Laber Evaluates Therapeutic Options by Lines of Therapy in GI Cancers

Damian Laber, MD

During Case Based Peer Perspectives event, Damian Laber, MD, senior member, Moffitt Cancer Center, Tampa General Hospital in Tampa, FL, discussed the case of a 53-year-old male patient with stage IV colorectal cancer.

Targeted Oncology™: What factors are most important in the assessment of prognosis and in systemic treatment selection?

LABER: One of the things that came [into] discussion a few years ago—[that] is still under discussion, because there are some conflicting results—is the question about right-sided versus left-sided colorectal cancer [CRC]. The distinction is basically right in the middle of the transverse colon. In general, the right-sided CRC is usually the one that [has] more KRAS mutations. The right-sided colon cancer is the one [where] we use the EGFR receptor inhibitors [such as] cetuximab [Erbitux] or panitumumab [Vectibix] much less.¹

There is also some research that is trying to differentiate the different genotypes and phenotypes of these colon cancers, hopefully to target the treatment much better, because until now, we were treating colorectal the same way, irrespective of where it came from. But if we look at most of the patients with right-sided colon cancer, the common mutations include the BRAF mutations, the PIK3CA, and the KRAS mutations. Also, many of them on the right side, they are microsatellite instability [MSI] high, or they are deficient in the mismatch repair [MMR] proteins. And those ones are the ones that we end up using the immune checkpoint inhibitors for. Those will be some of the important take-home messages.

On the left side, the mutations are more in the p53, and they might have an EGFR or a HER2 amplification. So that’s why they might respond better to the EGFR inhibitors than the other side. And also, it seems [as though] the prognosis for the patients with CRC is a bit better on [the left side].

What are your impressions of the case at this point?

The patient was started on FOLFOX and cetuximab because it was considered more on the left side, and the therapy was well tolerated. And then after the [treatment], he had a grade 2 rash, which we expect with these agents.

What data support the use of FOLFOX plus cetuximab?

This came from an intergroup study, the SWOG-80405 or CALGB study [NCT03641976].² What it looked at was FOLFOX or FOLFIRI [leucovorin, 5-FU, and irinotecan] as the backbone chemotherapy. It was not randomized, so the majority of the patients in North America chose FOLFOX. And in some parts of Europe, I think there was more FOLFIRI. Then they randomized the patients. They were all KRAS wild type or all RAS wild type. But they randomized the patients to either bevacizumab [Avastin] or cetuximab.

When you look at whether it’s left-sided or right-sided, [for the left-sided tumors], the survival was 38.7 months versus 34.4 [with] the right-sided if they received bevacizumab [adjusted HR, 0.62; 95% CI, 0.32-1.23; log-rank P = .918]. But if they received cetuximab, with the left-sided tumors, the median survival was 40 months versus 18 months [adjusted HR, 1.68; 95% CI, 0.85-3.34; log-rank P = .003]. So in these particular cases with the left-sided tumors, when they are wild type, cetuximab is probably more effective. The concern is that on the right side, it’s exactly the opposite, the survival is worse, so we should try to avoid it on the right-sided tumors.

Do other data support the use of cetuximab in this setting?

This [brings] you to the FIRE-3 study [NCT02934529].3 The FIRE-3 study used FOLFIRI as the backbone, and the patients were randomized to cetuximab or bevacizumab. Again, the data on the [patients who were] wild type for the RAS mutations [showed an overall survival of 33.1 months with FOLFIRI/cetuximab and 25.6 months with FOLFIRI/bevacizumab (HR, 0.70; 95% CI, 0.53-0.92; P = .011)]. If you look at the intention-to-treat population at the end of the study, there’s a slight survival advantage for the patients treated with cetuximab versus the patients treated with bevacizumab [28.7 vs 25.0 months; HR, 0.77; 95% CI, 0.62-0.96; P = .017].

But, the left-sided tumors are the ones that benefit from cetuximab. [For] the survival advantage, both curves separate. The survival advantage becomes much more, with a hazard ratio of 0.63 [95% CI, 0.48-0.85; P = .002]. So the median survival will be 28.0 months if you use FOLFIRI/bevacizumab versus 38.3 months by using FOLFIRI with cetuximab.

Now, the opposite holds true on the other side. If you look at the right-sided [tumors], the patients treated with bevacizumab or cetuximab made not much of a difference [18.3 vs 23.0 months, respectively; HR, 1.31; 95% CI, 0.81-2.11; P = .28]. But it seems [as though] the bevacizumab is better. If you look at where the median survival is, the curves are a bit separated. But then after that, they keep touching points, and they both go down.

How would you manage the cetuximab-mediated rash?

I think this used to be a big probability as soon as cetuximab came about 20 years ago. Now most of us are fairly good at this. The teaching point is that you can use a preemptive approach. Basically, you treat everybody before they develop a bad rash. And most of us, what we will [suggest] is sunscreen and moisturizing lotions, and then we use oral antibiotics, either doxycycline or minocycline. If you do that, then you decrease the incidence of the rash by about half.⁴ [With] the preemptive [approach], you have much less rash. With the reactive—which is wait until the rash occurs, and then you treat—then you have much more incidence. So you can decide on a patient-by-patient [basis] whether to wait to implement all the preventive therapies or treat them up front just to decrease the incidence of this adverse effect [AE] in the patients that wish to have it.

Now, the other big discussion that I remember we used to repeat, and also we used to tell the patients when they’re having a bad rash, is that patients [who] develop a rash have a better survival [rate] or better outcomes than patients [who] don’t develop a rash [HR, 0.51; 95% CI, 0.40-0.64]. And this comes from a meta-analysis of at least 7 studies.⁵ Combining all of them, if you go look at the patients [who] develop a rash versus the patients [who] did not develop a rash, then you have a survival advantage.

patient? What other frontline options might you consider for this patient?

So this comes from the latest version of the National Comprehensive Cancer Network [NCCN] guidelines in gastric cancer.6 The guidelines usually list most of the options that are appropriate, and then we can choose. It’s not a pathway that tells us what to do. And remember, this patient was HER2 negative.

So for the first-line treatment, they say that the 2-drug cytotoxic regimens are preferred because of lower toxicity. This comes from the original studies of the DCF [docetaxel, cisplatin, and fluorouracil]. Then the 3-drug cytotoxic regimen should be reserved for medically fit patients with good performance status and access to frequent toxicity evaluations.

They listed the preferred regimens, the fluoropyrimidine, which is either 5-FU or capecitabine and oxaliplatin or another fluoropyrimidine and cisplatin. These [were based on] a 4-arm randomized study that used either 5-FU or capecitabine. They used either oxaliplatin or cisplatin. All the arms show the same responses and the same survival, so you basically can interchange all that.

What treatment options are available for this patient at this point? And based on what data?

For the second-line treatment that is recommended by the NCCN guidelines,⁶ it really depends on the prior therapy. But if you have received the platinum and the fluoropyrimidine, then the preferred regimens, the category 1 [regimen] is ramucirumab [Cyramza] with paclitaxel, because there was a randomized study. Docetaxel is still listed, paclitaxel and irinotecan also. And then the trifluridine with tipiracil [TAS-102], which is Lonsurf.

That’s usually for third line after the patient fails the first 2 lines. Then 5-FU/irinotecan, something [such as] FOLFIRI, can be used. It doesn’t have a category 1 [recommendation]. Pembrolizumab [Keytruda] is listed for second-line or subsequent line of therapies, and anybody that has MSI-high or deficient MMR tumors; that’s for all tumor types, but also for third-line or subsequent therapy for gastric adenocarcinoma with a CPS of more than 1. You can still use it at third line just by having that, even if a patient doesn’t express MSI or MMRs.

Would the treatment choice be different if this were a gastroesophageal junction (GEJ) versus a gastric tumor?

Yeah, I do the same. Most of us would treat the same.

The RAINBOW study [NCT01170663] was published more than 5 years ago.⁷ This is the study that established ramucirumab as a category 1 therapy. It was a randomized study of patients with metastatic or locally advanced or unresectable gastric or GEJ adenocarcinoma—so it was the same—who had progressed after a firstline of therapy with a platinum and a fluoropyrimidine-based therapy. Half of the patients receive a placebo, instead of ramucirumab, and the standard, which was single-agent paclitaxel. They used a weekly regimen on days 1, 8, and 15. The other half received the drug, which is the ramucirumab, at 8 mg/kg. This was given every 2 weeks, so day 1 and day 15. And then the paclitaxel weekly, exactly the same as the other arm.

This was a quite large study for this population, [more than] 300 patients per arm. They were all treated until progression or toxicity. And the end point was survival, and safety and follow-up were measured.

The median progression-free survival was 4.4 months for the combination of ramucirumab and paclitaxel versus 2.9 months for the paclitaxel alone. The hazard ratio and the P value all were statistically positive [HR, 0.635; 95% CI, 0.536-0.752; P < .0001].

The median overall survival for the combination, which was the best arm, was 9.6 months versus 7.4 months, again, with a positive hazard ratio and P value [HR, 0.807; 95% CI, 0.678- 0.962; P = .017].

Based on this, the FDA granted the approval for ramucirumab with paclitaxel for second-line treatment of gastric or GEJ adenocarcinoma. And that’s why it has the category 1 [recommendation].

Now, if you look at the responses—again, this is in second line— the complete responses [CRs] are rare [less than 1%]. The partial responses [PRs] happen—that’s where the big difference was, about 27% for the combination versus 16% for the single arm. That’s basically what we expect. With single-arm, active chemotherapy, it’s usually around a 15% response rate, and when we combine it, usually we do another 10%, or we double those responses.

And the stable disease [SD] [rate is] about half of the patients. The disease control rate [DCR], which adds the CR, PR, and SD rates, which is basically when you consent the patient, that’s roughly how we practice. We tell the patient that we’re going to treat as long as they don’t progress. If we see progression, that’s when we stop, or we change therapy, unless there is toxicity. But that would be the 80% of the patients [who], most likely, if you do restaging quite often, at the first one, you might be happy, and then after the second or third restaging, that’s when you would expect the progressions in these patients.

What are your thoughts on this poll? Do you consider DCR to be a clinically meaningful end point?

The majority of the people say yes. It’s not something that we will likely use on a clinical trial as the final end point, because it could be subjective how we read the scans and how we measure them, and so forth. But in the day-to-day practice, I strongly believe that’s roughly how we practice oncology. The only thing we don’t want to see is the cancer growing, because that’s basically how the patients die.

What is the safety profile like with this combination?

When you add a second medication, you increase the AEs. Ramucirumab is an EGFR2 receptor inhibitor. So the AEs are basically the vascular AEs, which include the hypertension, the proteinuria, the concern for bleeding, and the concern for blood clots. We’ve been using these drugs for so many years that we’re accustomed. We know when to use it, and we also know when not to use them.

And then sometimes we also see more laboratory changes. So we might see a bit more neutropenia and anemia. But it’s rare that you will see an increased risk of the complications from that. So it’s rare that you’re going to see neutropenic fevers and infections.

What are the available treatment options for when the patient develops further disease progression?

There are several studies that [relate to further treatment options], because now that we follow these patients so closely, we are getting into third-line therapies for [them]. TAS-102 is now called Lonsurf, and this came from the study that led to the indication.⁸ These were patients with measurable metastatic gastric or GEJ cancer. They had received more than 2 prior regimens—it would be exactly like our patient. To be on the study, they still [had to] have adequate organ function. They were able to take oral medications, [had] good performance status, no serious comorbidities from before, no prior TAS-102, which is the Lonsurf, and no unresolved toxicity.

This was a 2:1 randomization, because they didn’t have a control arm because we didn’t have any established control at that time. So by doing a 2:1, they made sure most of the patients received the drug, versus the ones [who] received placebo.

The progression-free survival [curves] favor TAS-102 or the trifluridine/tipiracil [HR, 0.57; 95% CI, 0.47-0.70; 2-sided P < .0001]. The overall survival [curves] separate, and they favor the treatment arm [HR, 0.69; 95% CI, 0.56-0.85; 2-sided P = .00058]. And that’s what led to the approval and the indication of Lonsurf in the third-line treatment for patients with gastric or GE junction adenocarcinoma.

For all who have experience with Lonsurf, that’s not a big deal. But for the ones who don’t have too much experience, we give it usually day 1 to 5, so we usually take it Monday to Friday; we skip the weekends. We give it for 2 weeks on, and then 2 weeks off. So every 4 weeks, we repeat that. And it is an analogue of the fluoropyrimidine, but it’s considered to have much less or no cross-reactivity with prior 5-FU, and that’s why you get responses.

The KEYNOTE-059 study [NCT02335411] was looking at pembrolizumab monotherapy in advanced gastric or GEJ cancer following progression on 2 or more therapies.⁹ This was an open-label and a multicohort phase 2 study. This is not a randomized study, don’t get fooled by the 3 different cohorts. There were 3 different populations. Cohort number 1, they were all patients [who] progressed after 2 prior lines of therapy—so, like our patient—and all of them received single-agent pembrolizumab at the standard dose, 200 mg every 3 weeks. And they were monitored as a phase 2 study for responses, progression, and survival, but in a noncontrolled study.

Cohort number 2 were patients with no prior therapy, so first-line, and it was adding pembrolizumab to the combination of cisplatin and either 5-FU or capecitabine—similar approach that we do for lung cancer or other tumors. And cohort number 3, there were also patients with no prior therapies, but they tested positive for PD-L1. Same idea—high expressers, you avoid chemotherapy.

So each one of these cohorts will be presented as a different study. It’s not a randomized study. So the one that was published 2 years ago in JAMA Oncology is in the ones that have more than 2 prior therapies, so basically it’s cohort number 1.

These patients were treated for about 2 years. If [a patient was] still responding, [they] keep going. Nobody knows what to do after that. If [the patient has] a CR, and nothing happened after 2 years, maybe [the patient could] take a break. But honestly, we don’t know what to do in those.

So from the JAMA Oncology paper, in the cohort of patients [who] have received 2 or more therapies are the objective responses, which is the CR and the PR, in 30 patients, which is about 11.6% of the patients. About 27% of the patients basically end up benefiting from the DCR. Basically, you can expect somewhere around 27% of patients will respond in the third line to pembrolizumab.

What other potential treatment regimens are emerging in this space?

Nivolumab [Opdivo] and paclitaxel plus ramucirumab—using the backbone of paclitaxel and ramucirumab and seeing whether we can add the PD-L1/PD-1 inhibitors. On this particular study, 43 patients were treated, and then the DCR was 83.7%, with the overall response rate of 37.2% and SD in 46.5%.¹⁰ So these data are starting to appear in abstract forms, and we need to wait for the final studies.

Are there ramucirumab studies in the first line in gastric cancer?

They haven’t been completed or published, so they were mostly [based] on phase 2 studies.

Would you consider using pembrolizumab monotherapy for CPS 1 or higher as frontline therapy based on KEYNOTE-062 (NCT02494583)?

I think, so far, not yet. But once the study gets published, then we will be looking at that very closely, because most of us like to use that as first line if we expect a high response rate at least.

<sub>References:
1. Baran B, Ozupek NM, Tetik NY, Acar E, Bekcioglu O, Baskin Y. Difference between left-sided and right-sided colorectal cancer: a focused review of literature. Gastroenterology Res. 2018;11(4):264-273. doi:10.14740/gr1062w</sub>

_{2. Venook AP, Niedzwiecki D, Innocenti F, et al. Impact of primary (1º) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analysis of CALGB/SWOG 80405 (Alliance). J Clin Oncol. 2016;34(suppl 15):3504. doi:10.1200/JCO.2016.34.15_suppl.3504}

_{3. Heinemann V, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15(10):1065-1075. doi:10.1016/S1470-2045(14)70330-4}

_{4. Lacouture ME, Mitchell EP, Piperdi B, et al. Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-emptive skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer. J Clin Oncol. 2010;28(8):1351-1357. doi:10.1200/ JCO.2008.21.7828}

_{5. Petrelli F, Borgonovo K, Barni S. The predictive role of skin rash with cetuximab and panitumumab in colorectal cancer patients: a systematic review and meta-analysis of published trials. Target Oncol. 2013;8(3):173-181. doi:10.1007/s11523-013-0257-x}

_{6. NCCN. Clinical Practice Guidelines in Oncology: Gastric Cancer, version 3.2020. Accessed August 21, 2020. https://www.nccn.org/professionals/physician_gls/ pdf/gastric.pdf}

_{7. Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15(11):1224-1235. doi:10.1016/S1470-2045(14)70420-6}

_{8. Shitara K, Doi T, Dvorkin M, et al. Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2018;19(11):1437-1448. doi:10.1016/S1470-2045(18)30739-3}

_{9. Fuchs CS, Doi T, Jang RW, et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial. JAMA Oncol. 2018;4(5):e180013. doi:10.1001/jamaoncol.2018.0013}

_{10. Hironaka S, Kadowaki S, Izawa N, et al. A phase I/II study of nivolumab, paclitaxel, and ramucirumab as second-line in advanced gastric cancer. J Clin Oncol. 2020;38(suppl 4):352. doi:10.1200/JCO.2020.38.4_suppl.352}