Targeted Oncology Staff

Florida Cancer Specialists & Research Institute

A 72-year-old White man presents with chest discomfort, cough, and dyspnea ​

Medical history: mild chronic obstructive pulmonary disease​

Former smoker, 10 pack-years; quit 25 years ago​

CT of the chest and abdomen found a 9.0-cm spiculated mass in the left lower lobe, loculated pleural effusion in the left hemithorax​, right adrenal metastasis​

PET/CT: 18F-fluorodeoxyglucose uptake in the left lung mass, pleura and right adrenal gland​

Brain MRI: solitary brain lesion (1.5 cm)

Note: no central nervous system symptoms​

Physical exam: notable for decreased breath sounds in the left lung base; ECOG performance score of 1​

Laboratory work unremarkable with normal organ function and blood counts​

Image-guided biopsy of the lung mass shows a poorly differentiated adenocarcinoma of the lung​

Immunohistochemistry: PD-L1 tumor proportion score of 90% (22C3 pharmDx assay) ​

Tissue NGS (next-generation sequencing): negative for molecular aberrations in 

: What regimens are recommended for a patient with non–small cell lung cancer (NSCLC) with PD-L1 expression above 50%, who is negative for actionable biomarkers?

 Here we get very little guidance. The NCCN [National Comprehensive Cancer Network] guidelines have the full slew of opportunities between squamous and non-squamous histology…and I think the difference between single agent and combination is a mix of biomarker, PD-L1 assessment, maybe even some secondary markers like KEAP1, p53, and STK11 that may signify either a positive or negative response to immunotherapy, as well as the clinical assessment.

We looked at [my practice] and, overwhelmingly, we’re seeing the use of chemotherapy up front. So our patients, certainly during the pandemic, are coming in more symptomatic and requiring, in clinical judgement, the addition of chemotherapy. Otherwise, we don’t have any side-by-side comparison. So, those are all category 1 recommendation, based on phase 1 data, and so basically the selection is dependent on the clinician.

During the live virtual event, 9 participants (90%) chose pembrolizumab and 1 (10%) chose cemiplimab. There were 10 total votes.

What data support the use of pembrolizumab (Keytruda) for patients with stage IV lung adenocarcinoma PD-L1 greater than 50%?

This is the KEYNOTE-024 phase 3 trial [NCT02142738]. [Patients enrolled on this trial] had untreated stage IV NSCLC, independent of histology. They had a total percentage score greater than 50%, no 

 mutations, no untreated brain metastases, and no active autoimmune disease requiring systemic therapy.

They were randomized [between] chemotherapy and pembrolizumab. There was a second course of pembrolizumab [for 1 year] versus crossover to pembrolizumab upon progression with chemotherapy. They allowed basically every conceivable platinum doublet for an international study. There was a steep drop-off of patients that didn’t receive subsequent second-line therapy, so choosing the right [first-line therapy] is important. The data are here very strong. The crossover has relatively small numbers.

The long-term follow-up [for overall survival (OS)] is important. The tail is at the beginning of the [Kaplan-Meier] curve. There’s [not much] crossover. So, the curves start to split within 3 to 6 months in favor of immunotherapy, and we maintain a relatively stable absolute OS benefit between the years to over 30% at 5 years for pembrolizumab in this subset. The hazard ratio [HR] is 0.62 [95% CI, 0.48-0.81], and the median OS is 26.3 months [95% CI, 18.3-40.4] for pembrolizumab versus 13.4 months [95% CI, 9.4-18.3] for chemotherapy. It’s a pretty good intrinsic marker, that is pretty consistent across the phase 3 trials to gauge how sick the individual patients are that were selected to participate.

Which trial demonstrated the efficacy of atezolizumab (Tecentriq) for this subset of patients with lung cancer?

So, looking at the IMpower110 study [NCT02409342], it has very similar trial design [to KEYNOTE 024]. It is a prospective evaluation for squamous or non-squamous stage IV NSCLC. This was a little bit less aggressive with PD-L1 levels in a hierarchical manner. This has only been approved for the first hierarchy of PD-L1 greater than 50%. Here, [patients received] atezolizumab versus chemotherapy with cisplatin or carboplatin plus pemetrexed versus cisplatin/carboplatin/gemcitabine for squamous cell carcinoma. Then there is a maintenance option for non-squamous disease, and a best supportive care for the squamous cell population. Patients received treatment until progression of disease.

In this study, there is crossing of the Kaplan-Meier curves for OS [due to more OS events in the first 4 months for patients receiving atezolizumab].

I am not quite sure why that is; the numbers look relatively alike. The median OS for chemotherapy was 13.1 months [95% CI, 7.4-16.5], so the comparator arm is certainly looking very similar [to that of the KEYNOTE 024 trial]. And then, the median OS for atezolizumab was 20.2 months [95% CI, 16.5-not estimable (NE)] in this subset.

We have a crossing of the curves [between 4 to 6 months]. So, this would be a trial where the chemotherapy upfront may have been a more reasonable option, based on the visuals. The HR [with 17 additional months of follow-up] is only 0.76 [95% CI, 0.54-1.09], which is not quite as impressive as we’ve seen with KEYNOTE-024. This is also a different [PD-L1 measurement] because it’s not the 22C3 Dako but the SP142 assay for assessment, in this trial.

Please describe the design of the cemiplimab (Libtayo) trial in this patient population.

The third registration trial in this setting is EMPOWER-Lung 1 [NCT03088540]. This patient population was all-treatment-naive NSCLC, with PD-L1 greater than 50%; 

 mutations were excluded. They allowed clinically stable central nervous system metastases that were treated, and then patients with hepatitis B or C and HIV were allowed. There is not a good reason not to include them, but they’ve never done it before in this larger setting.

The 1:1 randomization was to cemiplimab or chemotherapy of investigator’s choice; this was an international study, so there was more flexibility. Then, cemiplimab was given for 2 years, and there was a little bit of a different concept: not a second course of treatment, but an addition of chemotherapy. So basically, immunotherapy to chemoimmunotherapy augmentation upon progression versus crossover [from chemotherapy to cemiplimab monotherapy]. About three-quarters of patients took that crossover option, and there weren’t many patients that were able to continue treatment who didn’t choose that option. So this was very interesting, like a sequencing approach to those that were clinically able to.

When you look at the baseline characteristics, you see in both the intent-to-treat [ITT] population—there was a little bit of a difficulty confirming all the PL-L1 levels centrally for tissue availability, so that we have 2 sets of data: PD-L1 greater than 50% confirmed, and then the full ITT population. About 1 in 8 patients had brain metastases; and, as a particular area of interestwe see a little bit of an over-representation of [current] smokers [versus past smokers]. We don’t have any never-smokers in this trial, I think this was felt to be not necessarily helpful for non-smokers as much as it is for smokers. There is also a slightly over-representation of patients with squamous cell disease; obviously, when you exclude non-smokers or light smokers, you see that increase in patients with squamous histology. And, it’s also [related to] the way [cigarettes] are smoked internationally, filter-free, [which can lead to]a little bit of a different precipitation of carcinogens in the airway.

What was the response to therapy on the EMPOWER-Lung 1 study?

We see a picture that’s very similar to KEYNOTE-024. The Kaplan-Meier curves run in parallel for the first 3 to 6 months or so, and then start parting.

 In the ITT population, there was median OS of 22.1 months [95% CI, 17.7-NE] for cemiplimab, and 14.3 months [95% CI, 11.7-19.2] for chemotherapy [HR, 0.68; 95% CI, 0.53-0.87; 

 The median progression-free survival showed slight increase in the ITT population: 6.2 months for cemiplimab versus 5.5 months for chemotherapy. There is a much larger tail of the curve on an ongoing basis.

So, looking at OS in the confirmed PD-L1 greater than 50% population, it looks better.

There was certainly the suspicion that there were patients slipped in that didn’t have central confirmation of PD-L1 levels greater than 50%. The HR [of 0.57] is in the same ballpark, maybe even trending a little bit better than with KEYNOTE-024, with an unreached benefit here for OS [95% CI, 17.9-NE] versus 14.2 months [95% CI, 11.2-17.5] of median OS for the chemotherapy arm, and that’s within the same range that we’ve seen for IMpower110, and for KEYNOTE-024.

 There is almost a 3-month benefit in median PFS [8.2 months for cemiplimab versus 5.7 months for chemotherapy]. But the largest part of benefit here is not extending to the median number of population, but for the strong responder subset.

This was also a crossover study, so there was not necessarily a catching up [from the comparator arm]; I think that’s important for those trials in evaluation.

1. NCCN. Clinical Practice Guidelines for Oncology. Non–small cell lung cancer, version 3.2022. Accessed June 27, 2022. https://bit.ly/3xZFzJF

2. Brahmer JR, Rodriguez-Abreu D, Robinson AG, et al. LBA51 - KEYNOTE-024 5-year OS update: First-line (1L) pembrolizumab (pembro) vs platinum-based chemotherapy (chemo) in patients (pts) with metastatic NSCLC and PD-L1 tumour proportion score (TPS) ≥50%. 

2020;31(suppl_4):S1142-S1215. doi:10.1016/annonc/annonc325

3. Herbst RS, Giaccone G, de Marinis F, et al. Atezolizumab for first-Line treatment of PD-L1-selected patients with NSCLC.

2020;383(14):1328-1339. doi:10.1056/NEJMoa1917346

4. Jassem J, de Marinis F, Giaccone G, et al. Updated overall survival analysis from IMpower110: Atezolizumab versus platinum-based chemotherapy in treatment-naive programmed death-ligand 1-selected NSCLC. 

 2021;16(11):1872-1882. doi:10.1016/j.jtho.2021.06.019

5. Sezer A, Kilickap S, Gümüş M, et al. Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomised, controlled trial. 

. 2021;397(10274):592-604. doi:10.1016/S0140-6736(21)00228-2

6. Sezer A, Kilickap S, Gümüş M, et al. LBA52 - EMPOWER-Lung 1: Phase III first-line (1L) cemiplimab monotherapy vs platinum-doublet chemotherapy (chemo) in advanced non-small cell lung cancer (NSCLC) with programmed cell death-ligand 1 (PD-L1) ≥50%. 

 2020;31(suppl_4):S1142-S1215. doi:10.1016/annonc/annonc325

Articles

During a Targeted Oncology live virtual event, Martin F. Dietrich, MD, PhD, discussed data from 3 trials of immunotherapy agents for patients with non–small cell lung cancer with high PD-L1 expression. 

Immunotherapies Offer Alternatives to Chemotherapy for PD-L1–High Lung Cancer

Donald D. and Elizabeth G. Cooke Cancer Distinguished Research Professor

Chief, Division of Cell Therapy in the Department of Medicine

: How do you stage and grade acute GVHD [aGVHD]?

There are multiple ways of staging aGVHD. The Mount Sinai Acute GVHD International Consortium [MAGIC] has 2 staging systems, organ staging and overall clinical staging, which are based upon the most severe target organ involvement. The organ staging goes from 0 to 4 and it’s straightforward, focusing on the skin, liver, and upper GI [gastrointestinal] and lower GU [genitourinary]. It hasn’t changed much; the main change in the last 10, maybe 15 years is the introduction of the upper GI GVHD, which includes nausea, vomiting, or anorexia. If you have those, you’re at stage 1 and then the output is measured. It used to be just volume in the Glucksberg criteria in the past, but I think with the more current staging, the episodes are added into the GI staging as well.

From the stage, the overall grade is developed, so grade 0 is none and then grade 1 is 2 skin symptoms without symptoms in any other organ. Grade 2 is skin symptoms with grade 1 symptoms of the liver or the gut, and so forth, and this gives one the ability to discuss GVHD staging and grading across trials.

[In 2012, investigators looked at a different system] to stratify the risk based on organ involvement and the number of organs involved. They looked at the grading of the organs of about 1600 patients and stratified based on standard vs high risk. For example, a single organ or just GI or liver with 2 organs was considered a standard risk. The high-risk group had very high single-organ magnification, like grade 4 skin, grade 3 to 4 GI, or grade 1 to 4 liver or 2 organs. If there are 3 organs, it is grade 1 to 3 of skin plus grade 3 to 4 of the gut or the liver. What they were able to do with this was by looking at this risk score, determine what the probability of response and probability to survival was.

High-risk GVHD is associated with lower responses to steroids and higher treatment-related mortality. Standard-risk responders, both partial and complete responders, did much better than those at high risk. The probability of treatment-related mortality also is much higher for high-risk compared with standard-risk patients. This probably reflects the total amount of immunosuppression of these patients, as high-risk patients have a much more advanced-stage disease.

How do you approach treatment for a patient with steroid-refractory GVHD?

This patient has steroid-refractory resistance, which usually progresses within 3 to 5 days. If you don’t get better within 5 to 7 days or after 20 days of immunosuppressive steroids, you’re not improving as expected. You’re improving, but you’re not much better. With steroid dependence, when you try to taper the patient, you get recurrence of aGVHD, and steroid intolerance is usually associated with unacceptable toxicity.

The NCCN [National Comprehensive Cancer Network] has suggested agents for steroid-refractory GVHD. Ruxolitinib [Jakafi] is approved in the acute setting, but I think the key piece is clinical trials. We have lots of drugs, including alemtuzumab [Campath], and the approval for most of the drugs was based on studies with 30 patients in general that showed some response.…In the chronic setting, ruxolitinib, belumosudil, and ibrutinib [Imbruvica] are approved.

What is the evidence for using ruxolitinib in patients with steroid-refractory aGVHD?

Ruxolitinib is pretty good at inhibiting STAT signaling, which basically decreases the signaling of interferon and IL-17, both of which are proinflammatory cytokines. The phase 2 REACH-1 study [NCT02953678] enrolled 71 non-[randomly assigned] patients with aGVHD, who were treated with 5 mg ruxolitinib twice a day, and the primary end point was overall response at day 28.

The overall response rate [ORR] at day 28 was 54.9%, with 26.8% achieving a complete response [(CR). On the whole,] the ORR was pretty good at 73% [CR, 56.3%]. The median time to response was 7 days [range, 6-49 days] and the duration of response [DOR], with more than 6 months of follow-up, was 345 days. There were [35] deaths [49.3%] and the nonrelapse mortality was fairly high at 44%, but the median OS [overall survival] for day 28 responders was not reached.

These 71 patients went on to the phase 3 REACH2 study [NCT02913261]. This was a prospective randomized trial with 294 patients enrolled in a 1:1 randomization to ruxolitinib 10 mg twice a day or the best alternative therapy. It’s an interesting design because the comparator included 10 different drugs 

[In the study,] you could use antithymocyte globulin, extracorporeal photopheresis [ECP], mesenchymal stromal cells, low-dose methotrexate, mycophenolate mofetil [MMF], everolimus [Afinitor] or sirolimus [Rapamune], etanercept [Enbrel], and infliximab [Remicade]. The numbers of patients enrolled in any one of these best alternative therapies was essentially driven by the institutions which enrolled these patients.

The primary analysis was done on day 28 and these were patients who had severe refractory aGVHD grade 2 vs grade 3 and 4 and [who were aged] greater than 12 [years]. They had myeloid engraftment, but…were excluded if they had active infections or severe organ failure, if they had failed prior allogeneic hematopoietic stem cell transplant [HSCT] in the last 12 months, or if the disease had relapsed.

The study did allow for crossover, so if patients in the best alternative therapy group had not had a response by day 28 they could cross over to ruxolitinib. Then they looked at OS, event-free survival [EFS], and chronic GVHD [cGVHD].

The primary end point of the study was ORR at day 28, which was 63% for ruxolitinib compared with 39% in the control arm. Both partial responses [PRs] and CRs were higher with the ruxolitinib over the control arm, and durable responses were almost double for ruxolitinib [vs] the control on day 56 [odds ratio, 2.38; 95% CI, 1.43- 3.94; 

When stratified by grade of disease, the odds ratios were significantly in favor of ruxolitinib. The odds ratio for the full analysis set was 2.64 [95% CI, 1.65-4.22]; for grade 2 it was [2.96 (95% CI, 1.30-6.76)], grade 3 was [2.15 (95% CI, 1.10-4.20)], and grade 4 was [3.76 (95% CI, 1.24-11.38)].

The percentage of patients who lost response was much higher in the control group—over 40% compared with 10% to 15% in the ruxolitinib group. So patients taking ruxolitinib were much less likely to lose their response.

Another interesting result was the shift in organ staging. Not every patient had a CR, but there was a shift to lower stages with ruxolitinib compared to the best alternative therapy. Overall, stage shifting downwards with ruxolitinib was better than [with] best alternative therapy.

The failure-free survival [FFS] was quite significantly in favor of ruxolitinib. The percentage of patients without treatment failure was better with ruxolitinib [vs] the control. Obviously, this is not the answer to all of it and some patients are still failing therapy.

Another cautionary point is that the toxicities are somewhat problematic with ruxolitinib. Thrombocytopenia is a known problem, and infections with CMV were perhaps a little higher than the control. But overall, the other adverse effects [AEs] were not very different between the 2 groups.

Considering the REACH2 data, what do you use as first-line therapy for steroid-refractory aGVHD?

Ruxolitinib is an approved drug and I think it’s quite reasonable. I think many of us still have clinical trials ongoing or patients with steroid-refractory aGVHD, and if there’s equipoise in the studies, the clinical trials could fall under the other section [of treatment decisions].

What are the therapeutic options for this patient?

The phase 3 REACH3 trial [NCT03112603] investigated the use of ruxolitinib in the chronic setting. The most remarkable part of this trial was the total number of patients: 329 patients enrolled with 1:1 randomization to 10 mg of ruxolitinib twice a day compared with best alternative therapy.

The best alternative therapies included ECP, low-dose methotrexate, MMF [mycophenolate mofetil], everolimus or sirolimus, infliximab, rituximab [Rituxan], pentostatin [Nipent], and imatinib [Gleevec]. The study did allow crossover to ruxolitinib after cycle 7, day 1, if the patient hadn’t responded. The time for the initial response was 24 weeks, which looked at the overall response with CR plus PR, and the secondary end point was FFS and patient’s symptoms at week 24.

What were the efficacy results of REACH3?

The response rates were higher for ruxolitinib, about 50% for ruxolitinib compared with 25% for the control on week 24. The best overall responses were 76% with both CRs and PRs compared with 60% with the best alternative therapy.

The FFS was statistically significant for ruxolitinib, significantly better than the control arm, with the median FFS greater than 18.6 vs 5.7 months [HR, 0.37; 95% CI, 0.27-0.51; 

< .001]. The DOR was also much better for ruxolitinib. The Kaplan-Meier median, estimating the probability of FFS at 6 months, was not reached for ruxolitinib compared with the control, which was 6.24 months.

Are there other therapies to consider for this patient population?

In July of last year, the FDA approved belumosudil for [patients with] cGVHD after failure of at least 2 prior lines of systemic therapy. That’s the label indication, but the toxicity profile for the drug was significantly quite favorable and patients seemed to tolerate this very well. [These data are from] a randomized open-label trial with 65 patients.

This [approval] was based on the ROCKstar study [NCT03640481], which was open label with 2 different doses at arm 1 with 200 mg a day and arm 2 with 200 mg twice a day. There’s no difference in the outcomes, so the recommended dose is once a day. The median time from cGVHD diagnosis was 25 months; 48% [of patients] had 4 more organs involved. The median number of prior lines of therapy was 3 and more than three-fourths [of patients] were refractory to the last therapy.

There were clearly significant AEs for these drugs, but most would not make it difficult for the patients to tolerate this drug. Overall, it was quite well tolerated.

The ORR in the 200-mg arm was about 50% and the overall response occurring within the 12 months of therapy was quite high for these patients. FFS was 73% and the mean change was quite good, with about 50% of the patients improving. Overall, the clinically significant improvement from baseline was about 40% of these patients. So, good responses in a drug that was well tolerated.

1. Harris AC, Young R, Devine S, et al. International, multicenter standardization of acute graft-versus-host disease clinical data collection: a report from the Mount Sinai Acute GVHD International Consortium. 

2016;22(1):4-10. doi:10.1016/j.bbmt.2015.09.001

2. MacMillan ML, Robin M, Harris AC, et al. A refined risk score for acute graft-versus-host disease that predicts response to initial therapy, survival, and transplant-related mortality. 

2015;21(4):761-767. doi:10.1016/j.bbmt.2015.01.001

3. Schoemans HM, Lee SJ, Ferrara JL, et al; EBMT (European Society for Blood and Marrow Transplantation) Transplant Complications Working Party and the “EBMT-NIH (National Institutes of Health)-CIBMTR (Center for International Blood and Marrow Transplant Research) GvHD Task Force. EBMT-NIH-CIBMTR Task Force position statement on standardized terminology & guidance for graft-versus-host disease assessment. 

 2018;53(11):1401-1415. doi:10.1038/s41409-018-0204-7

4. NCCN. Clinical Practice Guidelines in Oncology. Hematopoietic cell transplantation (HCT), version 2.2021. Accessed April 23, 2021. https://bit.ly/3z4IyTn

5. Chao N. Finally, a successful randomized trial for GVHD. 

2020;382(19):1853-1854. doi:10.1056/NEJMe2003331

6. Jagasia M, Zeiser R, Arbushites M, Delaite P, Gadbaw B, von Bubnoff N. Ruxolitinib for the treatment of patients with steroid-refractory GVHD: an introduction to the REACH trials. 

. 2018;10(5):391-402. doi:10.2217/imt-2017-0156

7. Jagasia M, Perales MA, Schroeder MA, et al. Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial. 

. 2020;135(20):1739-1749. doi:10.1182/blood.2020004823

8. Zeiser R, von Bubnoff N, Butler J, et al; REACH2 Trial Group. Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease. 

2020;382(19):1800-1810. doi:10.1056/NEJMoa1917635

9. Zeiser R, Polverelli N, Ram R, et al; REACH3 Investigators. Ruxolitinib for glucocorticoid-refractory chronic graft-versus-host disease. 

2021;385(3):228-238. doi:10.1056/NEJMoa2033122

10. FDA approves belumosudil for chronic graft-versus-host disease. Updated February 1, 2022. Accessed May 11, 2022. https://bit.ly/3NuPIEJ

11. Cutler C, Lee SJ, Arai S, et al. Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar study. 

. 2021;138(22):2278-2289. Published correction appears in 

During a Targeted Oncology case-based roundtable event, Nelson Jen An Chao, MD, discussed risk management and treatment of patients with steroid-refractory acute graft-versus-host-disease as well as chronic graft-versus-host disease. 

Chao Discusses Stratifying and Treating Patients With Graft-Vs-Host Disease

I have quite a few of these patients. I would tell them that the situation is not as bad as it used to be 25 years ago when I started out. You would not most likely be dead within 5 years, as would have happened 25 years ago, but right now, prognostically, he’s unlikely to have a normal life expectancy. Therefore, we should throw, in due order, the kitchen sink at him, including stem cell transplant, even though I am not a great fan of transplant in general for multiple myeloma.

Can anyone take a crack at what an expected overall survival [OS] might be for a 51-year-old patient with R-ISS [Revised International Staging System] stage II disease?

In general, probably I would discuss with them that it’s [approximately] 8 to 10 years on average, but with newer therapies coming it might be better.

Yes, I think that’s incredibly accurate, based on the literature that’s been published thus far. You’re right, too, that it’s a moving target with the immunotherapies, particularly these T-cell redirecting therapies that are in development. It’s in constant evolution. So, [patients with] ISS stage I disease have an OS well over 10 years, when they’re transplant eligible and ISS II is approaching that 10-year mark and beyond, as well.

 The [patients with] ISS stage III disease still don’t do as well as their stage I and II counterparts, for sure.

Now, this patient is 51 years old and, as Dr Bendandi suggested, [their doctor would] begrudgingly refer them for consideration of autologous stem cell transplant [ASCT]. I understand those reservations. Who would not refer this patient for a discussion of frontline ASCT and high-dose melphalan [Alkeran] therapy? If we were in the Northeast, we would have [clinicians] piping up and saying that they wouldn’t necessarily do it, but I’m sensing [for this group], this is the type of patient you would refer to someone who does ASCT.

[We refer] most of our patients, and the transplant physicians always request us to send them early on….They’d rather see them earlier and have all the information available as early as possible, so we always send them [early].

I completely agree with this because….I tell the patient, “Hey, I’m not a great fan of ASCT because of this and that. However, there are doctors who would be great fans of it. I think that you should hear from both sides…and then make your own decision.”

I agree with the [factors mentioned here]. I have to say, however, that we have objective ways to measure fitness, performance status, and adequate organ function. Of course, patient preference is paramount—it is yes or no in the end. With respect to age, precisely because with or without transplant, the goal for a patient [such as] this should be to try to live 8 to 10 years, and the average age of survival for the White population, at least in the United States, is 79.5 years.

 I would argue strongly against transplant after age 70, even in a perfectly fit patient.

I think that with or without CAR [chimeric antigen receptor] T-cell therapy, bispecific drugs are coming to fruition, and these patients should live 8 to 10 years probably even without transplant, unless [their] cytogenetics change.

Does anybody else have any thoughts about transplant eligibility?

I don’t know if there’s an actual [age] cutoff, because [transplanters even] say up to 80 years if they’re doing well. We’ve seen a whole range there, so I don’t know if the age plays that much of an important role at this point. My experience is that seems to be a moving number.

Precisely. The problem, in my opinion, is financial toxicity. You have a patient, he’s 77 or 74 years old, ECOG performance score of 1, decent heart, liver, kidney function and then you throw at him a $2 million procedure at [The University of Texas MD Anderson Cancer Center]. I think that’s not justified.

I guess what I would say regarding age is that it is tightly linked to fitness, frailty, performance status, and adequate organ function. But at the same time, there are patients in their 70s who, for all intents and purposes, are just as healthy as a 55-year-old you may have seen the previous day and counseled about ASCT. There [are] retrospective data from the Center for International Blood and Marrow Transplant Research showing that treatment-related toxicity and mortality with ASCT in patients beyond the age of 70 [are] actually very low and very similar to younger patients. Now, [those are] retrospective data and there’s selection bias, but if patients are picked appropriately, you can feasibly do ASCTs for patients in their 70s. As you get to [age] 80 and beyond, then things get quite dicey. It’s a case-by-case decision-making process, and you must look at all factors of the disease, including whether they have standard-risk or high-risk disease and what their preferences are.

Personally, if there [are] no high-risk cytogenetics, then no quadruplet. That’s the way I will use them.

[What do you think is the best approach (doublet, triplet, quadruplet) to primary therapy?]

Biologically they do not have high-risk disease, so why introduce a fourth drug and expose them to [adverse effects]?

I assume if we go for ASCT and a quadruplet does the job for the ASCT, then it’s very difficult to justify it

With the triplet, we know what to expect, and we know what to expect with ASCT.

Who voted for VRd [bortezomib (Velcade), lenalidomide (Revlimid), dexamethasone] as induction therapy for this patient?

I still debate this a lot myself, too. I know that daratumumab [Darzalex] obviously has some sort of survival benefit if you get it at some point during your therapy. In the GRIFFIN trial [NCT02874742] the 3-year progression-free survival [PFS] difference was [approximately] 8%.

 So that’s what I struggle with. For 3 years of daratumumab you get an 8% PFS difference. I know I’d like to incorporate it somewhere, but I struggle with where to put it in at this point. I know there’s survival benefit, [from the results of] the CASTOR [NCT02136134] and POLLUX [NCT02076009] trials, so there’s benefit, it’s just a matter of where to plug it into.

Anyone else on the triplet side of things want to comment?

I [have] started using it more and more. I agree that for high-risk patients, we need more data. But I think with the GRIFFIN trial the goal was to get as much disease control as possible prior to ASCT, especially in transplant-eligible patients.

Any other comments from those who voted for the quadruplet?

I voted for the quadruplet based on the GRIFFIN data. The GRIFFIN data do not necessarily support that this is only necessary for patients with high-risk cytogenetics. It has the survival advantage, or the trend toward the PFS advantage in all patients. It also had a deepening of response at all stages of treatment, so that’s before induction, after induction, after transplant, and with consolidation. The deeper response with the addition of a CD38 antibody is real, in my opinion. In the era we’re at with myeloma therapy, as many have said before, going for the deepest response that you can get, ideally, to a minimal residual disease [MRD]–negative remission makes a lot of sense to me, and that’s why I would use the quadruplet in patients regardless of their cytogenetic status.

I think it’s a discussion of the risks, the toxicities of a particular therapy vs the potential benefits as far as remission and durability of remission are concerned. Is the ability to achieve MRD-negativity, like Dr Paul just mentioned, of primary importance to you, or are you looking at something else?

To me, what matters is OS. Now we have more medications and treatment options and there is some attrition among lines of treatment, but we have more therapeutic options than chances to use them in any given patient. My concern with the patient is I’ll try to keep you alive any way I can—before we knew that you would die in 5 years. But from the lenalidomide era, if you stay alive, something else is going to come up, in fact, we have a redundancy in isatuximab [Sarclisa]. I have probably 15 patients who ask me to go on treatment holidays, and probably double digit of them have stayed 2 or 3 years without the paraprotein moving a milligram. Everything is possible. Of course, this is a patient who is 51 years old, and I can’t guarantee a normal life duration. I understand being more aggressive, but I don’t know that achieving MRD in any given line of treatment will prolong his life.

I agree that we do not have prospective data at this point to support that MRD negativity is consistent with an OS advantage. Retrospectively, there are some data that at least support that hypothesis. I would argue that, in my experience, an upfront MRD-negative remission is more valuable than an MRD-negative remission in subsequent lines of therapy, because I find that the duration of response still is higher in your earlier lines of therapy, even if you’re getting to an extraordinarily deep response. I’m a proponent of taking my best shot up front, when a patient ideally has the best performance status, has more treatment-naïve myeloma, has a healthier immune microenvironment to take advantage of. Again, that is why I typically would offer a quadruplet up front, but I can understand the argument to the contrary.

The most updated National Comprehensive Cancer Network [NCCN] guidelines for treatment of transplant-eligible multiple myeloma patients list VRd induction regimen as category 1 and the preferred regimen. The other recommended regimens include KRd [carfilzomib (Kyprolis), lenalidomide [Revlimid], dexamethasone], daratumumab-VRd, and, perhaps surprisingly and I think that they need to delete this, ixazomib [Ninlaro], lenalidomide, dexamethasone, which is a category 2B.

 The only reason I say that is because there are data out there suggesting that the addition of ixazomib to lenalidomide and dexamethasone for [patients who are] newly diagnosed transplant ineligible did not have any beneficial impact on PFS.

We’ve already talked about disease biology, whether you have standard-risk vs high-risk disease, with some participants suggesting that they would lean away [from] quadruplet therapy for somebody who has standard-risk disease, whereas others suggesting that the quadruplet performs better than the triplet regardless of cytogenetic risk.

At this point, I don’t usually weigh their genetic risk in how I select it yet. I don’t know if there are a lot of data to suggest, at least from my understanding, which helps in that direction for me. Obviously, the renal function’s a big deal, a lot of times [patients] come in the hospital and they have bad kidney function, and we try to get them on cyclophosphamide and bridge into lenalidomide. My biggest branching point is always [whether] they’re transplant eligible or ineligible and sometimes convenience as well. [For instance, I take into consideration] how far away they are from our center.

Does anybody else want to make a comment?

What about λ light chain? I don’t know whether this is just me, but in my experience, anything else equal, λ light chain carries one of the worst prognoses.

Yes, so I think when patients have λ light chain multiple myeloma, that does increase the risk of renal impairment at initial diagnosis. I think λ light chains in general tend to be more nephrotoxic than κ light chains, although they both can be, obviously. I think that there may be a gravitation toward a higher proportion of high-risk cytogenetic abnormalities in some of these free λ light chain patients. When accounting for the cytogenetic abnormalities, the fact that it’s λ light chain, in and of itself, does not carry as much weight. But I agree with you, those patients oftentimes are very difficult to treat because they have high-risk disease biology, whether it’s cytogenetic risk, high LDH, extramedullary disease, etc.

I don’t know whether you remember follicular lymphoma 25 years ago. It was watch and wait until you can’t, and then use CVP [cyclophosphamide (Cytoxan), vincristine (Oncovin), prednisone], RFMD [(rituximab (Rituxan), fludarabine (Fludara), mitoxantrone (Novantrone), dexamethasone], or R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone], then good luck with the transplant. Transplant in follicular lymphoma does not exist anymore. What am I implying? Once OS stops being the primary end point of clinical trials that’s great news. We don’t use OS in follicular lymphoma now, [we haven’t] for 20 years. Why? Because by the time the trial is over, one is long retired. No principal investigator would ever see the end of the trial, so I think we are getting there. Not to mention bispecific drugs, CAR T-cell therapy, and belantamab [Blenrep], you name it. Thank goodness we are going in that direction, but it’s going to take some time.

Are we at a point now where transplant is no longer necessary?

I think it still has a role, especially compared with a lot of these novel treatments. It’s still relatively cheap. Compared with a couple years of PFS benefit vs a new therapy, ASCT almost ends up being a [less expensive] option. It still has mortality benefit, and in higher volume centers it still has a low mortality. I still am a big believer in ASCT, and one sees a deepening response with it, too, so I think there are a lot of benefits for it.

It also depends on the nature of the practice. If you have an infusion center, infusion’s important and oral treatment is less important. If you work in a Veterans Affairs hospital, you have only 3 centers nationwide that perform transplant. Of course, there are logistics that can throw a wrench into the process of referring and having the transplant performed, and so on, but it depends on things that are not strictly clinical.

I think that all those points are very well taken. Are there any carfilzomib enthusiasts in the group? We’ve talked about bortezomib-based induction strategies for this group of patients. But carfilzomib, lenalidomide, and dexamethasone is one of the options listed in the NCCN guidelines.

I will consider using that in patients with significant baseline neuropathy, just because I worry about the addition of bortezomib, even in a quadruplet setting. I’ve tried to get Dara-KRd [daratumumab-KRd] off label for a handful of these patients with some success, but [it often is a] failure. In general, if I have a patient with lots of neuropathy at baseline I’ll try to avoid a bortezomib-based induction regimen.

Yes, I would agree with that, and that’s the most common space where I would use carfilzomib over bortezomib—in the frontline setting. Is there anybody who favors a carfilzomib-based platform for those patients who have high-risk cytogenetics at initial diagnosis?

I know there are some subgroup analyses that suggest for patients with 1q21 abnormalities, carfilzomib might mitigate that. I was getting [a few] referrals for patients who start on it because of that. I think it was an unplanned subgroup analysis of the trial, so I don’t know how much weight to put on it. I don’t know if there were any specific areas that I’d favor carfilzomib.

Yes, we have a head-to-head comparison of RVd and KRd in the ENDURANCE trial [NCT01863550] in patients who were either ineligible for or who elected not to pursue frontline transplant. There was no difference in outcomes with regards to PFS or OS; however it was exclusively in standard-risk cytogenetic patients. The question remains unanswered. I will mention that when we included the patients with 1q21 gain into our high-risk definition in the GRIFFIN analysis, we saw a clear improvement in MRD negativity.

Based on the data that I’ve reviewed, I think no one would question an improvement in MRD negativity by adding daratumumab to the RVd backbone. I think that’s clear. I think that the PFS data look awfully good. I hope [the data] continue to mature well over time, but [they are] looking good. We have no OS difference, and it’s going to take many years to see if it ever materializes. It very well may not because of all the therapies available in subsequent lines of therapy. So for those of you who voted for the triplet, what would you need to see to change practice from either the GRIFFIN or the PERSEUS trial [NCT03710603]?

I would be more tempted to use the quadruplet more and change my practice if it meant not having to use transplant. Or even adding daratumumab as a maintenance after the given number of VRd cycles that I’ve stipulated with the patient, assuming there is no progression, or resistance, or anything like that.

You feel that if there was a study that showed that using a quadruplet up front obviated the need for a frontline transplant, that would be enough to sway you over to the quadruplet?

Yes. Now, [are you using MRD assessment routinely in your practice?]

We don’t have access to that, except for being a send-out. So we’re not using it routinely. We do have patients who are seen at our main campus at Chapel Hill, [North Carolina], who do get that, but we don’t use it routinely.

Who here is using MRD testing to guide therapy?

I’ll use it at times if I have a patient who is [having a difficult time] with maintenance stage therapy as a possible breakpoint to consider taking them off maintenance if they’ve had a sustained MRD-negative remission for a period.

1. American Cancer Society. Survival rates for multiple myeloma. March 2, 2022. Accessed May 31, 2022. https://bit.ly/3N96tFp

2. Dong J, Garacci Z, Buradagunta CS, et al. Black patients with multiple myeloma have better survival than White patients when treated equally: a matched cohort study. 

 2022;12(2):34. doi:10.1038/s41408-022-00633-5

3. Voorhees PM, Kaufman JL, Laubach J, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. 

2020;136(8):936-945. doi:10.1182/blood.2020005288

4. Palumbo A, Chanan-Khan A, Weisel K, et al; CASTOR Investigators. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. 

2016;375(8):754-766. doi:10.1056/NEJMoa1606038

5. Bahlis NJ, Dimopoulos MA, White DJ, et al. Daratumumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended follow-up of POLLUX, a randomized, open-label, phase 3 study. 

. 2020(7):1875-1884. doi:10.1038/s41375-020-0711-6

6. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 5.2022. March 9, 2022. Accessed May 18, 2022. https://bit.ly/3fa9Yx5

During a Targeted Oncology case-based roundtable event, Peter Voorhees, MD, discussed therapy options and transplant eligibility for patients with multiple myeloma. 

Roundtable Discussion: Voorhees Discusses Managing Treatment in Multiple Myeloma

Clinical Director, Lank Center for Genitourinary Oncology

: What second-line therapy are you most likely to recommend for this patient?

Popular choices include a single-agent VEGF-targeted tyrosine kinase inhibitor [TKI] [eg, axitinib (Inlyta) or cabozantinib (Cabometyx)], a VEGF-TKI combination [specifically, lenvatinib (Lenvima) plus everolimus (Afinitor)], and an immune checkpoint inhibitor [ICI] regimen [eg, nivolumab (Opdivo) with or without ipilimumab (Yervoy)].

What are the National Comprehensive Care Network (NCCN) guidelines for subsequent ccRCC therapy?

Listed as preferred regimens are single-agent nivolumab, single-agent cabozantinib, and the combination of lenvatinib plus everolimus, all supported by category 1 data. I’m not sure many of us would choose nivolumab after progression on pembrolizumab [Keytruda]. Axitinib is listed among the “other recommended” regimens and is supported by category 1 data.

From your experience, are cabozantinib and the combination of lenvatinib and everolimus tolerated equally well, or is one tolerated better than the other?

We [use these] treatments at the regulatory-approved doses: cabozantinib at 60 mg, lenvatinib at 18 mg, and everolimus at 5 mg. I think tolerability is very [patient specific]. Both regimens tend to be challenging at the FDA-approved doses, and most patients will require a dose reduction. One of the challenges with something like lenvatinib plus everolimus is that you must manage toxicity from 2 different types of drugs and [you must be able to correctly] attribute the toxicities [to their respective] medications. But each drug probably can be reduced to a dose that has acceptable levels of toxicity.

If a patient received axitinib plus pembrolizumab as first line and had a good response but then progressed, would you give this patient axitinib again?

[In that case, there would] probably be no indication for giving axitinib again. [We need to keep in mind that the NCCN] guidelines don’t take prior therapies [into account].

What data support the second-line regimens that are listed as “preferred” by the NCCN?

The use of nivolumab is supported by the results of the CheckMate 025 study [NCT01668784], in which patients had TKI-refractory disease. The primary end point was overall survival [OS], [and the comparator was everolimus]. [The experimental arm] demonstrated an objective response rate [ORR] of 25%, a median progression-free survival [PFS] of 4.6 months, and an OS of 25.0 months [HR, 0.73; 95% CI, 0.57-0.93; 

= .002]. About 8% of patients required discontinuation [of treatment] due to adverse events [AEs].

The results of the phase 3 METEOR study [NCT01865747] support the use of cabozantinib, which was compared with everolimus in this trial. Again, patients had TKI-refractory disease, and the primary end point was PFS. [In the experimental arm], there was a median ORR of 17%, a median PFS of 7.4 months [HR, 0.51; 95% CI, 0.41-0.62; 

< .0001], and a median OS of 21.4 months. About 62% of patients required a dose reduction and 12% of patients had to discontinue treatment due to AEs.

Lastly, the combination of lenvatinib plus everolimus was compared with lenvatinib monotherapy and with everolimus monotherapy in the phase 2 Study 205 [NCT01136733]. Again, this trial was conducted in the context of TKI-refractory disease, and the primary end point was PFS. In this study, the ORR [of patients who received lenvatinib plus everolimus] was 43%, median PFS was 14.6 months [HR vs everolimus, 0.40; 95% CI, 0.24-0.68; 

= .0005], and median OS was 25.5 months. About 71% of patients required dose reduction, and about 24% of patients required discontinuation of treatment due to toxicity.

Could you summarize the properties of VEGF-TKIs?

Sunitinib [Sutent] and sorafenib [Nexavar] are first-generation TKIs. Some of the next-generation TKIs, with slightly different spectrums, include pazopanib [Votrient], cabozantinib, and lenvatinib. Axitinib and tivozanib [Fotivda] are more recent TKIs; they have very high specificity for VEGFR-1, VEGFR-2, and VEGFR-3 and lower specificity for things like fibroblast growth factor receptor and c-kit, compared with other regimens.

What data supported the approval of tivozanib?

The phase 3 TIVO-3 study [NCT02627963] led to the regulatory approval of tivozanib.

 Patients in this study had advanced or metastatic ccRCC and had progressed on 2 or 3 prior systemic therapies, including at least 1 VEGFR-targeted therapy. Patients were stratified [with respect to the nature of their prior treatment]: a VEGFR TKI plus a checkpoint inhibitor; 2 VEGFR TKIs; or a VEGFR TKI plus another agent. Patients were also stratified with respect to their International Metastatic RCC Database Consortium risk status (favorable, intermediate, or poor).

 [With regard to prior therapies], about half of the patients in each arm had received 2 prior ICIs. About a quarter of the patients in each arm had received an ICI plus a VEGFR-targeted therapy, and about a quarter had received a VEGFR-targeted therapy plus some other type of agent.

During a Targeted Oncology case-based event, Chung-Han Lee, MD, PhD, and Bradley A. McGregor, MD, discussed the case of a patient with recurrent metastatic renal cell carcinoma and that of a patient at risk of recurrence following resection. 

Targeted Oncology Staff | Authors

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