Targeted Oncology Staff

During a Targeted Oncology Case-Based Peer Perspective Roundtable, Mary Jo J. Fidler, MD, associate professor, Division of Hematology, Oncology, and Cell Therapy, Department of Internal Medicine, Rush Medical College, Rush University Medical Center discussed targeting 

 in patients with non–small cell lung cancer (NSCLC). 

™: What would be your next therapeutic step for this patient with stage IV NSCLC?

: The patient is anxious to start therapy. This is a never-smoking Asian man with adenocarcinoma with high PD-L1 expression of 100%.

You could argue that the patient may want treatment sooner [than waiting for molecular panel test results]. If that [were] the case, then I would recommend either a cycle of platinum doublet chemotherapy without immunotherapy or waiting before doing palliative radiation, something that wouldn’t delay systemic therapy down the road.

In this case, I would [wait] for the molecular panel testing results, hoping that we could control the patient’s pain until these came back. Starting with immunotherapy runs the risk of increased toxicity if this patient were to have a driver mutation. Schoenfeld and colleagues [published a study] showing high rates, close to 30%, of grade 3 to 4 toxicities in various organs, not just pneumonitis, when starting with immunotherapy and switching to an EGFR tyrosine kinase inhibitor [TKI].

This phenomenon also has been reported with 

 agents, so my choice would be to wait for molecular panel test results. If [the patient] needed treatment, then starting with 1 cycle of chemotherapy or potentially with palliative radiation could also make sense.

What are the National Comprehensive Cancer Network (NCCN) recommendations for molecular testing for patients with nonsquamous NSCLC?

The NCCN recommendations suggest using a molecular panel. This is thought to be cost-effective and also maximizes tissue use and avoids waste of tissue.

 It also allows for identification of rare driver mutations such as the 

 mutation. I’ve had a few patients with lung cancer with 

 exon 14 mutations and these [mutations] are standard drivers now. We saw some encouraging data at ASCO [the American Society of Clinical Oncology 2020 Virtual Scientific Program] looking at an antibody-drug conjugate with results in 

It’s important to do a broad panel, and it is [more] cost-effective than testing for 1 gene at a time. PD-L1 testing up front is also recommended.

Are molecular testing results for liquid biopsies (blood samples) concordant with results for tissue biopsies? We have some information on this. A study looking at the Guardant360 assay was published in 

 by [Charu] Aggarwal, MD, PhD, and colleagues. That study compared the Guardant360 assay with next-generation sequence testing on tissue in the frontline setting for NSCLC. Most of the time, tests in tissue and blood [samples] showed the same results, but about 13% of patients had a driver mutation noted only [in] the tissue and not in the serum. In about 13% of patients [with a] noted mutation in the circulating tumor assay in the blood but not in the tissue itself, regardless of how the mutation was noted, the response to the targeted therapy was appropriate.

 My takeaway is that if you find an activating mutation in circulating tumor DNA, you can act on it and it’s real.

In this case of a never-smoking Asian man, I would have a high suspicion that he had the 

 mutation. If I did a circulating tumor DNA assay and I didn’t find anything, then I would send off tissue and probably start with carboplatin/pemetrexed [Alimta] and not add immunotherapy up front because my suspicion is so high. If you don’t find [a mutation] either in the tissue or the blood and are suspicious, then it’s probably worthwhile to look a bit deeper.

Do you test blood samples and tissue samples at the same time?

Most circulating tumor DNA assay results are back within a week, and sometimes it takes about a week to get [a tissue] biopsy set up, so I have done that [because] you can get the results faster. Typically, if I get a result on the blood test, then I won’t order the tissue [biopsy]. But if I don’t get a result with the blood test, then I’ll have that [tissue biopsy] order [pending].

What options would you consider for frontline therapy? Do you prefer to use osimertinib [Tagrisso] up front or to withhold it in case an 

 T790M mutation develops during the period the patient is taking a first-generation TKI?

Say you start with a first- or second-generation TKI, and then upon progression you look for the 

 mutation and then come in with osimertinib. We’ll look at the frontline osimertinib data and what happened to the people on the control arm, which was [treatment with] gefitinib [Iressa] or erlotinib [Tarceva]. We do not have data comparing osimertinib and afatinib [Gilotrif] or dacomitinib [Vizimpro] [as first-line therapy] and I think we’ll see those data directly. The RELAY trial [NCT02411448] studied erlotinib with ramucirumab [Cyramza] as frontline [therapy], and [in May 2020] erlotinib plus ramucirumab received FDA approval.

 [In] the NCCN guideline, osimertinib and the other TKIs are listed as category 1 [recommendations]. Erlotinib plus ramucirumab is also listed in the guideline.

What is the most significant barrier to prescribing these medications?

I haven’t had instances where patients haven’t been able to get their targeted agent, but sometimes the patient needs support in filing for the appropriate patient-assistance programs and foundations. With so many oral drugs [available], some of the foundations that we initially relied on don’t have enough money to cover their patients. That being said, most patients have been able to get their therapy, in my experience at least, within a week or 2.

What data support the use of osimertinib as first-line treatment for patients with 

The FLAURA trial [NCT02296125] [compared] first-line osimertinib versus standard of care for [patients with] 

-mutant advanced NSCLC. It was randomized to compare [osimertinib] with erlotinib or gefitinib based on prescriber choice. [The 

 mutations allowed were] exon 19 and exon 21 [

]. Patients were stratified by mutation type and by race, Asian or non-Asian. Brain metastases were permitted and [the patient’s condition] had to be stable. Patients were not able to [receive] steroids and [continue] on the trial, but they were permitted at trial entry.

 The primary end point was progression-free survival [PFS]. [I will also go over] the overall survival [OS] data.

The PFS data [show] a highly significant difference in favor of osimertinib versus standard of care, with a median PFS [for osimertinib] of 18.9 months [versus median PFS for standard of care, 10.2 months; HR, 0.46; 95% CI, 0.37-0.57; P <.001]. The PFS benefit was seen regardless of 

There also was an OS benefit [when] comparing osimertinib with the standard of care. The median OS [with osimertinib] was 38.6 months [versus median OS with standard of care, 31.8 months; HR, 0.80; 95% CI, 0.64-1.00; 

 = .046]. [At 24 months] OS was 74% for osimertinib versus 59% for standard of care. [More than] half the patients [54%] in the osimertinib group were alive at the 3-year mark.

The crossover [effect] is a big question. [Patients in the trial] could cross over [from standard of care] to osimertinib. As part of the trial, patients who were randomized to a first-generation TKI [could receive a subsequent therapy after discontinuing the assigned treatment]. Of the patients [in the standard-of-care group] who received a subsequent therapy, about half (47%) went on to receive osimertinib.

With half of them receiving osimertinib, the survival benefit still persisted, and the main concern I have would [be] the sequencing strategy [in] some patients. [In this] clinical trial, 31% of all patients randomized to the standard-of-care arm [received osimertinib as subsequent therapy, but] not all of [the patients in this arm] went on to receive subsequent therapy.

That could also be why the survival benefit was more pronounced with osimertinib; some patients who potentially could have had access to the drug didn’t get it. That being said, the prevalence of a 

 mutation after gefitinib or erlotinib [treatment] is about 50%, so they did capture many of these patients.

Interestingly, the OS [result] did not hold statistical significance with the subset analysis in the Asian population and in [patients with] exon 21 mutations. Anecdotally, most of us think exon 21 mutations may perform [better] than exon 19 mutations. There definitely was a PFS benefit with osimertinib. This didn’t translate into OS in the final analysis, although this was powered by a different mutation subtype.

What data support using ramucirumab plus erlotinib as first-line therapy for patients with 

[The FDA approved] ramucirumab plus erlotinib for frontline [treatment of] metastatic NSCLC on May 29, 2020.

 The RELAY trial was a randomized phase 3 trial [of ramucirumab plus erlotinib for treatment of EGFR-mutated NSCLC]. The same mutations were allowed in the RELAY trial as in the FLAURA trial.

One significant difference in the inclusion criteria was that patients with brain metastases were not [included] in the RELAY trial, but they were [included] in the FLAURA trial. Brain metastasis is a huge problem for [patients with] 

 [mutations], with the prevalence of CNS [central nervous system] disease at some point in their treatment course close to 50%. Patients [in the RELAY trial] did not have brain metastases at baseline, which is a notable difference with the FLAURA trial.

The randomization was 1:1 between ramucirumab plus erlotinib versus placebo plus erlotinib. Treatment was carried on until progression, with the primary end point being PFS. We do not yet have OS data for this regimen. The PFS curves [show a] significant [difference between groups]. Median survival is [similar to that of] the FLAURA trial with a highly significant HR [median PFS: ramucirumab plus erlotinib, 19.4 months; placebo plus erlotinib, 12.4 months; HR, 0.59; 95% CI, 0.46-0.76; 

The subgroup analyses, at least for PFS, [show] no hint at a difference between [patients with] exon 19 deletions and [those with] 

 [exon 21] mutations [exon 19: HR, 0.65 (95% CI, 0.47-0.90); exon 21: HR, 0.62; 95% CI, 0.44-0.87]. [Results were] also stratified between [patients of] East Asian and other [races], and both of those groups [showed a] significant benefit of having ramucirumab added to erlotinib [East Asian: HR, 0.64; 95% CI, 0.49-0.83; non–East Asian: HR, 0.61; 95% CI, 0.36-1.01].

The adverse events of special interest [were those] we typically see when we add a vascular endothelial growth factor receptor agent, [including] bleeding or hemorrhage, hypertension, and proteinuria. Overall, the adverse events were thought to be manageable.

 T790M mutation rates after disease progression. They checked for the T790M mutation at baseline and did not find it in the patients entered in this trial. They looked at liquid biopsies [at baseline and at] a 30-day follow-up after progression. The T790M mutation rate was what they expected at 30 days after progression [mutation rates: ramucirumab plus erlotinib, 43% (95% CI, 30%-58%); placebo plus erlotinib, 47% (95% CI, 36%-58%); 

 =.85], suggesting that patients with T790M mutations could go on to receive osimertinib after their erlotinib/ramucirumab regimen.

Do you agree with the choice of therapy for this patient?

This patient received frontline osimertinib. As we mentioned for the RELAY trial, he also would have been eligible for erlotinib plus ramucirumab. A Japanese trial of erlotinib plus bevacizumab [(Avastin) for patients with 

 [but] adding bevacizumab to erlotinib [did not improve OS] in a United States cooperative trial [NCT01532089].

Ongoing frontline trials in this space include adding carboplatin and pemetrexed to osimertinib [NCT02151981] based on data showing improvement in survival by adding carboplatin and pemetrexed to gefitinib.

There are ECOG trials adding bevacizumab to osimertinib [NCT04181060] and adding ramucirumab to osimertinib [NCT03909334].

How do you treat patients with NSCLC that is resistant to first-line osimertinib?

With increasing reports of small cell and squamous transformation in 

-mutant NSCLC, I try to get a tissue biopsy, especially if there’s a central lymph node that’s grown quite a bit and [the patient has] a lot more disease burden in their chest.

Our practice has seen a few small cell transformations. I have a patient who’s had a squamous cell transformation, too. I think it does happen and it may influence your next therapy. I try to do tissue biopsy, but we can also find resistance mechanisms with liquid biopsy. That’s a good strategy if [tissue] biopsy cannot be easily obtained.

-mutant NSCLC who received frontline osimertinib, next-generation sequencing [was performed] on tumor tissue before and after [osimertinib administration]. Known mechanisms of quiet resistance [to EGFR TKIs] were identified in 41% of patients. The on-target 

 724S mutation was seen in 1 of 27 patients (4%). There were some other off-target mutations with 

We’re participating in the ORCHARD trial [NCT03944772], obtaining biopsies from patients [who have cancer] progression with osimertinib. [The study has] arms for patient [allocation depending on] different molecular targets. If there is no target, [the patient is] randomized to receive chemotherapy plus durvalumab [Imfinzi]. If you have a patient on osimertinib upon progression, we’d love to see them for the molecular targeted options after [the cancer has] progressed. I have heard from some of my colleagues at Massachusetts General Hospital and Memorial Sloan Kettering Cancer Center that [when] they found some mutations, [such as] 

 rearrangement, they have been able to get dual TKIs approved by insurance, but it can take some time because it is expensive.

How would this patient’s 100% PD-L1 expression affect your choice of therapy after failure of the first TKI treatment?

What we know about patients with driver mutations [is that] the benefit of an immune checkpoint inhibitor versus docetaxel is not that pronounced. PD-L1, interestingly, is expressed through downstream activity of the 

-activating mutation. It may not be the same mechanism as a tumor hiding from the immune system. That’s why I don’t typically use checkpoint inhibitors in the front line for these patients. A couple of small studies looked at frontline PD-L1 treatments in patients with 

-positive tumors, and they were both stopped for futility because it didn’t seem to be a good strategy.

If a patient has [no more] targeted treatment options, I think [immunotherapy] could be reasonable. The IMpower150 trial [NCT02366143] was the only trial of frontline platinum doublet plus immunotherapy that included patients with a history of EGFR or ALK inhibitors. The trial combined carboplatin, paclitaxel, atezolizumab [Tecentriq], and bevacizumab as quadruplet therapy for those patients.

There is some debate [as to] how much the immune checkpoint inhibitors work. I probably would not use them as single agents [and would] probably add them to the platinum doublet chemotherapy. But we try to look for [mechanisms] of resistance that we can target and keep people on osimertinib longer. The other thing that we’re doing commonly, and you could argue there [are] some data supporting this strategy, is to treat patients with oligometastatic progression and extend time on their TKI.

1. Schoenfeld AJ, Arbour KC, Rizvi H, et al. Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib. 

. 2019;30(5):839-844. doi:10.1093/annonc/mdz077

2. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 1.2021. Accessed November 30, 2020. https://bit.ly/2KHxJPR

3. Smit EF, Nakagawa K, Nagasaka M, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC): interim results of DESTINY-Lung01. 

. 2020;38(suppl 15):9504. doi:10.1200/JCO.2020.38.15_suppl.9504

4. Aggarwal C, Thompson JC, Black TA, et al. Clinical implications of plasma-based genotyping with the delivery of personalized therapy in metastatic non-small cell lung cancer. 

. 2019;5(2):173-180. doi:10.1001/jamaoncol.2018.4305

5. FDA approves ramucirumab plus erlotinib for first-line metastatic NSCLC. FDA. Updated June 1, 2020. Accessed October 19, 2020. https://bit.ly/3obLWDV

6. Soria JC, Ohe Y, Vansteenkiste J, et al; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378(2):113-125. doi:10.1056/NEJMoa1713137

7. Ramalingam SS, Vansteenkiste J, Planchard D, et al; FLAURA Investigators. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. 

. 2020;382(1):41-50. doi:10.1056/NEJMoa1913662

8. Nakagawa K, Garon EB, Seto T, et al; RELAY Study Investigators. Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial. 

. 2019;20(12):1655-1669. doi:10.1016/S1470-2045(19)30634-5

9. Maemondo M, Fukuhara T, Saito H, et al; North East Japan Study Group. Final overall survival analysis of bevacizumab plus erlotinib treatment for NSCLC patients harboring activating EGFR-mutations. Abstract NEJ026. 

. 2020;38(suppl 15):9506. doi:10.1200/JCO.2020.38.15_suppl.9506

10. Stinchcombe TE, J.nne PA, Wang X, et al. Effect of erlotinib plus bevacizumab vs erlotinib alone on progression-free survival in patients with advanced EGFRmutant non-small cell lung cancer: a phase 2 randomized clinical trial.

. 2019;5(10):1448-1455. doi:10.1001/jamaoncol.2019.1847

11. Mok TS, Wu YL, Ahn MJ, et al; AURA3 Investigators. Osimertinib or platinumpemetrexed in EGFR T790M-positive lung cancer. 

. 2017;376(7):629-640. doi:10.1056/NEJMoa1612674

12. Schoenfeld AJ, Chan JM, Kubota D, et al. Tumor analyses reveal squamous transformation and off-target alterations as early resistance mechanisms to first-line osimertinib in EGFR-mutant lung cancer. 

. 2020;26(11):2654-2663. doi:10.1158/1078-0432.CCR-19-3563

13. Socinski MA, Jotte RM, Cappuzzo F, et al; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. 

. 2018;378(24):2288-2301. doi:10.1056/NEJMoa1716948

Articles

During a Targeted Oncology Case-Based Peer Perspective Roundtable, Mary Jo J. Fidler, MD, discussed targeting VEGFR and EGFR in patients with non–small cell lung cancer.

Dual VEGFR/EGFR Targeting Strategies Gain Prominence in NSCLC

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FDA Grants Priority Review to Narsoplimab for Treatment of Post-Transplant Complications

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Trending News on Targeted Oncology, Week of January 22, 2021

The third-generation ALK tyrosine kinase inhibitor (TKI) lorlatinib (Lorena) appears to be an encouraging new treatment option for patients with 

-positive non–small cell lung cancer (NSCLC) following results from the phase 3 CROWN study. This study demonstrated a significant improvement in progression-free survival (PFS), as well as higher overall and intracranial response rates, compared with crizotinib (Xalkori) in 

The median PFS was not estimable (NE) at the time of data cut-off for lorlatinib (NE; 95% CI, NE-NE) compared with 9.3 months with crizotinib (95% CI, 7.6-11.1), resulting in a 72% reduction in the risk of disease progression or death (HR, 0.28; 95% CI, 0.19-0.41; 1-sided 

The highly potent, brain-penetrant agent received its approval in November 2018, for the 

-positive NSCLC who have progressed on 1 or more ALK TKIs

, which must include crizotinib. More recently in December 2020, the FDA accepted a supplemental New Drug Application for 

lorlatinib and granted it a priority review as a potential frontline therapy for patients with

 Benjamin Solomon, MBBS, PhD, consultant medical oncologist, professor, group leader, Molecular Therapeutics and Biomarkers Laboratory, Research Division, Peter MacCallum Cancer Center, discussed the findings from the CROWN study that compared lorlatinib with crizotinib as treatment of patients with 

: What options are currently available to treat these patients with ALK-positive lung cancer?

-rearranged lung cancers account for about 5% of NSCLCs. They tend to occur in younger patients and in patients who have never smoked, but they can be found across the spectrum of clinical scenarios, so current guidelines recommend testing all newly diagnosed adenocarcinoma patients for 

rearrangements. One thing that we've learned is that these tumors are very sensitive to treatment without TKIs, and first-line treatment without TKIs has been established as a standard of care, firstly with crizotinib, a first-generation ALK inhibitor, and more recently with second-generation ALK inhibitors.

: What was the rationale to evaluate these agents head-to-head in the treatment of patients with ALK-positive NSCLC?

-rearranged lung cancers are sensitive to TKIs, resistance is a major problem, and patients progress on treatment without TKIs, and progression in the brain can be a particular problem. Lorlatinib is a highly potent brain penetrant ALK TKI. It's what we call the third-generation ALK TKI. It's already received approval in patients who have progressed on prior ALK TKIs. The aim of the study was to evaluate lorlatinib in the first-line setting in previously untreated patients with 

 The CROWN study is a randomized phase 3 study comparing lorlatinib to crizotinib in previously untreated 

-rearranged lung cancer. The study included eligible patients with previously untreated 

-positive NSCLC who were randomized to treatment either with lorlatinib 100 mg daily or crizotinib 250 milligrams twice daily. Stratification was based on the presence of brain metastases and ethnicity, and the primary end point of the study was PFS by blinded independent central review.

: What were the findings in terms of efficacy?

 The key findings with respect to efficacy, the study made its primary end point. Lorlatinib significantly prolonged PFS by blinded independent central review compared with crizotinib. The hazard ratio was 0.28, which was highly statistically significant, and the median PFS with lorlatinib has not been reached compared with 9.3 months for crizotinib. The 12-month PFS rate was 78% with lorlatinib compared to 39% with crizotinib. We also looked at a number of secondary end points in this study in these interim results of this analysis. PFS by investigator report was also positive for their hazard ratio of 0.21. The response rate was improved with lorlatinib at 76% compared to 58%, and that difference was significant.

One important finding of this study was evidence of intracranial activity with lorlatinib, so every patient on the study had baseline MRIs and serial assessment of disease in the brain with MRI scans, which was centrally reviewed. The intracranial objective response rate by independent review in patients with measurable brain metastases was 82% with lorlatinib compared to 23% with crizotinib, with an intracranial complete response rate of 71%. We also looked at time to intracranial progression, and the hazard ratio for time to intracranial progression was 0.07, which is a remarkable result. This speaks to the ability of lorlatinib, not only to delay progression of existing brain metastases, but to potentially prevent the formation of new brain metastases.

: How did the toxicity profiles of these agents compare with each another?

 Lorlatinib has quite a distinct toxicity profile to ALK inhibitors, and it's very important that as clinicians treating patients with lorlatinib, we understand the toxicity profile and how to manage these toxicities. What we saw is that grade 3/4 toxicities were more frequent with lorlatinib with crizotinib at 72% compared with 56%, but in terms of adverse events (AEs) leading to actual discontinuation of therapy, these were pretty similar, 7% for lorlatinib compared to 9% with crizotinib. The toxicities that we saw with lorlatinib in this study were similar to that which have been reported from the previous phase 1 and 2 studies. The most common AEs were asymptomatic elevations of cholesterol and triglycerides, which were quite easily managed with statins, but there are also other AEs, such as edema, a reversible peripheral neuropathy, and some cognitive effects, which are a distinct feature of lorlatinib. There were some toxicities that were seen that were more frequent with crizotinib, and these included gastrointestinal side effects such as nausea, diarrhea, and constipation as well as elevation of alanine transaminase and aspartate aminotransferase.

: What are the clinical implications of these findings?

 The study shows that lorlatinib is a highly effective first-line treatment option for newly diagnosed patients with 

-rearranged lung cancer. The activity in the brain is pretty remarkable, and we know that brain metastases are a devastating event for patients with lung cancer. The study clearly establishes lorlatinib as a new option for first-line treatment of 

: Are there any next steps planned for this study?

 It'll be important to get additional long-term follow-up. For example, the overall survival data are not mature, there being fewer than 20% of survival events. It'll also be important to try to understand mechanisms of resistance to lorlatinib to work out how we can provide even further benefits for patients with 

-rearranged lung cancer, but it's clear that ALK inhibitors such as lorlatinib have transformed outcomes for this patient population.

In an interview with Targeted Oncology, Benjamin Solomon, MBBS, PhD, discussed the findings from the CROWN study that compared lorlatinib with crizotinib as treatment of patients with ALK-positive non-small cell lung cancer.

Lorlatinib Demonstrates Promise for ALK-Rearranged Patients With NSCLC

y Case-Based Peer Perspectives Roundtable event, Alex Mejia-Garcia, MD, medical oncologist, Cleveland Clinic, discussed the use of daratumumab as treatment of multiple myeloma. Mejia-Garcia's discussion was based on the case scenario of a 51-year-old patient. 

™: What factors influence your choice of therapy in a patient with newly diagnosed multiple myeloma?

: The presence of comorbidities and patient preferences [play a role]. I think comorbidities is a big one. If a patient comes in and has a history of cardiac problems, I may stay away from the carfilzomib [Kyprolis]–based regimens. Peripheral neuropathy is an adverse effect [AE] of bortezomib [Velcade], and that’s something to keep in mind in patients with diabetes. Perhaps these patients are not going to do very well with a proteasome inhibitor [PI], bortezomib. Then there is the cost to consider, as well, and the infusions. I have patients who have mentioned the challenges with frequent visits, especially when they are treated with CD38 monoclonal antibodies. So, those are different factors that can influence the therapy that we choose for patients with newly diagnosed myeloma.

Do the National Comprehensive Cancer Network (NCCN) guidelines currently recommend daratumumab (Darzalex) as a subcutaneous injection?

There’s a new version of daratumumab, which is noted as a footnote in the guidelines.1 Daratumumab and hyaluronidase-fihj Darzalex Faspro] are now available as a subcutaneous injection.

The guidelines identify bortezomib [plus] lenalidomide [Revlimid] as the preferred regimen. That also includes the bortezomib/cyclophosphamide–based regimen. Other regimens include carfilzomib/lenalidomide/dexamethasone. The guidelines also discuss the ixazomib [Ninlaro]/lenalidomide/dexamethasone regimen, although a press release [stated that] this trial did not meet the primary end point. However, I think that numerical values were different in this regimen. They also touch on other useful circumstances in other regimens, including a chemotherapy approach with patients who have more of a plasma-cell leukemia.

The FDA approved the subcutaneous form in May 2020 and listed the indications that the intravenous [IV] version was approved for.

These indications included in combination with bortezomib, melphalan, and prednisone in patients with new diagnoses who are ineligible for autologous stem cell transplant [ASCT]; in combination with lenalidomide and dexamethasone in patients with new diagnoses who are ineligible for ASCT and in patients with relapsed/refractory multiple myeloma who have received at least 1 prior therapy; in combination with bortezomib and dexamethasone in patients who have received at least 1 prior therapy; and as monotherapy in patients who have received at least 3 prior lines of therapy, including a PI and an immunomodulatory agent or who are double refractory to a PI and an immunomodulatory agent.

Where would you use the quadruplet therapy for multiple myeloma?

The quadruplet therapy features the combination of daratumumab, bortezomib, thalidomide, and dexamethasone [VTd]. There is no survival advantage when the monoclonal antibody is added, although the response and depth of response are higher than with the standard of care [VTd]. I have not necessarily adopted a quadruplet approach in the front line. Perhaps it’s something we can delay considering until we get more information on survival benefit. I will stick, probably, with the triplet therapy.

I will point out that if we’re thinking that the patient is a candidate for an ASCT, we need to consider that in a quadruplet combination; we see a lot of cytopenias. We have to be careful about how long we use this regimen prior to collection or following with stem cell transplantation. So, I think that’s something to take care of, as well, and I will likely not use this regimen in more than 3 or 4 cycles before either collecting and continuing the approach or moving to an ASCT.

A number of studies have explored the addition of daratumumab to current standard-of-care treatment. Could you explain the main findings?

I can start with the oldest trial, the IFM trial [NCT01191060].

 The trial evaluated a group of patients who were randomized to receive bortezomib, lenalidomide, and dexamethasone and then moved on to transplantation or not. Those in the transplant group had better response rates and depth of response than those patients who did not undergo transplant. The investigators reported a complete response rate of 48% in the nontransplant group versus 59% in transplant group. The transplant group also had a higher depth of response. That was a rate of very good partial response [VGPR] or more of 88% versus 77%.

When progression-free survival [PFS] by minimal residual disease [MRD] was examined, those patients who received maintenance therapy had a higher PFS rate compared with the nonmaintenance group. These findings were reported at the beginning of the treatment and after maintenance lenalidomide.

I think one of the most important findings that this trial established is the benefit of stem cell transplantation and obtaining depth of responses. So, I think the transplant still has a role.

In the FORTE trial, a newer PI, carfilzomib, was evaluated [NCT02203643].

 Carfilzomib was [compared] with a combination containing cyclophosphamide followed by single stem cell transplantation—4 induction cycles followed by 4 consolidation cycles after stem cell transplantation using cyclophosphamide or lenalidomide. The trial also evaluated…whether or not patients will benefit from 12 cycles of carfilzomib, lenalidomide, and dexamethasone without transplantation. Patients were subsequently randomized to maintenance with either lenalidomide or a combination of lenalidomide and carfilzomib.

Based on this trial, we can see that the combination of a PI with an immunomodulator is probably better than the combination of a PI with chemotherapy and cyclophosphamide. Those patients who went to transplant or who received just 12 cycles of carfilzomib, lenalidomide, and dexamethasone had more than a VGPR...across the board.

The area of relapse was lower for those patients who proceeded to stem cell transplantation versus no transplantation. So, the PFS or the rate of relapses was lower, 8% versus 17%, and this was driven mostly by the patients with higher-stage disease.

The next question is “Which is the better PI when used in combination with an immunomodulator and dexamethasone?” And that was explored in the phase 3 ENDURANCE trial [NCT01863550].5 When the findings were presented, the trial did not meet the primary specified end point for PFS. There were a lot of safety signals in this trial. But some of the criticism of ENDURANCE is based on the actual design of this study. It’s confusing at first. You are randomizing these patients to different PIs, and then there is the second randomization of patients receiving or not receiving maintenance therapy with lenalidomide. I think it was somewhat expected, but if you look into the details of the presentation there was a lot of toxicity. That includes cardiopulmonary and renal toxicity.

But for those of us who have used carfilzomib/lenalidomide/dexamethasone with some frequency in the setting of clinical trials, as well as in the standard practice, monitoring the fluids around the infusion can affect cardiopulmonary toxicity. Once you can do that, cardiopulmonary toxicity is not that prevalent.

One of the criticisms I have for the trial is that I don’t think they describe how much fluid was given around this. The investigators did not explain the management process. But then again, this was a trial that did not meet the PFS end point, and I think we’ll hear more from that, as well.

Another criticism of the trial is that it excluded those patients who had high-risk features. I think that’s potentially important information that is missing.

How do you see 4-drug regimens fitting into the treatment landscape for a patient in our case?

I think it will have a role in the treatment landscape of patients with newly diagnosed multiple myeloma, but I think until there is longer follow-up in terms of survival data, it’s something that we have not adopted as a standard approach in the frontline setting. I think the depth of response is what we see with these combinations, and since we’re not measuring MRD on a standard basis, I’m not sure if we are adopting that at the beginning.

What were the key findings from CASSIOPEIA (NCT02541383)?

The CASSIOPEIA trial evaluated the monoclonal CD38 targeted agent daratumumab in combination with bortezomib, thalidomide, and dexamethasone.⁶ This was in patients who were newly diagnosed and transplant eligible. The trial was mostly conducted in European countries. These patients were randomized in 2 arms. They are containing VTd versus not VTd, followed by the second randomization in terms of maintenance therapy.

The primary end point for this trial was complete response [CR] rates, which are the stringent CR rates. The primary end point was met with a stringent CR rate of about 29% compared with 20% in those patients who did not [receive] daratumumab. Patients who had high risk did not benefit. Most of the benefit of this trial was seen in patients who were a standard risk. However, the conclusions were that daratumumab/thalidomide before and after ASCT was favored. That combination increased the depth of response and the PFS in this population of patients who are transplant eligible with newly diagnosed multiple myeloma.

If you were to have survival data, I would probably think this would be a better end point. However, the investigators did show a subgroup analysis that showed PFS. Since it was delayed, that’s probably another reason they showed obtainment of the depth of response rather than survival benefit. We’ll have to see with longer follow-up if this continues to be the case. I think these were our registration trials, and I think that was an accepted end point, but there are no overall survival [OS] benefit as of yet.

In this trial, a higher number of cytopenias, thrombocytopenia, and lymphopenia were observed in the treatment arm. And because they were using IV daratumumab, we are going to see a higher degree of drug-related reactions.

However, the proportion of those AEs that were grade 3 or higher was less in general but still higher in the group of patients who received daratumumab. They also had a higher degree of infections, as seen in this trial. Another consideration is that some of these patients went into transplant and they used chemotherapy to mobilize these cells. They used a cyclophosphamide- based regimen, which is also something that we are not using too much in this part of the world.

What were the differences between GRIFFIN and Cassiopeia?

The GRIFFIN trial [NCT02874742] was conducted in the United States, and the regimens evaluated more closely mirror what we use here, which is a combination of lenalidomide, bortezomib, and dexamethasone with or without daratumumab.

The induction cycle was probably shorter than in patients who were enrolled in Cassiopeia. The doses for dexamethasone were also lower; in Cassiopeia, it was 40 mg in phase 1 and phase 2. And so far, these were all 20 mg the day before and after, even.

Patients were randomized to daratumumab-RVd versus RVd. Some patients had stem cells collected, and then there was a consolidation for an additional 4 cycles followed by the maintenance phase, which was daratumumab/lenalidomide versus lenalidomide alone. Again, the primary end point for this trial is still stringent CR, similar to the Cassiopeia trial, and secondary end points are depth of response and survival outcomes.

In the trial, the alpha was 0.1 for a stringent CR. So, this is why the P value is a bit more than .05. However, that may define barriers. So, this was significant, 42% versus 32% stringent CR rate with the addition of CD38 daratumumab versus no daratumumab. Also, the postconsolidation depth of response was a similar number and increased in those patients who had the monoclonal antibody. We see that these responses deepened over time—at the end of induction, at the end of ASCT, and at the end of the 4 cycles of consolidation. Then, in the clinical cutoff, some data included the maintenance phase. So, we can see that this is a common approach that had additional benefits with transplant maintenance and the use of the monoclonal antibody in induction.

The investigators reported a higher degree of MRD negativity in those patients who had the daratumumab-based combination.

Safety profiles were somewhat similar to the Cassiopeia trial, especially regarding cytopenias and possible infusion-related reactions. Any-grade infections were higher in daratumumab/RVd versus RVd, 82% versus 55%.

Regarding the mobilization of the stem cells—even though, numerically, there was less with the use of daratumumab, lenalidomide, and dexamethasone compared with no daratumumab— these patients were successfully collected using the nonchemotherapy–based approach. These patients used a growth factor mobilization as needed. Those patients have collected successfully.

Regarding safety concerns with the quadruplet therapy, my only concern will be that if we are using this quadruplet therapy prior to transplant, you have to make sure not to use it too much. I’m somewhat concerned that the collection of stem cells might be an issue if we use, let’s say, 5 cycles or more. I would probably send this patient to transplant early on.

Are you using MRD assessment routinely in your practice?

I think, as a group, we are not using MRD outside of a clinical trial, in general. For some patients we are, but typically, it depends on the high-risk characteristics—also, whether the patient wants to defer stem cell transplantation. I think in the very knowledgeable patient, that’s come up a couple of times. I will still suggest collecting stem cells and perhaps, if they want to defer, I would be more at ease if I know they are MRD negative. But that is something we are not using across the board; a few cases here and there, but not standard of care yet.

Do you think it’s reasonable to consider it in a patient who’s been on maintenance for a period of time and wants to get off it?

I would consider it. I would consider it in standard-risk myeloma. In a patient who is high risk and MRD positive, I would not take him off maintenance. So, [standard risk] is the only setting I will use it in. But I guess we are kind of learning about this as we go. And as I said, everybody is different in terms of their approach. But I’m not sure if there’s a right or wrong answer here.

What do you think about these poll results?

It appears that the frequency of therapy administration has changed, opting for oral therapy over IV therapy. And the oncologists also chose “none of the above,” at 28%.

Which study led to the approval of the subcutaneous form of daratumumab?

The COLUMBA phase 3 noninferiority study that was conducted in patients who had relapsed/refractory multiple myeloma led to this approval [NCT03277105].

Patients were randomized to receive daratumumab subcutaneous, which is given at this dose of 1800 mg in comparison with the standard dose of daratumumab IV, which is 60 mg. The coprimary end points were overall response rate [ORR] and the maximum drug concentration.

The reason this trial was carried out is that the daratumumab IV infusion involves multiple visits, with a 10-hour infusion that is a barrier for some patients who work. They view this as cumbersome, to come in weekly and spend so much time in the infusion room, along with the infusion-related reactions.

During a Targeted Oncology Case-Based Peer Perspectives Roundtable event, Alex Mejia-Garcia, MD, medical oncologist, Cleveland Clinic, discussed the use of daratumumab as treatment of multiple myeloma. The discussion was based on the case scenario of a 51-year-old patient.

Targeted Oncology Staff | Authors

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