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.

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

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 

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.

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 

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 

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].

 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 

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 

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 

= .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 

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; 

= .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; 

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; 

= .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; 

= .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.

 [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.

 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,

 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.

 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 

value all were statistically positive [HR, 0.635; 95% CI, 0.536-0.752; 

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 

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.

 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 

< .0001]. The overall survival [curves] separate, and they favor the treatment arm [HR, 0.69; 95% CI, 0.56-0.85; 2-sided 

= .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.

 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 

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.

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%.

 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.

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. 

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). 

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. 

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. 

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. 

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. 

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. 

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. 

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. 

2020;38(suppl 4):352. doi:10.1200/JCO.2020.38.4_suppl.352

Articles

Clinical Articles

During Case Based Peer Perspectives event, Damian Laber, MD, discussed the case of a 53-year-old male patient with stage IV colorectal cancer.

Laber Evaluates Therapeutic Options by Lines of Therapy in GI Cancers

During a Targeted Oncology Case Based Peer Perspectives event, Sandy Ting Liu, MD, assistant Professor of Medicine Hematology-Oncology, Ronald Reagan UCLA Medical Center in Los Angeles, CA, discussed the case of a62-year-old male patient with bladder cancer.

™: At this point, would you consider immunotherapy for treating this patient?

If they’re cisplatin ineligible, they can get atezolizumab [Tecentriq] or pembrolizumab [Keytruda], if their tumor is PD-L1 positive. It’s important to know their PD-L1 expression status. Performance status is also important to determine your treatment for the patient. Intolerance to prior therapy is also a consideration.

Would you consider a clinical trial for this patient?

At my [institution], yes. We always try to find a trial for patients, if possible.

How would you treat this patient with first-line metastatic disease?

This patient is young with a creatinine clearance of 51 mL/min. I tend to push for cisplatin, maybe split the dose of cisplatin on day 1 and day 8, since it is currently the gold standard.

What dosing options are available for patients in this setting who receive gemcitabine/cisplatin?

This patient received dose-dense gemcitabine plus cisplatin. [There is a] regimen that is still in clinical trials, but basically, patients receive split-dose cisplatin on day 1 and day 2, and then they get gemcitabine at 2.5 times the usual dose on day 1, for every 2 weeks. But again, for this patient, I would just give him split-dose cisplatin at the usual every-3-week cycle.

Would you repeat PD-L1 expression testing or other biomarker testing on this patient?

I would always consider redoing the biopsy upon progression. It’s not necessary to do the biopsy, but it may give us additional information. It won’t necessarily change management.

Which PD-1 or PD-L1 inhibitor would you select here?

For patients with recurrent disease after chemotherapy, there have been 5 FDA-approved PD-1/PD-L1 inhibitors…since May of 2016, with both atezolizumab and pembrolizumab also approved as first-line therapy for patients who are ineligible to receive platinum chemotherapy, or cisplatin, and whose tumors express PD-L1.

 In the absence of any head-to-head comparison among the 5 different agents, their activity is pretty similar [

KEYNOTE-045 [NCT02256436] with pembrolizumab is the only phase 3 study that showed a median overall survival [OS] benefit of 10.3 months with pembrolizumab versus 7.4 months with chemotherapy.

 The rest of the studies with atezolizumab, nivolumab [Opdivo], durvalumab [Imfinzi], and avelumab [Bavencio] showed an objective response rate between 14% and 20% and a median OS of between 6.5 and 18.0 months. About 15% to 20% of the patients have a durable long-term survival.

Just to put this in perspective, the response rate for second-line chemotherapy with docetaxel is 8% or less and the duration of response is about 3 to 6 months. These immunotherapies have outperformed chemotherapy.

As I mentioned before, KEYNOTE-045 with pembrolizumab as second-line therapy showed an OS benefit compared [with] chemotherapy, with a hazard ratio of 0.73 [95% CI, 0.59-0.91; 

= .002], and that’s statistically significant.

All the other second-line checkpoint inhibitors have a trend toward OS, especially [if the tumors being treated are] PD-L1 positive.

What do the National Comprehensive Cancer Network (NCCN) guidelines in bladder cancer recommend?

The NCCN guidelines for platinum-refractory, second-line therapy show that pembrolizumab is the preferred category 1 agent, based on phase 3 data for OS.7 However, the other 4 checkpoint inhibitors can be considered as well, along with erdafitinib [Balversa], which is an FGFR inhibitor, if patients’ tumors are 

positive. Enfortumab vedotin-ejfv [Padcev] is also approved as subsequent-line therapy after immunotherapy.

What is the recommendation for this patient now that he has developed pneumonitis?

The NCCN guidelines for pneumonitis [indicate that] for grade 1, you want to consider holding immunotherapy and reassess in 1 to 2 weeks. If [patients] don’t improve, you can consider a CT scan with contrast. For moderate grade 2 pneumonitis, you want to hold immunotherapy. Consider [a] pulmonary consult early, as well as [doing] a thorough infectious work-up and consider enteric antibiotics if the infection is not fully ruled out. Then, you want to start high-dose steroids and close monitoring every 3 to 7 days. If there’s no improvement after 48 to 72 hours with high-dose steroids, then you would treat it as grade 3.

For severe grade 3/4 pneumonitis, you definitely want to permanently discontinue immunotherapy and consider admitting the patient to the hospital with a full infectious work-up and pulmonary work-up. You may want to consider [getting a bronchoscopy] and continuing high-dose steroids. If there’s no improvement after 48 hours, then you would consider infliximab, intravenous immunoglobulin, or mycophenolate. I want to emphasize that this needs to be a multidisciplinary team effort, as these patients with severe pneumonitis can decompensate rapidly. You want to get everyone involved.

How do you define pneumonitis grades 1 through 4? Is it radiographic, or is it also clinical?

It’s mostly clinical. It’s basically mild, moderate, and severe. I would say [in this case] it’s more clinical, based on [the patient’s] symptoms.

What third-line options would you consider if this patient’s disease progresses?

Enfortumab vedotin is an effective drug; it is an antibody-drug conjugate to Nectin-4, which is expressed in over 90% of urothelial cancer cells. This has also been recently approved after immunotherapy with a high response rate,8 including a 38% response rate in [patients with liver metastases].9 If patients have an 

Other agents to look out for include sacituzumab govitecan [Trodelvy], an antibody-drug conjugate to TROP-2 that’s also expressed in urothelial cancer.

1. FDA limits the use of Tecentriq and Keytruda for some urothelial cancer patients. FDA. July 5, 2018. Accessed August 26, 2020. https://bit.ly/3lta1oz

2. Powles T, Durán I, van der Heijden MS, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. 

. 2018;391(10122):748-757. doi:10.1016/S0140-6736(17)33297-X

3. Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. 

. 2017;18(3):312-322. doi:10.1016/S1470-2045(17)30065-7

4. Powles T, O’Donnell PH, Massard C, et al. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study. 

. 2017;3(9):e172411. doi:10.1001/jamaoncol.2017.2411

5. Patel MR, Ellerton J, Infante JR, et al. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. 

. 2018;19(1):51-64. doi:10.1016/ S1470-2045(17)30900-2

6. Bellmunt J, de Wit R, Vaughn DJ, et al; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. 

. 2017;376(11):1015-1026. doi:10.1056/NEJMoa1613683

7. NCCN. Clinical Practice Guidelines in Oncology. Bladder cancer, version 6.2020. Accessed August 26, 2020. https://bit.ly/3lold5s

8. FDA grants accelerated approval to enfortumab vedotin-ejfv for metastatic urothelial cancer. FDA. December 19, 2019. Accessed August 26, 2020. https://bit.ly/3lnbLiQ

9. Rosenberg JE, O’Donnell PH, Balar AV, et al. Pivotal trial of enfortumab vedotin in urothelial carcinoma after platinum and anti-programmed death 1/programmed death ligand 1 therapy. 

During a Targeted Oncology Case Based Peer Perspectives event, Sandy Ting Liu, MD, discussed the case of a62-year-old male patient with bladder cancer.

Liu Discusses Treatments in Multiple Lines for Bladder Cancer

During a Targeted Oncology Case Based Peer Perspectives event, Rachel E. Sanborn, MD. the codirector of Thoracic Oncology Program, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute Providence Cancer Institute in Portland, OR, discussed the case of a 73-year-old woman with extensive-stage small cell lung cancer (ES-SCLC).

™: What are the recommended options from the National Comprehensive Cancer Network (NCCN) guidelines?

The updated NCCN guidelines, particularly after the recent FDA approvals, list the preferred regimens as carboplatin, etoposide, and atezolizumab [Tecentriq], followed by atezolizumab maintenance; then also options of either carboplatin or cisplatin with etoposide and durvalumab [Imfinzi], followed by durvalumab maintenance. For the next tier of categories, [the guidelines suggest] platinum doublets, or platinum chemotherapy and irinotecan doublets.

It’s certainly a lot more choices than we had in the past for patients with SCLC. Looking back 15 years ago, it was a little bit different. And I don’t think CAV [cyclophosphamide, doxorubicin, vincristine] would be a fair recommendation to have in there anymore.

Which data support the use of this regimen for this patient?

The IMpower133 study [NCT02763579] included patients with good performance status who were newly diagnosed. Now, this trial allowed for patients with treated brain metastases, but not de novo untreated brain metastases. [It] randomized to the reference regimen of carboplatin and etoposide; or carboplatin, etoposide, and atezolizumab; and then continuing atezolizumab until progression versus placebo.

This demonstrated improvements, both in overall survival [OS] and progression-free survival [PFS], with atezolizumab. With the initial follow-up at 13.9 months, there was improvement in median OS from 10.3 months with placebo to 12.3 months with atezolizumab [HR, 0.70; 95% CI, 0.54-0.91; 

In the updated OS, [with] a follow-up at 22.9 months, the same numbers are observed.

 The numbers are consistent in that the median survival is still 10.3 for chemotherapy only and 12.3 for chemotherapy and atezolizumab. I think that the chemotherapy numbers are in line with what we would expect.

The 18-month OS rate improved from 21% to 34% [with placebo and atezolizumab, respectively].

Looking at subgroup analyses, it favored the combination with immunotherapy. The numbers for brain metastases, which are the ones that cross midline most profoundly, were a small number of patients [compared with] the total [35 out of 403], as you would expect, because patients had to have been stable enough from their newly diagnosed SCLC to first get brain radiation and then have stable disease, and wait to start systemic chemotherapy, which I don’t see often.

In terms of responders, there were better responses and more ongoing responses with the atezolizumab versus the placebo.

The adverse effects [AEs] were pretty much as expected—fairly well tolerated, in that there was not any significant difference in grade 5 toxicities.

In terms of grade 3 or 4 AEs, the toxicities were still related to the chemotherapy. There was a slightly higher rate of immune-related AEs with the patients getting atezolizumab versus the placebo.

What studies show the role of durvalumab this setting?

The CASPIAN study [NCT03043872], which was the randomized trial that allowed patients with asymptomatic, treated, or stable brain metastases, was more accepting with brain metastases [than IMpower133]. The reference regimen was platinum chemotherapy and etoposide, with optional prophylactic cranial irradiation afterward, versus chemotherapy and durvalumab, versus chemotherapy, durvalumab, and tremelimumab.

The updated survival that was presented at the 2020 American Society of Clinical Oncology Virtual Scientific Program showed that for the durvalumab and chemotherapy arm versus chemotherapy, there was a survival benefit seen with the median survival improving from 10.5 months to 12.9 months—close to what we saw from IMpower133 [HR, 0.75; 95% CI, 0.62-0.91; 

= .0032]. The 18-month OS rate improved from about 25% to 32%.

For the CASPIAN study, the subgroups all favored the combination with immunotherapy versus chemotherapy alone. The PFS looked fairly similar with this and with IMpower133. The PFS curves overlap through the first [6 months] before separating later within longer PFS and PFS benefit further out in the curves. More patients responded with the combination than with chemotherapy alone. Then there was longer duration of response with the combination.

The durvalumab and tremelimumab quadruplet combination versus the chemotherapy reference regimen did not show the same survival benefit. The median OS with the chemotherapy was 10.5 months, and with the quadruplet combination it was 10.4 months. Although the combination curve lands on top, the OS still does not come out as the advantage there.

The safety summarization among the 3 arms of the trial showed there were more grade 3/4 AEs with the durvalumab and tremelimumab arm, and relatively more serious AEs as well; also, a higher rate of patients with AEs leading to discontinuation, as well as more immune-related AEs. This may be why the outcomes don’t look the same as those [for] patients with durvalumab alone.

How do the atezolizumab and durvalumab regimens compare?

The IMpower133 regimen with atezolizumab and the durvalumab in the CASPIAN study had a median follow-up and number of patients [that] were similar. The control arm for IMpower133 was 4 cycles of carboplatin. The CASPIAN study allowed up to 6 cycles of either carboplatin or cisplatin. The OS looked close in both. Hazard ratios, PFS, and grade 3 AEs were also close.

What do you think of the patient’s case thus far?

The patient had constipation and nausea after the second cycle that were treated with supportive care. In terms of supportive care and follow-up, 2 cycles in, we’re going to presume the patient is responding.

1. NCCN. Clinical Practice Guidelines in Oncology. Small cell lung cancer, version 1.2021. Accessed August 17, 2020. https://bit.ly/2Q1HB6q

2. Horn L, Mansfield AS, Szczęsna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. 

2018;379(23):2220-2229. doi:10.1056/NEJMoa1809064

3. Reck M, Liu SV, Mansfield AS, et al. IMPOWER133: updated overall survival (OS) analysis of first-line (1L) atezolizumab (atezo) + carboplatin + etoposide in extensive-stage SCLC (ES-SCLC). 

2019;30(suppl 5):v710-v717. doi:10.1093/ annonc/mdz264

4. Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. 

. 2019;394(10212):1929-1939. doi:10.1016/S0140-6736(19)32222-6

5. Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab ± tremelimumab + platinum-etoposide in first-line extensive-stage SCLC (ES-SCLC): updated results from the phase III CASPIAN study. 

2020;38(suppl 15):9002. doi:10.1200/ JCO.2020.38.15_suppl.9002

Sanborn Addresses Different Immunotherapies for ES-SCLC

 Case Based Peer Perspectives event, Thomas Hutson, DO, PharmD, the director, Urologic Oncology Program cochair, Urologic Cancer Research Center, at Baylor University Medical Center in Dallas, TX, discussed the case of a 66-year old woman with bladder cancer that  presented post chemotherapy.

™: When do you give platinum-based chemotherapy in the frontline setting for patients with bladder cancer? Which regimen do you use?

We generally feel that creatinine clearances above 45 mL/min would be good for platinum chemotherapy. When you start getting below 40 to 45 mL/min, the ability to give cisplatin reliably becomes challenging in that setting. It’s dealer’s choice; it really becomes about your own comfort level.

But looking at the cisplatin-based [regimens in a presentation of cross-trial comparisons from the 2020 American Society of Clinical Oncology (ASCO) Annual Meetin], you see the 2 [regimens]: the dose-dense MVAC [methotrexate, vinblastine, doxorubicin hydrochloride, and cisplatin] and [gemcitabine and cisplatin].

 From the EORTC trials, there was a 72% objective response rate [ORR], a 25% complete response [CR] rate, and a median overall survival [OS] of 15.1 months [with MVAC]. Then gemcitabine and cisplatin [had a lower response], with a 49% ORR, a CR rate of 12%, and a median OS of 14 months.

Another trial compared MVAC versus gemcitabine and cisplatin. It was a noninferiority study, and it showed that gemcitabine and cisplatin was close to dose-dense MVAC in activity. The trial wasn’t completed, so it was underpowered, but that allowed people to feel more comfortable using gemcitabine and cisplatin.

For the median OS, there was about a month difference between the 2 [regimens].

 But when you’re looking at tumor ORR, I feel that dose-dense MVAC gives you a better [response].

So, if I have a younger patient, I would generally lean that way. But those are the regimens we’ve used.

Then, for the patients who were cisplatin ineligible, there was definitely a reduction in benefit [with gemcitabine and carboplatin]. The median OS dropped off by 5 or 6 months, and the CR rate dropped, and the response rate dropped. So that’s clearly an inferior regimen.

What are the drawbacks of comparing trials in this way?

Because we’re [discussing] cross-trial comparisons, if you look at the cisplatin-ineligible population, you’re going to find a greater population that will have more comorbidities, impaired kidney function, and they’re going to have [a greater] volume of cancer. Really, the only way to compare them adequately would be to stratify for those factors in a randomized trial, but we don’t have that. But truly, the response rates are noticeably different, and that’s the bias that’s built into this kind of discussion; there’s a bias there. I think we agree that carboplatin is inferior, but the degree of inferiority could be questioned.

Would you give these regimens as adjuvant or neoadjuvant therapy?

A lot of people think of dose-dense MVAC in the neoadjuvant setting. Everything we use in the neoadjuvant setting is an extrapolation from the metastatic setting. We often think about [the scenario that] if someone was presenting to you with a curative-intent therapy goal, then give them dose-dense MVAC if they’re young and if it makes sense. I think we’re reminding ourselves that there’s a small group of patients who come in with metastatic disease that has spread beyond the lymph nodes or have lymph node metastases, who historically wouldn’t be offered surgery unless they had some type of response or CR to up-front chemotherapy. You would try to use dose-dense MVAC in that situation.

When do you offer surgery to patients in this setting?

At Baylor [University Medical Center], we tend to be a little bit more aggressive than our colleagues down in Houston. My colleagues there will sample anything suspicious, and if they find 

that there’s cancer or lymph node involvement, they will not plan on curative surgery; they will treat with 2 or 3 cycles of a chemotherapy regimen such as dose-dense MVAC or gemcitabine and cisplatin, and then they’ll sample the lymph nodes. If the lymph nodes still have any viable cancer, even if it’s microscopic, they will not proceed with surgery.

At Baylor, we don’t sample the lymph nodes. If we see enlarged lymph nodes, we will give something like 3 cycles of dose-dense MVAC or 3 or 4 cycles of gemcitabine and cisplatin. If we see some type of response there, we don’t sample; we go in and remove it. We cut it all out because we think that’s the only way to give the patient, in our opinion, the best chance of having the best disease control moving forward. I think that we see a difference in practice pattern there.

An example for me would be doing an evaluation before you give neoadjuvant chemotherapy and get scans done. Usually the urologist has only done an abdomen, pelvis, or chest x-ray, and you’re getting a CT chest and a bone scan, and you pick up some [small] nodules in the lung with uncertain significance, maybe some lymph nodes in the pelvis. [I would] move forward with chemotherapy and follow those [patients]. But I’m not going to play games with trying to do biopsies of the lung nodules after chemotherapy or try to base things on any type of response. I go forward [with surgery] if it’s an otherwise fit person. I let them know that [there is a concern with this], but if we don’t go for [it], we’re never going to get them to a good outcome.

During a Targeted Oncology Case Based Peer Perspectives event, Thomas Hutson, DO, PharmD, discussed the case of a 66-year old woman with bladder cancer that  presented post chemotherapy.

September Solid Tumor CBPP Spotlight

Laber Evaluates Therapeutic Options by Lines of Therapy in GI Cancers

Liu Discusses Treatments in Multiple Lines for Bladder Cancer

Sanborn Addresses Different Immunotherapies for ES-SCLC

Hutson Considers Maintenance Treatment for Bladder Cancer Post Chemotherapy

Arnaoutakis Makes a Case for Immunotherapy Following Concurrent Chemoradiotherapy in Stage III NSCLC