Adding a subcutaneous formulation of daratumumab (Darzalex Faspro) to the triplet regimen cyclophosphamide, bortezomib (Velcade), and dexamethasone (CyBorD) may hold promise for patients with newly diagnosed light chain (AL) amyloidosis who are in urgent need of new treatment options. Data from the phase 3 ANDROMEDA (NCT03201965) trial, which demonstrated the superiority of CyBorD plus subcutaneous daratumumab (Dara-CyBorD) versus CyBorD alone, were presented virtually during the 25th Congress of the European Hematology Association. The experimental combination resulted in deeper and more rapid hematologic responses and led to better clinical outcomes with an acceptable safety profile.

The combination of Dara-CyBorD therapy improved major organ deterioration progression-free survival (MOD-PFS) and resulted in substantially higher organ responses in patients with newly diagnosed AL amyloidosis, according to Efstathios Kastritis, MD, associate professor of clinical therapeutics/medical oncology at the National and Kapodistrian University of Athens in Greece.

Systemic AL amyloidosis is a rare disease characterized by insoluble amyloid fibril deposition in tissues and organs. There is no approved treatment, and about 30% of patients die within the first year of diagnosis. Treatment with the CyBorD combination has improved outcomes, but sustained hematologic response is needed to reverse amyloid-mediated organ dysfunction and improve overall survival.

The primary end point of the phase 3, randomized, open-label, active-controlled study was overall hematologic complete response (CR) rate in the intention-to-treat population. Secondary end points included MOD-PFS, organ response rate, time to hematologic response, survival, and safety.

Results showed that hematologic CR rate was 53% for Dara-CyBorD compared with 18% for CyBorD alone (OR, 5.1; 95% CI, 3.2-8.2; 

 <.0001). The 6-month organ response rate was nearly doubled for patients treated with the addition of subcutaneous daratumumab versus CyBorD alone for both cardiac (42% vs 22%) and kidney (54% vs 27%) responses.

The Dara-CyBorD combination achieved higher rates of overall hematologic response (92% vs 77%) and very good partial response or better (VGPR; 79% vs 49%) (FIGURE).

 Among responders, median time to VGPR or better was 17/60 days for the daratumumab arm compared with 25/85 days for CyBorD alone. MOD-PFS favored DARA-CyBorD-treated patients (HR, 0.58; 95% CI, 0.37-0.93; 

There were 388 patients randomized to either Dara-CyBorD (n = 195) or CyBorD (n = 193). All patients received weekly cyclophosphamide (300 mg/m

 orally or intravenously), bortezomib (1.3 mg/m

 subcutaneously), and dexamethasone (20-40 mg orally or intravenously) for six 28-day cycles. Subcutaneous daratumumab was administered weekly by injection in cycles 1 and 2, every 2 weeks in cycles 3 through 6, and every 4 weeks thereafter for up to 24 cycles.

The efficacy and safety profile of intravenous and subcutaneous daratumumab are well characterized. The agent showed no new safety concerns, according to Kastritis. The rate of discontinuation due to treatment-emergent adverse events (TEAEs) was 4% in both arms.

The most common grade 3/4 TEAEs occurring in more than 5% of patients treated on the daratumumab arm were lymphopenia (13% with Dara-CyBorD vs 10% with CyBorD), pneumonia (8% vs 4%, respectively), diarrhea (6% vs 4%), cardiac failure (congestive; 6% vs 5%), neutropenia (5% vs 3%), syncope (5% vs 6%), and peripheral edema (3% vs 6%). Fourteen patients (7%) experienced systemic administration-related reactions with daratumumab-CyBorD; all were grade 1/2 in severity, and most occurred during the fi rst infusion. A total of 56 deaths occurred in the entire trial, 29 patients treated with Dara-CyBorD and 27 who got CyBorD.

Daratumumab is the first and only subcutaneous CD38-directed antibody approved globally. In May of this year, the FDA approved the subcutaneous formulation alone and in combination for the treatment of adult patients with multiple myeloma.

The manufacturer responsible for producing daratumumab, Janssen Biotechnologies, collaborated with Halozyme Therapeutics to develop the subcutaneous form of the agent. Halozyme’s Enhanze system works to degrade hyaluronan, a polysaccharide found in the extracellular matrix of the subcutaneous tissue, thus allowing large volumes of the drug to be delivered in a single subcutaneous injection.

1. Kastritis E, Palladini G, Minnema MC, et al. Subcutaneous daratumumab + cyclophosphamide, bortezomib, and dexamethasone (CyBorD) in patients with newly diagnosed light chain (AL) amyloidosis: primary results from the phase 3 ANDROMEDA study. Presented at: 25th Congress of the European Hematology Association; June 11-21, 2020. Abstract LB2604. https://bit.ly/32eSmJU

2. FDA approves daratumumab and hyaluronidase-fi hj for multiple myeloma. FDA. May 1, 2020. Accessed July 13, 2020. https://bit.ly/2BYcnKd3

3. Enhanze drug delivery technology. Halozyme. Accessed June 3, 2020. https://bit.ly/3fqTjm2

Articles

Clinical Articles

Adding a subcutaneous formulation of daratumumab to the triplet regimen cyclophosphamide, bortezomib, and dexamethasone may hold promise for patients with newly diagnosed light chain amyloidosis who are in urgent need of new treatment options, according to a clinical trial.

Patients With AL Amyloidosis May Benefit From Subcutaneous Daratumumab/CyBorD Combination

Leslie M. Randall, MD, MAS, professor, Department of Obstetrics and Gynecology Division Director, Division of Gynecologic Oncology, Virginia Commonwealth University, discussed the treatment regimens available for an African American patient with ovarian cancer. 

™: Are you choosing oral regimens over intravenous regimens because of coronavirus disease 2019? Are you making changes to therapy schedules and dosages or choosing different agents?

I’ve tried to change to oral [treatment] where I could. We don’t have a lot of options for oral gynecologic oncology. It’s why the data I’ll be talking about are exciting. Mostly in my purely palliative-intent chemotherapy, I’ve definitely de-escalated doses and schedules. I’ve used more growth factor support, trying to keep people out of the hospital for things that can be prevented, like neutropenia and sepsis. So I’ve changed my practice in that way.

What testing would you order for this patient? Do you typically test for 

and somatic mutations? And, if so, how do you test and when?

We have to test for germline mutations, for the benefit of the family and the patient, to understand their breast cancer risks. I think “Do you have to do somatic testing anymore?” is the debate. If you have a patient with a germline 

mutation, you don’t need to somatic test.

I think many of us still believe that we need to test in order to counsel our patients on what the magnitude of benefit would be—maybe to [switch] our patients who are biomarker negative off therapy and onto something else sooner, if we felt like they weren’t receiving benefit from niraparib [Zejula]. If the drug is approved for all-comers, do you have to test? I think you still have to get a germline 

test, but if you’re not going to change your management based on the results of a somatic 

or a homologous recombination deficiency [HRD] test, it’s a great question.

How do you use HRD testing in this patient population?

The Myriad HRD assay accompanied niraparib with the FDA approval [documentation].1 [The manufacturer] had hoped for a companion diagnostic, but they got a complementary diagnostic. It was because the assay was not discriminatory enough to show that the benefit was isolated to the germline in the HRD [population]. There was still a benefit outside that population. Plus, I don’t feel like the [cutoff] point has been sufficiently defined for the Myriad assay.

Interestingly, the Myriad assay includes the somatic 

mutations, but it does not include the other mutations. So the benefit of getting a Foundation Medicine Somatic 

test, [for example], is that you get all the other mutations, including the microsatellite instability [MSI]. That would be available on many other assay platforms, such as CARIS. But [if] you’re not going outside MSI, you probably wouldn’t use that information in the frontline setting for treatment anyway. We may want to use that later, and then you may want to retest later, because the tumor could change. So I think that we’re all over the map right now in the testing realm, but I think the 1 thing that remains certain is that you still have to germline-test these patients.

Do you explain to patients what the National Comprehensive Cancer Network (NCCN) guidelines say about HRD?

The NCCN guidelines state that in the absence of 

mutations, HRD might provide information on the magnitude of benefit of PARP therapy.2

When I first started [practicing], I thought that it was important to counsel patients about [NCCN guidelines], but in my opinion [now], that doesn’t mean a lot to them. They’re either going to respond to therapy or they are not. What the magnitude of benefit was on the women enrolled on a clinical trial may or may not apply to the patient who is sitting in front of you. Every now and then, you have a patient who’s a scientist or physician, or who understands granularity of data, and they want to know those things. But I would say my average patient is not informed by those data.

What are the different molecular testing assays available for this patient?

The Myriad myChoice HRD test is a tissue-based test.3 This measures 3 different phenotypic changes that denote HRD. One of those is loss of heterozygosity [LOH], [and the others are] telomeric allelic imbalance and large-scale state transitions. This gives you a myChoice score. The PRIMA trial used 42 as a cutoff for the score.4 The VELIA trial used the same assay and used 33 as a cutoff.5 The thought is that the lower you set the cutoff, the more sensitive the assay is to pick up HRD; however, those [cutoff] points have never been rigorously tested or rigorously determined by Myriad.

Foundation Medicine has a similar assay called the 

LOH assay.6 It’s a complementary diagnostic to rucaparib [Rubraca] that was approved when rucaparib got its platinum-sensitive recurrent maintenance indication, and it reads out a similar score, but, unlike the Myriad myChoice HRD test, it does not include telomeric allelic imbalance and large-scale state transitions. The idea of these assays is to detect 

-like changes in the cell for reasons other than a 

mutations. It would not explicitly diagnose them, but it would pick up that dysfunction. So I call these the phenotypic versus the genotypic assays.

Does the LOH assay from Foundation Medicine have a cutoff?

They have a percentage, but their cutoff has never been studied. The LOH was studied in the rucaparib trial, ARIEL3 [NCT01968213], but that’s the only trial.⁷ The ARIEL2 trial [NCT01891344], which established LOH as a marker of rucaparib sensitivity, was investigated by Elizabeth Swisher, MD, at the University of Washington, and it’s a different LOH assay from the one that was used by Foundation Medicine.⁸

But Foundation Medicine had a commercial assay, and when the program went to phase 3, they needed an assay that could be done commercially if they got approval [of the drug that was] conditional with the companion [assay]. But it did not receive companion designation; it received complementary designation, just as the myChoice got complementary designation for niraparib. The designation applied to both the NOVA and PRIMA trials.

What would you use as therapy for this patient?

This patient has stage IIIC ovarian cancer and optimal resection. Her tumor is 

[Options are] carboplatin and paclitaxel, carboplatin and bevacizumab [Avastin], and then carboplatin and liposomal doxorubicin. Most of us would use carboplatin and liposomal doxorubicin more in a recurrent setting, but that’s acceptable treatment—especially for someone who’s not tolerating a taxane. Most [physicians] would typically start with carboplatin and paclitaxel.

At this point, what would you recommend for this patient?

This patient was treated with paclitaxel and cisplatin, which we don’t do often, but when we do, it’s to treat these patients with low risk and no residual disease. After completion, CA-125 was within the normal limits, and she was clinically without disease.

[The main options are] observation or niraparib.

If you start with niraparib and there are some issues with dosing, would it be a possibility to transition to drugs such as olaparib or rucaparib?

We have no data on that, but there are [physicians] who do that. I think for this patient, who has a germline wild-type mutation, you would start with niraparib. We didn’t get too much granularity on the adverse effect profile.

For niraparib, the investigators tested the weights [of the patients] and platelet [counts per] dose. We know that thrombocytopenia is [high] with niraparib at the 300-mg starting dose, but you can decrease that by more than 50% if you drop that starting dose to 200 mg specifically in patients who weigh less than 77 kg or have platelet counts less than 150,000 μL [

What will be interesting to see, which will be reported soon, are the efficacy data between the 2 doses. The platinum-sensitive niraparib trial, NOVA, reported that most of the patients were dose-reduced. Only 23% of the patients remained on that 300-mg dose because of the thrombocytopenia. They did not show an efficacy difference.

I would rather switch to another PARP inhibitor than my patient not have the chance to get a PARP. I think they’ve demonstrated sufficient activity, and PARP is probably—as many other drugs we give—the most effective the earlier we give it. While it’s not on label per se, I would rather try another PARP inhibitor than not use PARP at all, and I’ve done that in my practice.

Did you use niraparib as soon as data came out for it, or did you wait for the approval?

I know many people who started using niraparib after the European Society for Medical Oncology Annual Congress 2019, and they were getting it approved. I did not; I didn’t use it until the approval came, and that’s just kind of how I function and practice. If I had a patient who was highly motivated to receive it, I probably would have tried to get it for her, but I did not use it until the approval.


1. FDA approves niraparib for HRD-positive advanced ovarian cancer. FDA. October 23, 2019. Accessed May 21, 2020. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-niraparib-hrd-positive-advanced-ovarian-cancer

2. myChoice CDx. Myriad. Accessed May 21, 2020. myriad.com/products-services/ precision-medicine/mychoice-cdx/

3. NCCN. Clinical Practice Guidelines in Oncology. Ovarian cancer, version 1.2020. Accessed May 21, 2020. NCCN.org/professionals/physician_gls/pdf/ovarian.pdf

4. González-Martín A, Pothuri B, Vergote I, et al; PRIMA/ENGOT-OV26/GOG-3012 Investigators. Niraparib in patients with newly diagnosed advanced ovarian cancer. 

. 2019;381(25):2391-2402. doi:10.1056/NEJMoa1910962

5. Coleman RL, Fleming GF, Brady MF, et al. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. 

. 2019;381(25):2403-2415. doi:10.1056/NEJMoa1909707

6. FoundationOne CDx technical information. Foundation Medicine; 2017. Accessed May 21, 2020. rochefoundationmedicine.com/f1cdxtech

7. Coleman RL, Oza AM, Lorusso D, et al; ARIEL3 Investigators. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. 

. 2 017;390 (10106):1949-1961. Published correction appears in 

. 2017;390(10106):1948. doi:10.1016/S0140-6736(17)32702-2

8. Swisher EM, Lin KK, Oza AM, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. 

. 2017;18(1):75-87. doi:10.1016/S1470-2045(16)30559-9

9. Mirza MR, Monk BJ, Herrstedt J, et al; ENGOT-OV16/NOVA investigators. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. 

2016;375(22):2154-2164. doi:10.1056/NEJMoa1611310

10. Berek JS, Matulonis UA, Peen U, et al. Safety and dose modification for patients receiving niraparib. 

. 2018;29(8):1784-1792. Published correction appears in 

2019;30(5):859. doi:10.1093/annonc/mdy255

Leslie M. Randall, MD, MAS, discussed the treatment regimens available for an African American patient with ovarian cancer. 

Randall Discusses Testing and Treatment Choices for Ovarian Cancer

Robert A. Vescio, MD, medical director Multiple Myeloma and Amyloidosis, Program Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, discussed two treatment options for a 51-year-old male patients with newly diagnosed multiple myeloma.

™: The standard treatment in general for multiple myeloma is bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone, or the VRd regimen. When would you consider using the cyclophosphamide, bortezomib, and dexamethasone (CyBorD) regimen? 

: That regimen is more useful in treating amyloidosis. I believe that lenalidomide has been challenging for some patients with amyloidosis, I think mainly because of the clotting that can occur, which can lead to nephrotic syndrome. This is the regimen that I tend to use, but I’m not certain that that’s the best regimen for these patients.

Have you been using carfilzomib (Kyprolis), lenalidomide, and dexamethasone for patients with multiple myeloma as initial treatment? 

If the patient is experiencing peripheral neuropathy prior to treatment, I’ll substitute a proteasome inhibitor. Instead of Velcade, I’ll use carfilzomib if they have neuropathy. Given [a preexisting condition], it’s hard to embark on a regimen with bortezomib. It’s not always approved by insurance companies. But when I have used it, it has worked well. Insurance companies sometimes play a role [when deciding on treatment].

Have you encountered diastolic dysfunction in patients when treating with carfilzomib?

 I haven’t encountered patients experiencing diastolic dysfunction. I think patients are more likely to develop cardiac dysfunction with carfilzomib over bortezomib. I treated a gentleman with amyloidosis, and he developed reversible cardiomyopathy from the drug. It is definitely something you have to watch out for. Some [patients] get significant congestive heart failure [within] 3 months [of starting] their treatment. It seems that once they get beyond that [period], it doesn’t seem to occur.

What are the data to support quadruplet therapy for newly diagnosed multiple myeloma? 

Some studies have looked at typical regimens that use VRd with a stem cell transplant [SCT]. Michel Attal, MD, and colleagues compared VRd with and without SCT to determine whether there was a benefit for SCT [NCT01191060].

 The standard regimen of VRd and an SCT led to about a 78% VGPR [very good partial response] rate versus 69% without a transplant. Adding a transplant to carfilzomib therapy did not achieve much more of a benefit.

CASSIOPEIA [NCT02541383] evaluated the benefit of adding daratumumab [Darzalex] to bortezomib, thalidomide [Thalomid], and dexamethasone [VTd] versus VTd, so a quadruplet therapy versus a triplet therapy.

The trial evaluated adults less than 65 years of age. The median age of the patients in the trial was 58 years, and most were standard-risk patients. Patients were randomized 1:1 to receive VTd with or without daratumumab.

After 4 cycles, patients received a SCT. This was followed by 2 more cycles of VTd with or without daratumumab. Arm A did not receive daratumumab, and arm B received daratumumab. After this step, patients were randomized again and observed or received daratumumab every 8 weeks until progression.

Please describe the efficacy in the CASSIOPEIA trial. 

The primary end point was response, including the response after the transplant. The patients all had the transplant, and then they went on to get more cycles of either VTd or daratumumab with VTd. Then stringent complete remission [sCR] was observed to be higher in the daratumumab arm [29% vs 20%; 

 = .001]. The CR rate was also improved in the patients who received daratumumab, 39% versus 26%.

The investigators also noted that MRD [minimal residual disease]–negative rates were higher, as well, 64% versus 44% [in patients who received daratumumab].

What was impressive were the higher CR rates and sCR rates if patients received the daratumumab plus VTd, as well as the higher MRD-negative rates. But what was most impressive was the good progression-free survival [PFS] rates for the daratumumab plus VTd arm, with 1.5-year PFS rates approaching 90% and a hazard ratio of 0.47. So it looks promising from those results.

I have a patient who is on this regimen, and he is debating whether to do a transplant, with the whole COVID-19 [coronavirus disease 2019] scenario that we’re dealing with. He asks a lot of questions; I tend to get a lot of those types of patients. I showed him the [PFS] rates, and he was happy to see how well [patients] do if they go ahead with a transplant.

Now, if you start giving patients 4 drugs, the question [of extra adverse effects] remains. It was well tolerated. The daratumumab has some infusion reactions. There are a few patients who had secondary malignancies, which is a continuing concern, but not much else. I think daratumumab adds to bone marrow suppression. So at first, it didn’t seem to make much sense to me that daratumumab, when given as monotherapy, caused a lot of bone marrow suppression. But when it’s added in clinical trials, the rates for grade 3 and grade 4 neutropenia were higher [29% vs 15% for grade 3 and 4, respectively], thrombocytopenia was higher [11% vs 4% for grade 3/4], and lymphopenia was higher [17% vs 10% for grade 3/4].

Overall, [this] is a well-tolerated regimen. I’ve started to give it more, mainly using it more often for my younger, pretransplant patients.

The other trial that is getting a lot of [attention] is the GRIFFIN trial [NCT02874742].3 It hasn’t been fully published yet. The regimen [in that trial] is VRd with or without daratumumab. That’s the easiest way…of thinking about it.

When you administer VRd for a patient, do you choose the day 1, 4, 8, and 11 regimen or the once-a-week regimen? 

I tend to use it once a week for most patients, unless there’s some immediate need, such as if the patient is in the hospital with renal failure, and I’ve put them on CyBorD. Then I’ll maybe give the day 1, 4, 8, and 11 regimen to get a quick response.

For convenience, the once-a-week regimen is good for patients who do not want to drive. It also results in less neuropathy for the patient. I have patients who have received bortezomib 8 or 10 years ago, and they’re still complaining about the [subsequent] neuropathy.

In GRIFFIN, patients followed the day 1, 4, 8, and 11 regimen. They all had a transplant after 4 cycles. They went on to have more consolidation, followed by a maintenance regimen with either lenalidomide alone or lenalidomide plus daratumumab.

We don’t have the final answers yet, but what we do have is response rates, and the investigators reported that by the end of consolidation, all patients had responded, and during maintenance, there was a 63% sCR rate. I’ve never seen that in any other clinical trial. It looks promising.

Post consolidation, the overall response rate was 99% in patients who received daratumumab versus 91% for patients who did not. It’s still good without the daratumumab. Response rates continued to improve over time, as you might anticipate with very good response rates in the daratumumab-containing arm. The MRD-negative rates were high, with 68.8% of patients in the daratumumab arm and 32.3% of patients in the control arm reported.

The adverse effects were well tolerated and comparable between the 2 groups. There was more grade 3/4 neutropenia in the daratumumab arm [32% vs 15%] and more thrombocytopenia [16% vs 8%] and not much else that was different.

Do oncology centers still use tandem transplants for patients in this setting? 

There are still cancer centers that conduct tandem transplants. It’s difficult to carry out a great randomized trial, however. The early data suggested that [patients] who are not in remission benefited by doing the tandem transplant. The past couple of [patients] I’ve done it for were those who didn’t seem to respond well to their initial therapy, and then the transplant itself was profoundly effective for them. It was clearly their best treatment, and they tolerated it reasonably well. I think you have to be a pretty good salesman to persuade [patients] to undergo 2 transplants, though.

Would you consider a bortezomib-free regimen in non– high-risk patients? 

I would still use a proteasome inhibitor until proved otherwise for those patients who have the high-risk features—those with translocation(14;20), translocation(14;16), or the 17p deletion abnormalities in their myeloma cells. It does seem the proteasome inhibitors work best in them. But maybe we could get by without proteasome inhibitors in other patients? It’s a good thought.

What kind of schedule do you use for dexamethasone? 

I give it weekly because I usually give bortezomib weekly. So if they take Velcade, I try to give dexamethasone the day they get bortezomib. It helps with nausea and reduces some of the adverse effects they get from the bortezomib. So I tend to base dosage on the frequency of the bortezomib. This is similar with carfilzomib, whether it’s once-a-week or twice-a-week regimens. The patients are coming in for infusions anyway, so I tend to give it with the drug. But I don’t think there’s a right answer to that.

Are you comfortable switching patients from Ninlaro (ixazomib) to Velcade, given the current COVID-19 environment? 

I have not done that; I’ve kept patients on treatment. I guess my colleagues and I were focused on transplant versus no transplant during [COVID-19]. We’re back up to doing transplants. So far, so good. I know the Dana-Farber [Cancer Institute] made changes to move [patients] to oral regimens.

I had one woman who had her transplant right before this all happened, and then her husband, who travels for his job, came down with it. He tested positive. She had undergone a transplant 1.5 months prior.

She shipped him out of the house, and he recovered, and she never got sick. I didn’t test antibody titers for her. So it’s kind of strange; the whole process is kind of hard for me to understand. I haven’t had anybody get significantly ill from it, but I also had only 1 person get COVID-19, and he’s not on treatment.

1. Attal M, Lauwers-Cances V, Hulin C, et al; IFM 2009 Study. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376(14):1311-1320. doi:10.1056/NEJMoa1611750 

2. Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study Lancet. 2019;394(10192):29-38. doi:10.1016/S0140-6736(19)31240-1 

3. Voorhees PM, Kaufman JL, Laubach JP, et al. Daratumumab, lenalidomide, bortezomib, & dexamethasone for transplant-eligible newly diagnosed multiple myeloma: GRIFFIN. Blood. Published online April 23, 2020. doi:10.1182/blood.2020005288

Robert A. Vescio, MD, discussed two treatment options for a 51-year-old male patient with newly diagnosed multiple myeloma.

Vescio Debates Quadruplet Versus Triplet Therapy in Newly Diagnosed Multiple Myeloma

In a live case-based peer perspectives discussion, Alicia K. Morgans, MD, MPH, associate professor of Medicine (Hematology and Oncology), Northwestern University Feinberg School of Medicine, Chicago, IL, reviewed treatment and testing strategies for metastatic castration-resistant prostate cancer (mCRPC), based a real case of 75-year old patient. 


™: What are your initial impressions of this case? Do you agree with the treatments used?

: At this point, if we consider this gentleman’s prognosis, we recognize that he received a diagnosis of an initial high-risk localized prostate cancer. Although he was getting his initial therapy that his care team hoped would cure him of his disease, he had progression of disease. He developed meta-static castrate-resistant prostate cancer [CRPC] while on initial androgen deprivation therapy, which is a poor prognostic sign. His second sign of poor prognosis was that, in terms of disease control, he lasted only about 8 months on enzalutamide. 

Enzalutamide in the first-line setting for metastatic CRPC can typically last—or we hope will last—at least 12 months and ometimes a little longer. For this patient, disease control was maintained for only 8 months. Those are 2 signs that this patient had an aggressive disease, and we know it’s already metastatic, making his prognosis poor and making it important for us to find a highly effective therapy that uses a different mechanism of action than an androgen receptor [AR]–directed therapy to get the disease down and allow him to maintain quality of life and disease control.

Would you order biomarker testing for this patient? If so, which would you order?

It’s important to consider in metastatic prostate cancer that biomarkers are a critical aspect of our treatment decision making. Biomarkers can include things like DNA-repair defect markers, and this is important in any patient with metastatic disease. We would determine this with germline genetic testing and somatic genomic testing of the tumor tissue. Both are important in understanding whether there may be a targetable DNA-repair defect mutation. We would target these mutations with things like PARP inhibitors. In the third-line metastatic CRPC setting, it might be a good opportunity to use this treatment.

When we think about other biomarkers [such as] AR-V7 [andro-gen receptor variant 7], I wouldn’t necessarily use that marker in this patient, because we already know that he has been exposed to enzalutamide and likely has a cancer that’s resistant to an AR-directed therapy. Having a test showing that he did or did not have the expression of AR-V7 wouldn’t necessarily change my decision process about giving him another AR-directed therapy. I wouldn’t do it because I already know that he has developed resistance and developed it in a relatively short [time].

That’s not a test I would order, but I would order genetic testing and genomic testing to make sure I understood if this patient had a DNA-repair defect that can be targeted. When this patient was tested for DNA-repair defects, he did not have anything in his germline or tumor tissue that was targetable with a PARP inhibitor. 

How do you decide on treatment for the patient population with progressive disease?

When deciding on treatment for patients with metastatic CRPC after progression on an AR-directed therapy, I consider whether he disease is symptomatic or asymptomatic. We could consider using sipuleucel-T [Provenge] in patients who have a low burden of metastatic disease and are completely asymptomatic. We are also thinking about whether patients have liver metastases, because we did not test sipuleucel-T in the phase III trial that led to its approval in patients with liver metastases.

With this patient, we know that he has had some symptoms and a high PSA at the time of his recurrence. Usually, we think about things like sipuleucel-T in patients who do not have any pain or are relatively asymptomatic and also have a relatively low PSA. Those are the patients in whom we think it will work best.

What factors and other therapy options should be considered for this patient? 

I would think about other exposures. This patient received chemo-therapy, and so in the setting of exposure to an AR-directed therapy and chemotherapy, I would want to change the mecha-nism of action away from an AR-directed therapy and focus on things like PARP inhibitors if the patient had DNA-repair defect; another chemotherapy if the patient did not have that defect; or, potentially, radium, which could be an option in patients who have only bone metastases, no lymph node metastases, and no visceral disease.

For this patient, we know he started with lymph node meta-static disease, so radium would not be expected to maintain disease control because it does not affect any disease outside the bone. Chemotherapy would be my choice [for him]. Even though he’s had progression on docetaxel chemotherapy, we know that switching to cabazitaxel [Jevtana] chemother-apy can be highly effective both in terms of pain control and prolonging life. 

Why do patients benefit from the use of cabazitaxel? Please discuss the trial that showed these benefits. 

When I think about tolerance to chemotherapy, particularly the tolerance of cabazitaxel, I think about some studies that were done for cabazitaxel that demonstrated that at the 20 mg/m

 dose, [patients] had less fatigue and less neuropathy than docetaxel at a standard dose of 75 mg/m

. Cabazitaxel in my clinic and in those trials is quite well tolerated, even in older patients.

We could consider using sipuleucel-T in patients who have low burden of metastatic disease and are completely asymptomatic. We are also thinking about whether patients have liver metastases, because we did not test sipuleucel-T in the phase III trial that led to its approval in patients with liver metastases.” 

What we saw in the CARD trial [NCT02485691] was that cabazitaxel was better tolerated than a second-line AR-targeted agent in patients who had already had progression on AR-targeted agent and at least 1 line of chemotherapy.

 For those patients, there was a longer time to pain progression, and they had a better pain response than patients treated with a second AR-targeted agent. These patients felt better than those on what we normally consider to be tolerable treatments. Even in older patients or in patients who have pain, cabazitaxel chemotherapy can be well tolerated with relatively low neuropathy and fatigue compared with other chemotherapy agents, and we would want to [help] these patients with our supportive measures. We can get them through it, and they seem to tolerate it well.

In the CARD trial, patients who had metastatic CRPC and had progressed on 1 AR-targeted agent and docetaxel chemotherapy were randomized to receive treatment with the other AR-directed therapy or cabazitaxel at its standard dose, 25 mg/m

, plus pegfilgrastim. Patients were followed for radiographic progres-sion-free survival [PFS] and overall survival [OS] in this trial.

Describe the efficacy and the toxicity profile of this trial.We found that patients had prolonged PFS and OS in the CARD trial.

 Importantly, the CTCAE [Common Terminology Criteria for Adverse Events]–graded events, which tell us about the toxicity of the agents, suggested that the chemotherapy did not have any adverse effects [AEs] outside its traditionally considered AE profile. There were more grade 5 AEs leading to death in the arm of patients who were treated with the AR-targeted therapy and fewer grade 5 events in those who received chemotherapy.

These patients had a better pain response when they were treated with chemotherapy, probably because of better disease control. We saw that this was what I consider a practice-changing study in that it defined for us a path forward in the third-line setting in metastatic CRPC, where we had not had trials that told us what happens to patients who already received first- and second-line treatments for patients with metastatic CRPC.

Patients seemed to tolerate the treatment well—as I said, both in terms of CTCAE and patient-reported outcomes—with their overall quality of life also reported to be better when they were treated with cabazitaxel compared with the AR-directed therapies at the 3-month assessment by the overall quality-of-life measure, FACT-P [Functional Assessment of Cancer Therapy-Prostate]. The drug was well tolerated and ultimately improved survival in this heavily pretreated third-line metastatic CRPC population.

Do any data support the use of sequential AR-targeted therapies in this setting?

When I think about using a second AR-targeted agent after exposure to and progression on a prior AR-targeted agent in the metastatic CRPC setting, I talk to patients about the inadequacy of that therapy, sequencing, and my expectation that the treatment probably will not help them. This has been demonstrated in the control arm of the CARD trial, but it has also been demonstrated in other settings.

For example, in the phase III PROfound trial [NCT02987543] that looked at men with metastatic CRPC who had DNA-repair defects, men were randomized to treatment with olapa-rib [Lynparza] or the other AR-targeted agent [enzalutamide or abiraterone (Zytiga)]. This was in patients who had already progressed on chemotherapy and an initial AR-targeted agent. We saw that the radiographic PFS of that control arm, the second AR-targeted agent, was about 3.5 months, which is similar to what we saw in the CARD trial.

We are consistently seeing in patients who have already progressed on an initial AR-targeted agent—whether they progress within 12 months, as they did in the CARD trial, or whether they simply progress at any time point, which they did in the PROfound trial—that the expected time to controlling disease and preventing radiographic progression is short.

And the reason it’s probably around a 3-month time point is because that is when they were doing the radiographic assessment. Most of these patients are progressing on the first or the second radiographic assessment, suggesting that we’re not controlling the disease growth. 

There are a few patients who may respond to a second AR-targeted agent. Usually I think about use of enzalutamide after abiraterone being potentially more effective, but this is not my first choice, and it’s something I highly recommend patients consider
 Case-Based Peer Perspectives Spotlight 55Case-Based Peer Perspectives Spotlight 55not doing, because we know that the mechanisms of resistance are similar. Especially in settings where we have an aggressive cancer and need to control the disease, doing this is not expected and could waste time for patients, leading to decline in functional status, potentially closing the door for them to get something like chemotherapy, which may prolong their life. But this has to be given in patients who are well enough to tolerate it.

How do you decide on sequencing for the available regimens in this setting?

When I think about treating patients with metastatic CRPC, I think about all the agents we have at our disposal, and there are many. The most important thing to me, when I’m thinking through their next treatment, is understanding what they had in the past and how we can use a diff erent mechanism of action for their next line of treatment to sequence one therapy after another—hopefully, prolonging time and quality of life multiple times over by sequencing available treatment options that patients have over time. For example, if a patient has had an AR-targeted agent and docetaxel chemotherapy, the things I think about next will be something with a new mechanism of action or something that has demonstrated that after those 2 agents, it can still be eff ec-tive in terms of prolonging life and making patients feel better.

The option could be, in an asymptomatic patient, sipuleucel-T, although if this is a heavily pretreated population, most patients seem to benefit with sipuleucel-T. For cabazitaxel chemotherapy, we now have the CARD data to show that we can certainly sequence it and, in the third-line setting, prolong life and improve quality of life. Or perhaps we could use radium in patients who have only bone metastases and no lymph node metastases or visceral metastases.

I also always think about sequencing a patient’s DNA and the tumor DNA to understand whether there are genetic germline mutations that may be targetable or somatic genomic mutations in the tumor tissue. We can use PARP inhibitors to potentially target these DNA-repair defect mutations that make patients sensitive to these drugs.

Would you use regimens that are being examined in clinical trials? 

I [will] think about clinical trials and expanding the options for patients by giving them something that’s not yet FDA approved. There are multiple things, whether they’re radiopharmaceuti-cals, AR-degrading agents, or other combinations that may be eff ective that we’re just starting to understand. These options are available only through clinical trials, so that is always some-thing I think about, as well.

The landscape of treatment for patients with metastatic CRPC is changing rapidly and dramatically, with options demonstrating efficacy in both prolonging OS and maintaining quality of life. This includes treatments we’ve already had approved, such as cabazi-taxel, as well as things on the horizon, like PARP inhibitors.

 It also includes things that are still to come, such as radiopharmaceuticals or other agents—whether they are vaccines, AR degraders, or other approaches that are new for our patients. 

There are so many options that it’s important for us to consider what patients have had before and think about changing the mechanism of action, or using treatments that we know can be effective after exposure to these other agents, to get the best results for our patients and not waste time with things that we think have a low likelihood of working. Because when we waste time, it’s not only the potential for other treatments that we waste but patients’ quality of life suffers, as well. The landscape is changing. There are many opportunities, and it’s an exciting time to be a treating physician for men with metastatic CRPC. 

1. Provenge. Prescribing information. Dendreon Pharmaceuticals LLC; 2017. Accessed April 24, 2020. provenge.com/Portals/_default/skins/provengedtc/downloads/PRV.0039.USA.18-%20Provenge%20Prescribing%20Information.pdf 

2. Oudard S, Fizazi K, Sengeløv L, et al. Cabazitaxel versus docetaxel as fi rst-line therapy for patients with metastatic castration-resistant prostate cancer: a randomized phase III trial-FIRSTANA. J Clin Oncol. 2017;35(28):3189-3197. doi:10.1200/JCO.2016.72.10683. 

3. de Wit R, de Bono J, Sternberg CN, et al; CARD Investigators. Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer. N Engl J Med. 2019;381(26):2506-2518. doi:10.1056/NEJMoa1911206

4. Sandhu SK, Hussain M, Mateo J, et al. PROfound: phase 3 study of olaparib versus enzalutamide or abiraterone for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene alterations. Ann Oncol. 2019;30(suppl 9):ix188-ix189. doi:10.1093/annonc/mdz446.0075.

5. FDA approves lower dose of cabazitaxel for prostate cancer. FDA. Published September 14, 2017. Accessed April 23, 2020. fda.gov/drugs/resources-information-approved-drugs/fda-approves-lower-dose-cabazitaxel-prostate-cancer

Alicia K. Morgans, MD, MPH, discussed treatment and testing strategies for metastatic castration-resistant prostate cancer. 

Morgans Discusses How to Sequence Therapies in Metastatic CRPC

 case-based peer perspectives live discussion, David H. Ilson, MD, PhD, medical oncologist, Memorial Sloan Kettering Cancer Center, New York, NY, discusses the treatment options for patients with hepatocellular carcinoma (HCC).

Would you consider a liver transplant for this patient? What are the frontline options in this setting?

Liver transplant is reserved for patients with HCC who have liver dysfunction. In a patient with a healthy liver, hepatic resection is the up-front treatment for this disease, and he under-went hepatic resection.

Then, 6 months later, he had metastatic disease and was started on standard sorafenib 400 mg twice daily and toler-ated it well. Alternatives to sorafenib in the first line [are] lenvatinib [Lenvima], which is also a multitargeted tyrosine kinase inhibitor.

Please describe the data for these 2 therapies.

This was the subject of the REFLECT trial [NCT01761226], a large, randomized trial in nearly 1000 patients with untreated HCC. Stratifi cation included the region they were treated, and they were randomized 1:1 to lenvatinib versus sorafenib with a primary end point of overall survival [OS]. The investigators were trying to demonstrate that lenvatinib was noninferior to sorafenib. Secondary end points were progression-free survival [PFS], time to progression, and response rate.

Lenvatinib was noninferior to sorafenib in OS, but there were trends suggesting better PFS for lenvatinib, better time to progression, and a higher response rate for lenvatinib over sorafenib. But in terms of the primary end point, lenvatinib was noninferior; it was not superior with suggestion of a better PFS and response rate.Based on these data, lenvatinib has been approved.

 Adverse effects [AEs] with lenvatinib were more hypertension, diarrhea, and anorexia; there was incidence of more hand-foot syndrome and cutaneous toxicity with sorafenib. There was a suggestion of a longer treatment duration for lenvatinib over sorafenib and a slightly higher rate of discontinuation for AEs.

What other drugs are being evaluated for this patient population?

The IMbrave150 trial [NCT03434379] recently reported results. This was first-line treatment with atezolizumab [Tecentriq] plus bevacizumab [Avastin], so a PD-L1 inhibitor plus bevacizumab versus sorafenib in first-line treatment.

IMbrave150 may potentially be a practice-changing trial globally. Until the presentation of this trial, sorafenib was the standard first-line treatment for HCC. This was a randomized first-line trial in 500 patients with HCC without previous systemic therapy. The stratification was by region, performance status, and AFP. The standard arm was sorafenib 400 mg twice daily, and the investigational arm was the anti–PD-L1 drug atezolizumab every 3 weeks with bevacizumab every 3 weeks. There were 2 co-primary end points: OS and PFS.

How did atezolizumab and bevacizumab compare with sorafenib in the IMbrave150 trial?

There was a striking survival benefit for atezolizumab plus beva-cizumab versus sorafenib. The 6-month OS rate was 85% for atezolizumab and bevacizumab versus 72% for sorafenib. The median survival had not yet been reached on the experimental arm compared with 13.2 months for sorafenib. The hazard ratio was 0.58 [95% CI, 0.42-0.79; P = .0006], so that translates into over a 40% reduction in the risk of death. This was highly statistically significant. These data were presented at the European Society for Medical Oncology Asia 2019 meeting.

PFS was also improved with a median difference of about 2.5 months [6.8 months with atezolizumab and bevacizumab, 4.3 months with sorafenib]. There was a hazard ratio of 0.60 [95% CI, 0.47-0.76; P <.0001]...and a 40% reduction in progression, which is statistically significant. There was a significant portion of patients who were still progression free into the second year of treatment.

I suspect that regulatory approval for atezolizumab and beva-cizumab will be forthcoming. This is the first randomized trial [whose results] show a survival benefit above sorafenib. The response rate and disease control rates were also higher with atezolizumab and bevacizumab.

What treatment would you recommend for the patient considering his status at follow-up?

He has a high AFP [level] and progressed on sorafenib. There are a lot of options here: regorafenib [Stivarga], cabozantinib [Cabometyx], ramucirumab [Cyramza], nivolumab [Opdivo], and pembrolizumab [Keytruda]. All of these are options for this patient. In terms of the options that show a survival benefit in a randomized clinical trial, [there is] regorafenib.

The RESORCE trial [NCT01774344] was a randomized trial with patients who progressed on sorafenib but tolerated it and had Child-Pugh A disease. Investigators looked at second-line regorafenib versus [placebo], and OS was the primary end point. This showed a significant improvement in median survival [10.6 months with regorafenib vs 7.8 months with placebo]. Median PFS was also modestly improved, and AEs were manageable.

This is now an FDA-approved drug in the second line.

What other drugs are approved in this setting?

The next approved drug in the second line is cabozantinib.

CELESTIAL [NCT01908426] was a second-line trial in patients with Child-Pugh A disease. Patients with progression on first-line sorafenib were randomized 2:1 to cabozantinib, which is a meta-inhibitor, versus placebo. The primary end point was OS. There was no crossover.

This was another positive trial of a second-line agent. Median OS was improved by about 2 months with cabozantinib, and there was improvement in disease control favoring the cabo-zantinib arm. There were few responses, though, only about a 4% response rate, but there was disease stabilization and improvement in PFS.

Ramucirumab in the second line [is also approved].

 The original REACH trial [NCT01140347] treated all patients with sorafenib progression, and this was a negative trial; however, in the subset of patients who had a high AFP [level], there was a survival benefit.

In a Targeted Oncology case-based peer perspectives live discussion, David H. Ilson, MD, PhD, discusses the treatment options for patients with hepatocellular carcinoma

May 2020 CBPP Spotlight | Case-Based Peer Perspectives Spotlight Live

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