivarga] and TAS-102 [Lonsurf] are both reasonable options. Good performance status, good liver function; everything else seems to be reasonable.

We&rsquo;re actually about to publish the [ReDOS] study inLancet Oncology. We presented this at ASCO [American Society of Clinical Oncology Annual Meeting] and the [Gastrointestinal Cancers Symposium]. This was a phase II randomized study that looked at starting [regorafenib] at 80 mg, then going to 120 mg, with a goal of getting to 160 mg in the absence of toxicities. Arm B was given 160 mg, the standard. The primary endpoint of the study was the proportion of patients able to initiate cycle 3. This was 120 patients; the primary endpoint focused on whether the patients were able to start cycle 3. In other words, they hadn&rsquo;t progressed on a scan, so that&rsquo;s a measure of efficacy. They were able to get to cycle 3 because they didn&rsquo;t have any toxicities that started from doing this. We were hoping for 50% improvement with the dose-escalation strategy versus without it. In fact, the study met its primary endpoint, so this was a positive trial. About 43% of the patients went from 80 mg to 120 mg to 160 mg, able to make it to cycle 3, versus just 25% in arm B.5

What was interesting was the OS of the patients—9 months with the regorafenib dose-escalation arm versus 5.9 months with regorafenib at 160 mg. In other words, when you look at the CORRECT trial, the initial trial that looked at regorafenib 160 mg, the primary endpoint was survival, and it was about 6 months.6The standard arm on the ReDOS trial was also 6 months with 160 mg, but when you look at the 80 mg to 120 mg to 160 mg, the dose-escalation strategy, the last updated data were close to 10 months, which was superior to 160 mg. But it didn&rsquo;t reach statistical significance—mind you, this was a secondary endpoint. Progression-free survival is now close to 3 months versus 2 months with 160 mg. Again, this was not statistically significant.

The interesting part of the study is that as you go over the dose-escalation strategy, the patients not only end up with an improved outcome but also seem to have fewer toxicities, less hand-foot syndrome, less hypertension, and significantly less fatigue, but they also have the quality of life preserved. What we have seen is that patients do not lose any of their quality of life when you measure it across the spectrum, whereby with 160 mg, the patients&rsquo; quality of life dips around week 2, which is where we expect the toxicities to start going up. Regorafenib&rsquo;s toxicities show up early, and actually, the severity is the worst in the first 4 weeks, so it&rsquo;s quick and bad when it happens. For the dose-escalation strategy, that toxicity did not seem to be significant for those patients, and the quality of life ended up being pretty well preserved all the way through. For those patients who just went straight on the 160-mg dose, their quality of life dipped at week 2 and then recovered by week 4, but they never recovered completely after week 4. This now is part of the NCCN guidelines, and it&rsquo;s likely to change some of the label of this to add the option of dose escalation.

Case 1 (continued):

The patient was started on regorafenib.

Targeted Oncology:What are your impressions of the patient at the point of third-line therapy and beyond?

Bekaii-Saab:The patient went on regorafenib with 80 mg, 120 mg, and then 160 mg and then received TAS-102, and then the patient progressed. The patient still has a good performance status and wishes to be treated. But frankly, you&rsquo;ve consumed almost all your treatment options.

Targeted Oncology:Let&rsquo;s say you find anNTRKfusion. How would the patient be treated then?

Bekaii-Saab:NTRKfusions have a presence in about 0.5% to 0.7% of colon cancers, so this is a lucky patient if you find theNTRKfusion. This comes from the study [of larotrectinib (Vitrakvi)], which was a tumor-agnostic study&hellip;[NTRK] is a target across all diseases, so the study included any patient with a TRK-fusion cancer and essentially showed these results, [which] are actually short of amazing for many patients. You do see some effects that are very similar to what you observe with microsatellite instability [MSI]—high patients and immune therapy. In this particular study, 7% of the patients had colon cancer. You can see some of these patients had a complete response [CR], as well as a partial response [PR]. You can see the majority had a response, many had CRs, many had PRs, and some of these responses actually happened later rather than earlier, so they continued to progress into a better response.7

Foundation Medicine detectsNTRKfusions [via DNA sequencing]; Caris Foundation and Tempus [tests detect&nbsp;NTRKfusions via both DNA and RNA sequencing]. The problem with this is that for fusions you need to capture both DNA and RNA, &nbsp;to be able to get close to 100%. &nbsp;Even the tests that are broadly available commercially will still lose some of the&nbsp;NTRKfusions, especially in the absence of RNA seq. That&rsquo;s 1 of the problems, but most companies are working on improving the tests.

If you have anNTRKfusion, you want this drug [larotrectinib]. These are refractory patients; they progressed on multiple lines of therapy.

Another study was with entrectinib. You can see very similar results in colon cancer—7% of patients. In sarcoma and lung cancer, 19% and 24%. This is a piece of the pie of the patients who were recruited. When you look at the percentage of patients with colon cancer who haveNTRKfusions, that&rsquo;s about 0.5% to 0.7%, so you have to screen at least 100 patients to maybe find 1. With MSI high, you have to screen 100 to find 4 in colon cancer. These are rare, but if you&rsquo;re that 1 patient, that makes a huge difference.

Targeted Oncology:And what if the patient had aHER2amplification instead? How would he have been treated?

Bekaii-Saab:In colon cancer, HER2 amplifications can be found in about 4% to 5% of patients. HER2 amplifications are important for a lot of reasons. A number of studies are looking at HER2. HER2 has 2 things that are important; that&rsquo;s why I think every patient with colon cancer, in addition toRAS,BRAF, MSI, andNTRK, should also have [testing done for] HER2 amplification, so at minimum, these are the 5 things you need to have tested for in your patients with CRC.

[One] reason HER2 is important is that clinical trials look at HER2-targeted therapies in colon cancer, but the other thing that is very important is that HER2 amplifications actually confer resistance to EGFR inhibitors. So a patient could beRASwild-type orBRAFwild-type but have a HER2-amplified tumor; these patients do not respond to EGFR inhibitors. In fact, 2 studies—1 from MD Anderson and 1 from the Italian group, Siena et al&mdash;showed similarly that if you have HER2-amplified CRC, you have 0% likelihood of responding to an EGFR inhibitor. Now, if you track back, it makes sense. Biologically, one of the mechanisms in which you get resistance to EGFR is by essentially amplifying all the other family members, HER2 and HER3. [They] are primary drivers of resistance for HER1 or EGFR. It makes biological sense. For that, it is very important to think of HER2 amplification because it can affect how you treat those patients. It&rsquo;s primarily on the left side, where you have most of the&nbsp;RASwild-type,BRAFwild-type tumors.

One study is looking at tucatinib and trastuzumab [Herceptin] in amplified colon cancer [NCT03043313]. We have about 25 patients on this study; it&rsquo;s going to be expanded to about 100. In about 4% of patients, max, you will have HER2 amplification. A study from Italy that was published inLancet Oncologylooked at lapatinib [Tykerb] and trastuzumab. It showed some impressive responses in some patients that were durable.8The study from Genentech that included trastuzumab and pertuzumab [Perjeta] actually wasn&rsquo;t that impressive, so it doesn&rsquo;t look like putting 2 antibodies together is going to make much of an impact. It seems that a tyrosine kinase inhibitor [TKI] and trastuzumab have a much better effect. Tucatinib is an oral agent—it&rsquo;s a TKI; it&rsquo;s much cleaner than lapatinib in targeting HER2. I can tell you that we&rsquo;re starting to see some interesting responses with the combination. That&rsquo;s something to keep in mind for patients with colon cancer that may have a HER2 amplification.

Case 2

February 2014

A 63-year-old Asian man with chronic hepatitis B virus (HBV) infection was referred for further imaging studies after routine ultrasound surveillance for hepatocellular carcinoma (HCC) revealed suspicious findings.

His&alpha;-fetoprotein (AFP) level was 5400 IU/mL. He had a Child-Pugh score of A due to: platelets of 230,000 cells/mcL; bilirubin, 1.0 mg/dL; albumin, 3.5 g/dL; no hepatic encephalopathy; and no present ascites.

A CT scan revealed 2 lesions in the right hepatic lobe measuring 2 cm and 5 cm but no extrahepatic disease; no cirrhosis. Biopsy findings showed grade 2 HCC with moderate fibrosis. The patient underwent liver resection with an R0 margin.

August 2016

Routine follow-up imaging showed a new lesion in the liver measuring 2.3 cm. A chest CT showed 3 small lesions (<1 cm) in the left upper lobe of the lung. The patient was started on sorafenib 400 mg twice daily and tolerated therapy well after management of grade 1 diarrhea.

Targeted Oncology:What are your impressions of this patient?

Bekaii-Saab:The patient continued on routine follow-up imaging and now has a new lesion 2.3 cm and then 3 spots in the lung. This was more metastatic disease. The patient was started on sorafenib with 400 mg twice a day. He happened to be one of the 25% of patients who tolerate it well without dose reductions, with just grade 1 diarrhea.

With all these TKIs, the biggest challenge is the toxicities and compliance. You send them home—it&rsquo;s not like when you give them chemotherapy and you&rsquo;re bringing them in every week or 2 weeks; they&rsquo;re not getting their infusions where someone is looking at them. These guys sometimes go for a whole month [without follow-up].

Targeted Oncology:Would the results of the REFLECT trial possibly change the treatment option for this patient?

Bekaii-Saab:The REFLECT trial is a noninferiority study, so it wasn&rsquo;t designed for superiority, 1:1 randomization.9The primary endpoint was essentially to show that lenvatinib [Lenvima] was noninferior to sorafenib. I frankly don&rsquo;t like these types of studies because they&rsquo;re not informative for our practices, and we want to support studies that bring agents that are superior. Noninferior is like having 10 ACE [angiotensin-converting enzyme] inhibitors for hypertension—you have to choose the one you like or the one that brings the nicest pen to your clinic.

The point is that we, unfortunately, have almost 1000 patients [in this trial, which is asking] whether the drug is about the same in terms of effectiveness than the other. It wasn&rsquo;t even asking the question whether this is superior or not. Indeed, it was noninferior. Lenvatinib and sorafenib seem to perform about the same. The 1 finding I must say that was very interesting in this study is that the PFS with lenvatinib was actually higher than with sorafenib—although, when you look at sorafenib, it was 3.7 months, when you would expect it to be about 4.5 to 5 months from historical studies. It was not very clear why there was a difference. It didn&rsquo;t seem to translate into any significant survival differences. The 1 thing about lenvatinib I would say is worthwhile looking at is primarily the response rate. There is a 24% response rate in a disease where you rarely see a response; it was about 9% with sorafenib, which is much higher than you would expect with sorafenib, which is 3% to 4%.

I remember pretty well that with bevacizumab in brain cancer, initially, these tumors were looking so great on the MRI [magnetic resonance imaging], and then it turned out that primarily, what the bevacizumab was doing to these brain tumors essentially was altering how the blood flows and how they appear in the MRI. Liver cancer is incredibly vascular, very similar to brain tumors—to glioblastomas, at least&mdash;and it&rsquo;s unclear whether that response rate [to lenvatinib] is real or if it&rsquo;s affecting how the blood flows around the tumor and perhaps part of the tumor is silent in some ways because of the changes in the blood flows. Lenvatinib is a pure VEGF inhibitor; sorafenib is a dirtier drug&mdash;it tackles a lot of things other than VEGF. I think it&rsquo;s a worthwhile finding; a 24% response rate is reasonable. A substudy of this, which was presented at the [Gastrointestinal Cancers Symposium] in January, suggested that response rate in liver cancer translates to a significant improvement in survival.10Here, the added response rate from that study didn&rsquo;t seem to affect survival; 24% is a lot of patients.

I think the 1 thing we can say is that lenvatinib is another option with sorafenib in the first line. These are our 2 options in HCC—lenvatinib and sorafenib, and that&rsquo;s based on a noninferiority study. The biggest challenge is, of course, that most of the second-line studies were built on sorafenib in the first line. We don&rsquo;t have any data on second-line studies following lenvatinib, and that&rsquo;s another challenge with understanding how to place lenvatinib in that space. The toxicities are different. Lenvatinib tends to have more hypertension and diarrhea but has much less hand-foot syndrome than sorafenib does. The discontinuation rate for adverse events was actually slightly higher for lenvatinib versus sorafenib, and when you account for patients who were removed from the study for toxicities, more of them were on lenvatinib than sorafenib.

Frankly, when you look at all the data and you put everything together, all that tells you, essentially, is that they are both reasonable options to use for your patients, and you can pick one versus the other. [They have] different toxicity profiles, but they have about the same effect on survival.

Case 2 (continued):

April 2017

The patient complained of increasing fatigue.CT scans showed new lesions in the lung nodules.His ECOG performance status was 1. And his AFP had increased to >10,000 IU/L.

Targeted Oncology:What treatment options are available to this patient after progression on first-line therapy?

Bekaii-Saab:This is a patient who received sorafenib first line and is now going to second line. You have regorafenib, nivolumab [Opdivo], and cabozantinib [Cabometyx]. I would have said pembrolizumab [Keytruda] a few months ago, but now pembrolizumab is off because the phase III study was negative. Nivolumab is on life support, I would say, because of the fact that the first-line study versus sorafenib is still being analyzed. It&rsquo;s complete, but we don&rsquo;t have any results.

I will give you my editorial piece here. For PD-1 inhibitors—so, nivolumab and pembrolizumab&mdash;when you look at the tail of the curve, there are about 10% to 20% of patients that do incredibly well. Those are the patients who likely benefit from PD-1 inhibition. The other 80% do not.

Targeted Oncology:Is ramucirumab (Cyramza) an option for this patient?

Bekaii-Saab:There is an indication for ramucirumab in patients with an AFP more than 400 IU/L. Why it didn&rsquo;t work when AFP was less than 400 is unclear, but this is the approval.

Case 2 (continued):

The patient was started on regorafenib 160 mg.He complained of intermittent diarrhea.

Targeted Oncology:What is the rationale for the choice of second-line therapy?

Bekaii-Saab:This patient actually ended up on regorafenib, and that&rsquo;s based on the RESORCE trial. The RESORCE trial was 2:1 randomization for regorafenib versus placebo.11The patients had sorafenib and then went on regorafenib. They went on 160 mg. It was a large study. Survival was better with regorafenib; PFS was almost double. The most common toxicities, as you would expect, were hypertension and hand-foot syndrome. Surprisingly, all the toxicities that you see more of with regorafenib in CRC, you see much less of in HCC. People think that HCC is a tougher disease to deal with. The main reason for this is that all the patients had another TKI before they went onto regorafenib; they went on sorafenib first and regorafenib second. A lot of them actually are pretty well indicated on the adverse effects.&nbsp;

Overall survival is quite improved for regorafenib versus placebo, with a hazard ratio of 0.63. Interestingly, if you look at patients essentially that had sorafenib, then regorafenib, the median OS was about 26 months from the day they started sorafenib. If they went from sorafenib to placebo, the median OS was 19.2 months. This is interesting because we&rsquo;re seeing now that for patients who go through 2 lines of therapy, their survival is going north of 2 years for advanced HCC.

The study with nivolumab essentially included patients with hepatitis C virus and HBV infection, as well as those that are noninfected. The response rate was 20% overall.12The median OS was not reached at the time of this presentation. The median PFS was not that impressive, but that&rsquo;s because most patients progressed earlier, so at the median, the PFS is not better than any of the TKIs historically. The survival may be higher.

I think the biggest element here is the response duration; that is why the FDA approved this. For those 20% of patients that have a response, the median response was about 10 months, and that was the basis for approval.

This was a nonrandomized study; the randomized study is complete, the analysis is not complete, so we&rsquo;ll see where this is at. Again, if I want to take a guess, it&rsquo;s going to be negative. &hellip;I don&rsquo;t know the results, though, so that&rsquo;s a pure guess. I&rsquo;ll be frank with you; I made this guess before the pembrolizumab data even came out. The problem with the PD-1 inhibitors is that when they were taken to approval, they were taken to a fast track, based on a 19% to 20% response rate. They were taken on the basis of median PFS that is no better than what you would expect with a TKI. If you look at most of the patients, they don&rsquo;t seem to benefit from those agents. When you actually design studies to look at medians when most of your patients barely make it to the median, then you know that you&rsquo;re in trouble and your drug is going to fail. I wouldn&rsquo;t be surprised if the nivolumab versus sorafenib study [NCT02576509] is negative. That doesn&rsquo;t mean that PD-1 inhibitors are dead in HCC—that means that we need to work very hard at understanding who are those 15% to 20% of patients who have remarkable responses. Those are the patients who end up with the best responses we see in HCC.&nbsp;

Going to the cabozantinib trial, this is now published in theNew England Journal of Medicine; this study randomized patients to cabozantinib versus placebo 2:1, showing an OS benefit.13The OS benefit is very similar to what you see with regorafenib—much better than what you see with ramucirumab, except for the AFP 400, which is a different subgroup. [There is] definitely an OS benefit and a PFS benefit, but PFS benefit is actually quite steep. It&rsquo;s 5.2 versus 1.9 months. This was statistically significant. This study actually included third-line patients, so patients went on sorafenib, then 10% to 15% of patients had second line before they get cabozantinib, but most of them had sorafenib then cabozantinib.&nbsp;

The REACH trial, ramucirumab versus placebo, was negative, and then when they went back and looked at some of the patients that may have had a larger benefit from&nbsp;ramucirumab, it turns out—at least from the study&mdash;that AFP more than 400 was a better predictor for outcome. So they took this into what they call the REACH-2 study, which was&nbsp;ramucirumab versus placebo in patients with AFP more than 400 with a primary endpoint of OS. This study was positive for its primary endpoint, survival, versus placebo, and you can see the difference is about 1.2 months.14This is about where you hit the median and those curves are close together. This is not an incredible response, granted—that AFP more than 400 confers a worse prognosis than less than 400, so these patients typically do worse, and you can tell from the placebo survival. The PFS was, at the median, a little bit higher, but the hazard ratio was pretty impressive [0.452]. When you look at the study, the conclusion is that patients, if they have an option, if they have an AFP more than 400&mdash;that&rsquo;s about 40% of your patients who get to this level; so for 60% of your patients, it doesn&rsquo;t matter because they won&rsquo;t be eligible for this agent&mdash;ramucirumab may become an option.

Targeted Oncology:What is being looked at in terms of sequencing for such patients in HCC?

Bekaii-Saab:When you look at HCC and potentially how to best sequence those patients, in the first line, you have sorafenib, lenvatinib; and then maybe for patients with a Child-Pugh score of 7 or those patients that may not be eligible for TKIs, you might want to consider nivolumab. Although again, at this point, I would put all this stuff on hold until we have the results of this study of nivolumab versus sorafenib, which essentially is ongoing. I told you what my prediction is, and I hope I&rsquo;m wrong, because it would be great for patients to have another option. For second line, regorafenib, nivolumab was from phase II data. The phase III study with pembrolizumab was negative. That really puts the kibosh on PD-1 inhibitors in the space. Cabozantinib is another option. For those patients with AFP more than 400,&nbsp;ramucirumab would be the option. And for third line, the only data we have are on the few patients who ended up on the cabozantinib study.&nbsp;

This patient was started on regorafenib 160 mg. He started complaining of intermittent diarrhea. The patient got sorafenib/regorafenib, and then third line, maybe cabozantinib.


  1. NCCN Clinical Practice Guidelines in Oncology. Colon Cancer, version 2019. March 15, 2019.&nbsp;Accessed April 4, 2019.&nbsp;
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