Evolution of Targeted Therapy in Advanced NSCLC

Targeted Therapy in NSCLC: Improvements in Molecular Testing

History of KRAS Testing in Advanced NSCLC

An Overview of KRAS Tumor Biology

Videos

Shared insight on recent advances in KRAS-mutant NSCLC, with a focus on new therapies on the horizon.

Targeting KRAS Mutations in Advanced NSCLC

Rebecca Dent, MD, a senior consultant and head of Medical Oncology Department at the National Cancer Centre Singapore, discusses how investigators are targeting pathways in patients with triple negative breast cancer (TNBC).

Dent says that physicians in this setting having been trying to target the AKT pathway considering how important it is in carcinogenesis. PI3K and mTOR inhibition have been looked at previously, but she believes the importance of AKT inhibitors have been underappreciated, especially in the TNBC space.

Up to 40% of patients with TNBC have loss-of-function negative regulator and gain-of-function positive regulator aberrations in the AKT pathway, according to Dent. Some things can things can up-regulate AKT in a patient beyond their mutational status, such as the impact of chemotherapy. Preclinical data looking at cell lines in these patients showed that when investigators added AKT inhibitors for taxane-based chemotherapy, the benefits were not just additive, but synergistic, she thinks. This data was the basis for the randomized phase 2 LOTUS trial (NCT02162719) of paclitaxel versus ipatasertib (RG7440) in patients with metastatic TNBC.

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Rebecca Dent, MD, discusses how investigators are targeting pathways in patients with triple negative breast cancer.

Addressing the Mechanism of Action for the AKT Pathway in TNBC

The FDA has approved the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) with limited platinum-doublet chemotherapy for the frontline treatment of patients with metastatic or recurrent non–small cell lung cancer (NSCLC) who do not have 

The approved indication for this combination is for patients regardless of histology or PD-L1 expression. With this indication, chemotherapy is given concomitantly with the immunotherapy doublet for 2 cycles.

"We have come a long way in understanding the role of dual immunotherapy-based approaches in cancer and the potential impact on patients’ long-term outcomes,” said investigator David P. Carbone, MD, PhD, director of the James Thoracic Oncology Center at The Ohio State University, in a statement. “The positive findings from CheckMate -9LA demonstrate the benefit of combining dual immunotherapy with limited chemotherapy for NSCLC patients regardless of PD-L1 status. With today’s approval, more patients now have access to an Opdivo + Yervoy-based option and a chance at a longer life.”

Findings supporting the approval, which was completed through the FDA's Real-Time Oncology Review pilot program, came from the ongoing phase 3 CheckMate-9LA trial. Bristol Myers Squibb announced in October 2019 that the trial met its primary end point,

 demonstrating superior overall survival (OS) with the combination compared with the use of chemotherapy alone.

According to findings from the prespecified interim analysis, the combination of nivolumab and ipilimumab with limited chemotherapy demonstrated a median OS of 14.1 months (95% CI, 13.2-16.2) versus 10.7 months (95% CI, 9.5-12.5) with chemotherapy alone (HR, 0.69; 96.71% CI, 0.55-0.87; 

At 1 year, 63% of patients treated with the immunotherapy/chemotherapy combination were still alive compared with 47% of those treated with chemotherapy alone.

The overall response rate by blinded independent central review was 38% (95% CI, 33%-43%) versus 25% (95% CI, 21%-30%) in the immunotherapy and limited chemotherapy and chemotherapy-alone arms, respectively. 

Full findings from the CheckMate-9LA trial will be presented at the upcoming 2020 American Society of Clinical Oncology Virtual Scientific Program.

In the open-label, multicenter, randomized phase 3 study, patients with previously untreated advanced NSCLC were given 360 mg of nivolumab every 3 weeks, 1 mg/kg of ipilimumab every 6 weeks, and 2 cycles of chemotherapy in the experimental arm. These patients were treated for up to 2 years or until disease progression or unacceptable toxicity. In the comparator arm, patients received up to 4 cycles of chemotherapy, which could be followed by optional pemetrexed maintenance treatment if the patient was eligible.

The trial enrolled patients regardless of their PD-L1 expression level or histology; patients were, however, required to have measurable disease and an ECOG performance status of 0 or 1. Those with 

alterations as well as patients with untreated central nervous system metastases were excluded from participating in the trial.

Secondary end points in the trial included progression-free survival and overall response rate in both the intention-to-treat population and in PD-L1 and tumor mutational burden subgroups.

The toxicities of the combination was consistent with the known safety profiles for the individual components. 

the FDA also approved the combination of nivolumab and ipilimumab for the treatment of patients with metastatic or recurrent NSCLC

 whose tumors express PD-L1 (≥1%), as determined by an FDA-approved test. This approval was based off of findings from part of the phase 3 CheckMate 227 trial.

1. U.S. Food and Drug Administration Approves Opdivo® (nivolumab) + Yervoy® (ipilimumab) Combined with Limited Chemotherapy as First-Line Treatment of Metastatic or Recurrent Non-Small Cell Lung Cancer [news release]. Princeton, NJ: Bristol Myers Squibb; May 26, 2020. 

2. Opdivo (nivolumab) Plus Yervoy (ipilimumab) with Limited Chemotherapy Significantly Improves Overall Survival vs. Chemotherapy Alone for Patients with First-Line Metastatic Non-Small Cell Lung Cancer in CheckMate -9LA Study [news release]. Princeton, NJ: Bristol Myers Squibb; May 13, 2020. 

Articles

Nivolumab plus ipilimumab  in combination with chemotherapy was granted accelerated approval for the frontline treatment of patients with metastatic or recurrent non–small cell lung cancer who do not harbor EGFR or ALK genomic tumor abberations.

FDA Approves Frontline Nivolumab/Ipilimumab/Chemo for Advanced NSCLC

Statistically significant improvement in overall survival was not achieved with the combination of entinostat plus exemestame (Aromasin) compared with hormone therapy alone in patients with hormone receptor (HR)–positive, HER2-negative breast cancer, missing the primary end point of the phase 3 E2112 trial (NCT02115282).

"We're disappointed that the combination of entinostat and exemestane did not demonstrate a survival benefit in this historically difficult-to-treat patient population," said Briggs W. Morrison, MD, CEO of Syndax, in a statement. "On behalf of the entire Syndax team, we extend our sincerest gratitude to all the patients, their families, and the investigators who participated in this important trial, as well as our colleagues at ECOG-ACRIN and the NCI [National Cancer Institute]. Based on these results, we will not be filing a New Drug Application with the U.S. Food and Drug Administration for metastatic breast cancer."

Prior results from the study showed that the combination also failed to improve progression-free survival (PFS); however, researchers at Fox Cancer Research Center remained hopeful because PFS prolongation was not the goal of the study, even though it was a coprimary end point. Additionally, prior data from the phase 2b ENCORE 301 trial signaled that entinostat plus exemestame could improve OS. The hypothesis was proven wrong.

E2112 is a double-blind, placebo-controlled, trial of 608 patients with HR-positive, HER2-negative breast cancer. The study was sponsored by the National Cancer Institute and independently designed and carried out by ECOG-ARIN. In the study, patients received exemestane on days 1, 8, 5, and 22 of a 28-day cycle with entinostat on days 1 through 28, in the experimental arm. In the comparator arm, placebo was administered on the same days as exemestane.

The secondary end points being assessed in the trial are objective response rate, toxicity, and time to treatment deterioration. The exploratory study outcomes include the percent of change in protein lysine acetylation, overall health-related quality of life, and adherence to study protocol.

Patients were eligible for enrollment into E2112 if they had histologically confirmed disease that was measurable or non-measurable, adequate laboratory values, an ECOG performance status of 0 or 1, and a life expectancy of at least 12 weeks. Patients could not have prior concurrent anti-cancer therapy, valproic acid treatment, or central nervous system metastasis.

Entinostat is currently being evaluated in combination with axatilimab, a monoclonal antibody, as a potential treatment for adult patients with relapsed or refractory acute leukemias. Full data from the phase 3 E2112 study are expected in the second half of 2020.

1. ECOG-ACRIN Provides Syndax Pharmaceuticals With Results of Phase 3 E2112 trial of entinostat plus exemestane in patients with hr+, her2- breast cancer [news release]. Whalthan, Massachusetts: Syndax Pharmaceuticals; May 21, 2020. 

2. Syndax to host conference call to provide update on the phase 3 breast cancer trial (e2112) and to announce its registration trial of entinostat with keytruda in pd-(l)1 refractory non-small cell lung cancer [news release]. Waltham, Massachusetts: Syndax Pharmaceuticals; October 25, 2018. 

Entinostat plus exemestame did not improve overall survival in patients with hormone receptor–positive, HER2-negative breast cancer.

Entinostat Combo Fails to Meet End Point in Phase 3 HR+/HER2– Breast Cancer Study

Jeffrey Matous, MD, medical director of Colorado Blood Cancer Institute in Denver, CO discussed strategies for treating a 51-year-old male patients with transplant-ineligible multiple myeloma, during a live 

 case-based peer perspectives conversation with other experts.

™: How do you discuss prognosis with your patients?

: I tell my patients I’m going to treat with curative intent. I think it’s a great way to tell them that we’re going to treat. Patients want to be hopeful. The goal of treatment is longer survival with excellent quality of life.

What is the age cutoff for transplant-eligible patients in this setting?

In Europe, the cutoff has been 65 years of age, but in the United States, that has been long abandoned. When discussing transplantation, it’s more of a physiological definition than a chronological definition for who is eligible.

How do you define fit patients at your institution? What questions do you normally ask to find out?

It takes me about 3 seconds to assess the patient’s fitness when I walk into the examination room. You can tell their level of activity, and you can ask the patient what they do for exercise. And if they reply with “I skied 60 days last winter,” then you know their fitness.

Do you refer to the National Comprehensive Cancer Network (NCCN) myeloma guidelines

Occasionally. Interestingly, the guidelines contain just 1 regimen that is a quadruplet treatment, which is daratumumab [Darzalex]–VTd [bortezomib (Velcade)/ thalidomide (Thalomid)/dexamethasone]. VTD was the standard for a few years, but adding daratumumab-VTd is the result of the Cassiopeia trial [NCT02541383].

What are the role of and timing for the use of stem cell transplant in newly diagnosed multiple myeloma?

Four studies looked at stem cell transplant in the patient with newly diagnosed multiple myeloma: IFM 2009 [NCT01191060], FORTE [NCT02203643], Cassiopeia, GRIFFIN [NCT02874742]. 

IFM 2009 was published in the New England Journal of Medicine, and it looked at up-front transplant versus delayed transplant.. The FORTE trial is an important trial out of Italy.⁴ This trial looks at up-front KRd [carfilzomib (Kyprolis), lenalidomide (Revlimid), dexamethasone] versus KCd [carfilzomib, cyclophosphamide, dexamethasone] with a transplant arm. Cassiopeia is a trial that resulted in the approval of daratumumab-VTd.⁵ GRIFFIN is still early on, with fewer patients than Cassopeia.⁶ GRIFFIN is a trial that we’re keeping an eye on. Patients in the consolidation maintenance phase are still being followed. Across these 4 trials, we’re seeing high postconsolidation VGPR [very good partial response] rates in these patients.

IFM 2009 evaluated patients who were 65 years of age or younger who were treatment na.ve and asymptomatic. The trial involved 3 cycles of RVd, after which stem cells were collected. After the patients were randomized, treatment with 6 more cycles of RVd followed versus stem cell transplant. All arms received lenalidomide maintenance therapy. For patients in the RVd-delayed transplant arm who progressed, undergoing transplant was recommended.

What are the significant findings from the FORTE study?

In FORTE, a 3-arm trial, patients were randomized to either 4 cycles of KCd, 4 cycles of KRd, or 4 cycles of KrD. After induction, patients who received KCd and 1 arm of patients who received KRd underwent allogeneic stem cell transplant. The patients in the remaining KRd arm continued with 8 more cycles of KRd, for a total of 12 cycles of KRd [KRd12].

This is followed by a second randomization between KR and lenalidomide. None of the maintenance data have been reviewed at medical conferences at this point. Currently, response data are available, including MRD [minimal residual disease]. What I’m curious about is if we should be inducing with KRd or RVd. This study does not address that question, but I think SWOG evaluated this, and findings are expected to be presented during ASCO [American Society of Clinical Oncology Annual Meeting].

SWOG looked at up-front KRd versus RVd in the nontransplant setting. ASCO will have an uncharacteristically heavy myeloma session, with practice-changing data likely to be reported.

Getting back to FORTE, if we review the stringent CR [complete response; sCR], CR, and MRD-negative data, for KRd versus transplant plus KRd, all these responses are close together, and there appears to be no difference in the findings.

This suggests that both these treatment modalities offer similar benefit. These data are not mature yet, but it appears that for patients who received transplant plus KRd, the early relapse rate is lower, 8% versus 17% in the KRd arm, which is observed in the higher-risk group. Reviewing multivariate regression, the risk of early progression is reduced in the transplant arm versus the KRd12 arm. For patients who relapsed in the nontransplant arm, it’s presumed that they underwent transplant. Either arm suggests that you can delay relapse through transplant.

Cassiopeia evaluated a quadruplet regimen versus a triplet regimen. What was significant in this trial?

[With] Cassiopeia, it appears, based on the sheer number of patients, like a breast cancer trial with its 1085 patients. This European study enrolled garden-variety, standard-risk, younger patients with myeloma. These patients were randomized to receive VTd or daratumumab-VTd. Stem cells were harvested and transplanted for both arms, followed by consolidation. Patients underwent 6 cycles of either the triplet or quadruplet regimen and then had a second randomization. At the second randomization, patients were either observed with no maintenance therapy or received daratumumab maintenance.

The primary end point of sCR was met, with patients in the daratumumab-VTd arm reporting an sCR of 29% and patients in the VTd arm reporting an sCR of 20%. What’s interesting in this trial is that sCR favored the quadruplet regimen except for patients at high risk. Similarly, MRD-negative status favored the quadruplet arm reported at 64% versus the triplet arm, reported at 44%.

Please discuss important data from GRIFFIN.

This trial is going to be a practice changer. It looked at newly diagnosed, transplant-eligible patients up to 70 years of age. Inclusion criteria to enroll was reasonable renal function. The trial evaluates daratumumab—RVd versus RVd—the induction phase if 4 cycles of each, then stem cell collection, followed by 2 cycles of consolidation with patients on the same regimen. It’s interesting to note that 90% of patients on the quadruplet regimen get transplanted, and 76% of patients in the triplet get transplanted, and this is due to progression.

For GRIFFIN, the initial data were just from a safety run-in that involved 16 patients. And yet, in these patients, VGPR is high after transplant. The sCR is 25%, CR is 38%, and VGPR is 38%. Everyone responded. During maintenance, a deepening response was observed. This allowed the trial to go forward to phase III.

The sCR by the end of consolidation was 42.4% in the daratumumab-RVd arm versus 32.0% in the RVd arm. That’s a decent sCR rate after therapy with daratumumab-RVd. The other thing we have learned again and again in myeloma is that responses deepened over time. Response rates and depths were greater for daratumumab-RVd at all time points.

Will MRD be a factor in the FDA’s decision to approve a treatment moving forward?

Currently, the FDA bases its approval on progression-free survival [PFS]. I think the FDA is going to be more open to MRD. In the GRIFFIN trial, the MRD negativity rate at data cutoff for the quadruplet therapy arm was 51.0% compared with 20.4% in the triplet therapy arm.

MRD rate is growing in importance, so it is important to obtain accurate readings. In fact, more studies are looking at the MRD rate but also noting if MRD is sustained over time or not. That will be critical.

The easiest way to obtain an MRD rate is to use high-quality, at least 8-color flow cytometry—the standard is EuroFlow because it’s readily available—and next-generation sequencing [NGS]. Good flow cytometry is 10-5, and good sequencing depends on how many cells you are sequencing. If you are sequencing enough cells, then attaining a 10-6 [concentration] is obtainable.

If you attend a lecture and an investigator is talking about MRD, the question you need to ask is “What was your technique?”

How did the quadruplet regimen compare with the triplet regimen for sCR and MRD in GRIFFIN?

What was demonstrated in GRIFFIN was that for MRD, the quadruplet therapy was favored over the triplet therapy. D-RVd was favored across all subgroups for MRD negativity and across all subgroups for sCR rate, except high-risk cytogenetics and ISS [International Staging System] stage III disease. I emailed Peter Voorhees, MD, about this, and he said that the numbers got really small for high-risk disease. He had 100 patients, and basically 15% of patients are usually high risk.

How should clinicians address the neuropathy that is usually associated with bortezomib for this patient population? What do you tell your patients when they are about to go on this drug?

We see a significant number of patients develop neuropathy, most likely attributed to bortezomib. I’ll mention that the way our nurses ask about neuropathy is important. If they ask “Do you have neuropathy?” the patient will respond “No,” because they fear that if they say yes, you will stop their treatment.

However, if we ask if patients have numbness or tingling or lightning bolts of pain in there, we’re going to get more positive answers. It’s better to explain to patients that we can attenuate their dose of bortezomib so that they are treated longer and more effectively. We’re still seeing a lot of patients referred to us for transplant on RVd coming in with grade 2 neuropathies with pain. We have to do better than that.

The first thing I do when considering neuropathy is tell the patient to be paranoid about neuropathy. That’s the terminology I use. Be paranoid about neuropathy and report anything more than mild numbness or tingling. If I see that, I immediately hold the bortezomib. I hold it until the adverse effects dissipate down to grade 1 or less. Then I will consider reinstituting the drug with a dose modification, either by decreasing the dose or going to weekly dosing or both.

1. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Multiple myeloma (version 3.2020). Accessed April 24, 2020. https://bit.ly/352Twrb

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. 

. 2019;394(10192):29-38. doi:10.1016/S0140-6736(19)31240-1

3. Attal M, Lauwers-Cances V, Hulin C, et al; IFM 2009 Study. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. 

. 2017;376(14):1311-1320. doi:10.1056/NEJMoa1611750

4. Gay F, Cerrato C, Petrucci MT, et al. Efficacy of carfilzomib lenalidomide dexamethasone (KRd) with or without transplantation in newly diagnosed myeloma according to risk status: results from the FORTE trial. J 

. 2019;37(suppl 15; abstr 8002). doi: 10.1200/JCO.2019.37.15_suppl.8002

5. 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. 

. 2019;394(10192):29-38. doi:10.1016/S0140-6736(19)312401.Published correction appears in Lancet. Published online June 14, 2019. doi:10.1016/S0140-6736(19)31403-5

6. Voorhees PM, Kaufman JL, Laubach JP, et al. Daratumumab, lenalidomide, bortezomib, & dexamethasone for transplant-eligible newly diagnosed multiple myeloma: GRIFFIN. 

. Published online April 23, 2020. doi:10.1182/blood.2020005288.

Jeffrey Matous, MD, discussed strategies for treating a 51-year-old male patients with transplant-ineligible multiple myeloma, during a live Targeted Oncology case-based peer perspectives conversation with other experts.

Matous Evaluates Treatment Strategies for Transplant-Ineligible Multiple Myeloma

In the field of renal cell carcinoma (RCC), researchers are pursuing clinical trials of novel combination regimens that can approve upon the efficacy of existing drugs. Such a drug is telaglenastat (CB-839), which is currently being evaluated in combination with everolimus (Afinitor) as treatment of patients with advanced or metastatic RCC in the phase 2 ENTRATA study (NCT03163667).

Based on results reported in 2019, the study of 69 patients showed a significant improvement in progression-free survival (PFS) with telaglenastat/everolimus versus telaglenastat and placebo. The median PFS was 3.8 months compared with 1.9 months (HR, 0.64; 95% CI, 0.34-1.20; 1-sided 

The safety profile with the combination was tolerable with the most common grade ≥3 adverse events being anemia (17% vs. 17%), pneumonia (7% vs. 4%), abdominal pain (7% vs. 0%), thrombocytopenia (7% vs. 0%), fatigue (4% vs. 9%), in the telaglenastat comparator arm versus the control arm respectively. The treatment discontinuation rate observed with telaglenastat plus everolimus was 28% and telaglenastat plus placebo was 30%.

, Chung-Han Lee, MD, PhD, medical oncologist, Memorial Sloan Kettering Cancer Center, provided background on the phase 2 ENTRATA study and discussed the next steps with telaglenastat in the RCC treatment landscape.

: What was the rationale for the ENTRATA study?

 Telaglenastat is a glutaminase inhibitor. It is well known that kidney cancer is a disease of altered metabolism. The hypothesis was that GLS inhibition of both glucose and glutamine metabolism would improve responses within metastatic kidney cancer.

: The trial that we designed was a randomized, double-blind phase 2 clinical trial of the combination of telaglenastat plus everolimus versus everolimus plus placebo. The design of the trial was for patients who progressed on at least 2 prior lines of systemic therapy and allowed for things like brain metastases. The primary end point was investigator-assessed for progression-free survival with a key secondary end point of overall survival. In terms of prior progression, most patients had progressed on tyrosine kinase inhibitors.

: What was exciting about the study results?

: The results were that the trial did meet its pre-specified PFS end point and demonstrated an improved PFS with the combination of telaglenastat plus everolimus versus Placebo plus everolimus.

: Were there any toxicities associated with the combination of telaglenastat and everolimus?

: The toxicities that were seen were fairly similar across both cohorts. There were equal numbers of patients who required either a dose reduction or discontinuation of either drug.

Overall, it's very important to remember that in the study we had very heavily pretreated patients. We were able to treat with full doses of everolimus without adding significant toxicity. That speaks to the safety of the drug.

: What are the next steps with this research?

: This study serves as a proof of concept of the mechanism of action, and glutaminase inhibition represents a new mechanism of action that has not yet been applied to metastatic kidney cancer. The study that will further define the role of telaglenastat is the CANTATA study, which is a randomized trial of 400 plus patients with the combination of telaglenastat and cabozantinib versus placebo plus cabozantinib (Cabometyx).

Motzer RJ, LeeCH, Emamekhoo H, et al. LBA54 - ENTRATA: Randomized, double-blind, phase II study of telaglenastat (tela; CB-839) + everolimus (E) vs placebo (pbo) + E in patients (pts) with advanced/metastatic renal cell carcinoma (mRCC). 

. 2019;30(5): 889-890. doi: 10.1093/annonc/mdz394.048.

In an interview with Targeted Oncology, Chung-Han Lee, MD, PhD, provided background on the phase 2 ENTRATA study and discussed the next steps with telaglenastat in the RCC treatment landscape.

Bettering Survival With Telaglenastat Combinations in RCC

The FDA has granted a Fast Track Designation to the novel small-molecule phospholipid drug conjugate, CLR 131, as treatment of patients with lymphoplasmacytic lymphoma (LPL)/Waldenström’s macroglobulinemia (WM) who have received at least 2 prior therapies, Cellectar Biosciences, Inc announced in a press release.

“[Patients with] LPL/WM [who] do not respond optimally or are intolerant of ibrutinib [Imbruvica], currently have limited treatment options and poor survival rates. Fast Track Designation for LPL/WM further supports our clinical development strategy to quickly and efficiently provide these patients with an effective therapeutic alternative,” said James Caruso, president and CEO of Cellectar in a statement. “All 4 [patients with] LPL/WM treated in our CLOVER-1 phase 2 study to date achieved a 100% overall response rate and a 25% complete response rate. This strong response rate may represent an important improvement in the treatment of relapsed/refractory LPL/WM as no approved or late-stage development treatments for relapsed or refractory patients have reported complete responses.”

CLR 131 is currently under investigation in the phase 2 

CLOVER-1 study, an open-label, multicenter trial evaluating patients with select relapsed or refractory B-cell malignancies. Positive results from this study were announced in February 2020, showing high response rates in the relapsed/refractory multiple myeloma (MM) and relapsed/refractory non-Hodgkin lymphoma (NHL) population. Patients included those with MM, diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), LPL, and WM. The primary end point of the study was overall response rate (ORR).

A total of 80 participants were enrolled in the study. The ORR was 34.5% in the overall MM population and 42% in the NHL population, which included a complete response (CR) rate of 11%. In the LPL and WM population, the ORR was 100%. The drug was well tolerated in all patient groups.

Adverse events (AEs) were seen in both subgroups, and cytopenias were the most frequently observed AE in the MM subgroup. The DLBCL subgroup achieved a response rate of 30% with a CR in 1 patient. The response rate in the CLL, SLL, and MZL subgroups was 33%.

In CLOVER-1, all patients with LPL and WM received either 50 mCI of 75 mCI of CLR 131.

The grade 3 or higher AEs seen in patients with MM were at the high dose (75mCi) of CLR 131 and were most commonly thrombocytopenia (65%), neutropenia (41%), lymphopenia (35%), leukopenia (30%), and anemia (24%). There were no cases reported of cardiotoxicities, neurologic toxicities, infusion site reactions, peripheral neuropathy, allergic reactions, cytokine release syndrome, keratopathy, renal toxicities, or changes in liver enzymes. In the NHL group, the safety profile observed with CLR 131 was similar with the exception of fewer any-grade cytopenias.

The study was expanded to assess 2 cycles of dosing with CLR 131 in the overall study population, based on these positive results.

Preliminary efficacy measures consisting of ORR, time to progression, and overall survival are the secondary end points of the study.

Patients are eligible for CLOVER-1 if they have histologically or cytologically confirmed MM, CLL/SLL, MZL, MCL, or DLBCL, along with an ECOG performance status of 0 to 2, adequate laboratory values, and a life expectancy of at least 6 months. Patients were excluded from the study given they had ongoing toxicities of grade 2 or higher, prior treatment with external-beam radiation, hemi-body irradiation, anti-cancer therapy within 2 weeks of beginning treatment in the study, as well as radiation therapy, chemotherapy, immunotherapy, or investigational therapy with 2 weeks of starting the study. Individuals who had undergone major surgery within 6 weeks of enrollment and those with a known history of HIV or hepatitis B or C infection were also excluded.

In addition to LPL and WM, CLR 131 also has a prior Fast Track Designation from the FDA for the treatment of patients with 

. Other Orphan Drug Designations for the agents are under macroglobulinemia, neuroblastoma, rhabdomyosarcoma, Ewing sarcoma, and osteosarcoma.

1. Cellectar receives FDA Fast Track Designation for CLR 131 in lymphoplasmacytic lymphoma/waldenstrom’s macroglobulinemia [news release]. Florham Park, NJ: Cellectar Biosciences, Inc; May 26, 2020. 

2. Cellectar Biosciences announces CLR 131 achieves primary efficacy endpoints from its phase 2 CLOVER-1 study in relapsed/refractory b-cell lymphomas and completion of the phase 1 relapsed/refractory multiple myeloma dose escalation study [news release]. Florham Park, NJ: Cellectar Biosciences, Inc; February 19, 2020. 

"Fast Track Designation for lymphoplasmacytic lymphoma and Waldenstrom’s macroglobulinemia further supports our clinical development strategy to quickly and efficiently provide these patients with an effective therapeutic alternative."

FDA Grants Fast Track Designation to Novel Small Molecule Drug in LPL and WM

The landscape for metastatic triple-negative breast cancer (mTNBC) offers limited treatment options, and even as new agents circulate as potential options, few clinical trials have provided long-term data on the efficacy of these available agents. One drug showing significant promise is 

sacituzumab govitecan-hziy (Trodelvy), which recently received accelerated approval by the FDA as treatment of patients with for adult patients with mTNBC

 who have received at least 2 prior therapies for metastatic disease.

“The real lesson for me and the excitement of this approval is that we are finally beginning to make progress for the treatment of our patients who have chemotherapy-resistant triple-negative breast cancer,” Hope S. Rugo, MD told 

In the phase 1/2 basket trial (NCT01631552), which supported the approval of sacituzumab govitecan in mTNBC, the drug demonstrated a response rate of 33% in the heavily pretreated patient population.

The next step for the development of the drug is to evaluate it in a phase 3 clinical trial with an active comparator. The phase 3 ASCENT trial (NCT02574455), an international, multi-center, open-label, randomized trial, launched to assess the efficacy and safety of sacituzumab govitecan against a treatment of physician’s choice.

 following the announcement of sacituzumab govitecan accelerated FDA approval, Rugo, professor, Department of Medicine (Hematology/Oncology); and Director, Breast Oncology and Clinical Trials Education at the University of California San Francisco, discussed the published data from the phase 1/2 basket trial and the relevance of having sacituzumab govitecan available for the treatment of patients with mTNBC.

: As you know, the FDA just recently approved sacituzumab govitecan in mTNBC. What will it mean to have this drug available for use in the community setting?

: We're excited about the approval of sacituzumab govitecan. There are a number of reasons for this, but the most important one is that when patients have mTNBC, they have a remarkably small number of treatment options, and particularly, a small number of treatment options that are effective durable disease control.

The other part of this is the treatment that we give patients and the toxicity of the treatment. Having sacituzumab govitecan available for patients who had progressive disease after at least two lines of chemotherapy in the metastatic setting and you have triple-negative breast cancer is a tremendous advantage for patients in community or academic centers because the drug hasn’t been available to any of us. At least a third of the patients responded to sacituzumab govitecan who had extensive prior exposure to chemotherapy from metastatic breast cancer.

It’s also nice to know is more than half of the patients responded for at least six months,which is a big difference from some other chemotherapy agents that we can offer these patients.

As always, when we're treating patients who have bad metastatic cancer in a limited expected survival, having more treatment options makes a big difference. We don't know yet what the survival will be from sacituzumab govitecan compared to chemotherapy of physician’s choice. That will be presented at some point in the future from the results of the phase 3 ASCENT trial.

What we do know is that the approval leaves us with an additional treatment option that allows patients to start with immunotherapy first, if the patient has PD-L1-positive disease based on the Impassion130 results and it allows patients who had a recurrence to potentially derive benefit even a short time after their adjuvant chemotherapy.

Lastly, sacituzumab govitecan was overall well-tolerated. We don't see any major life-threatening toxicities or issues that would be difficult to manage in the outpatient setting. I think this is a win/win situation for patients, with the only downside being that many patients lose their hair with this particular antibody-drug conjugate.

: The long-term efficacy data that is available around treatment options for mTNBC is limited. Can you discuss what outcome are generally like for these patients?

: The accelerated approval of sacituzumab govitecan was based on data from a phase 2 trial where 108 patients received sacituzumab govitecan. The drug is given on days 1 and 8 every 21 days, and there was no comparator, but we know that there are very limited treatment options as I mentioned in this situation. If you treat patients who have had more than two lines of prior chemotherapy in the metastatic setting, we already know that the outcome isn’t very good. The accelerated approval was based on having an additional treatment option that seemed to be a good option in terms of efficacy with tolerable toxicity.

In the patients who were treated about 33% of them had a complete or partial response to sacituzumab govitecan and as you would expect, most of the responses were partial responses. The medium duration was just under eight months, at about 7.7 months and that's encouraging.

I mentioned earlier that more than half the patients were responding at six or more months. If you looked at 12 or more months, it was almost 17% of the patients.

You can look at survival in that group of patients but that does not help you because you don't have a comparator as in the ASCENT trial which looked at progression-free survival as the primary end point, but we have not seen the data yet. I’m looking forward to seeing that as well as longer-term results that will help us understand the potential survival impact.

: Can you discuss the toxicity profile of sacituzumab govitecan?

: The primary higher-grade toxicities are blood-related, and we have a much easier time managing blood toxicity than we do toxicities that occur outside of the hematopoietic system.

Neutropenia of grades 3/4 were seen in 43% of patients and anemia in only 12% and thrombocytopenia, which is hard for us to manage was a very uncommon toxicity occurring in less than 5%. That’s promising because if you don't have a lot of febrile neutropenia, you can manage the neutropenia fairly well by using growth factors. I have found in the patients that I’ve treated with sacituzumab, thatmost patients do require growth factors, but not all. It depends on the extent of prior treatment. I mentioned that alopecia is quite common in these patients, but not everybody loses all of their hair. It’s just something to warn patients about. We don't yet know if scalp cooling could help this.

Relative to gastrointestinal (GI) toxicities, the toxin that is attached to this antibody-drug conjugate is SN-38. This is a metabolite of irinotecan and we know the toxicity of irinotecan very well from our colleagues in the GI oncology arena. Interestingly, if you give SN-38 even at the high toxin per antibody level that’s seen with these newer antibody-drug conjugates, you don't see the toxicity that you see from giving naked irinotecan, where the body determines how much is metabolized to SN-38 and how rapidly it's cleared.

In this situation, grade 3/4 diarrhea and other GI toxicities were uncommon. Grade 3/4 diarrhea was seen in 9% of patients and mostly grade 3. You could manage this by telling patients in advance and giving them anti-diarrheal therapy. In patients that have treated, I haven't seen much of this. We need to educate patients carefully and make sure they all have Imodium at home. In addition, we give antiemetics as prevention, but the high-grade nausea is very rare, and was only seen in 6% of patients in this phase 2 study population. Low-grade nausea, and diarrhea were seen in more than 50%.

: What is unique about the results seen in this trial that were recently published in the 

: What is unique is that we don't have a lot of trials that have done two different things. One is that it focused on patients who received a lot of prior chemotherapy with the registration-based pathway. That’s 2 to 4 prior lines of chemotherapy, which is a lot of chemotherapy for a patient population where the median survival after diagnosis of metastatic disease is about 18 to 19 months, based on the data from the Impassion130 trial. These patients are beat up, in terms of the treatment, and they have resistant disease and that makes this trial unique.

The other unique thing about this trial, I think is that it focused on triple-negative breast cancer. The prior trial that looked at heavily pretreated patients called the EMBRACE trial, which led to the approval ofthat left to the approval eribulin (Halaven), did not focus on any one subset of patients.

: Like all clinical trials, there were some limitations in the basket study. Can you explain those limitations?

: The main limitation of this study is that it’s a single-arm study and therefore has no comparator.

You don't know how it compares to standard therapy and that limitation is being addressed in the phase 3 ASCENT trial that randomizes patients who have received at least two prior chemotherapy regimens for metastatic triple-negative breast cancer to receive either sacituzumab govitecan or treatment of physician choice. There is a menu of specific chemotherapy agents that patients can receive. There were no other significant limitations in the phase 2 trial.

A limitation of sacituzumab govitecan, in particular, is that we don't have a marker to know which patients might respond better. The antibody is to Trop-2 and Trop-2 is overexpressed quite commonly in triple-negative disease as well as in other subsets of breast cancer. So far, we don't have any data that has told us that we need to test for expression of Trop-2. As a result, we just treat everybody. We’re hopeful that some of the trials that are ongoing now and trial of the future will give us better information about this.

The ongoing TROPiCS-02 trial is evaluating sacituzumab govitecan in patients with metastatic hormone receptor-positive breast cancer and in this trial, we are looking at Trop-2 and I think it will be interesting to look at those data retrospectively.

There also is one other small limitation to mention and that's hypersensitivity. Any drugs that we give that have an antibody attached to it could potentially have hypersensitivity. Anaphylactic reactions are rare with this antibody-drug conjugate but some hypersensitivity reactions did occur. These reactions were higher grade and only 1% of patients that were treated in all different trials that were investigating sacituzumab govitecan. That’s a population of 408 patients in which only 6 patients had grade 3/4 hypersensitivity reactions, and it only led to permanent discontinuation in 3 patients.

We do recommend pre-infusion medications for patients for nausea and blood reactions. Physicians should have orders available to treat patients in case they have an infusion-related reaction, similar to what we do for paclitaxel. The rate is not any greater than what we see for taxane.

The last thing is that physicians may want to observe patients during the infusion and for 30 minutes after just to make sure they don't have one of these rare transfusion reactions. We have not seen it in a few patients who were treated with the drug.

: Now that the drug is approved, there will likely be questions about how to manage patients while they’re on this drug. What advice can you give to community oncologists?

: I think this drug is a great option for patients. We should be able to prescribe it. It's important to get pre medications as I mentioned earlier, and it's important to be cautious about the day 8 blood counts.

If the neutrophils are not reasonable on day 8, oncologists should think about using prophylactic growth factors in the future. Sometimes when patients come in for cycle, even though their accounts were fine on day 1, they will have low neutrophils. Having a neutrophil count under 1.5 on day 1 should prompt consideration for growth factors to avoid more severe neutropenia complications with future cycles.

: What is your overall outlook on the treatment landscape for mTNBC now that there’s a new treatment option is available?

: I think that progress in the field of triple-negative breast cancer has been long-awaited and slow to come. We're understanding the biology better now to some degree and we now have several new treatment options. They're improving our ability to treat patients and, most importantly, helping us to move agents that might offer a benefit for resistant disease to earlier in the phase of treatment. When we find something that works well and is reasonably well-tolerated, the first thing we want to do is move it into the early-stage setting and there are trials planned to open in the near future that will look at sacituzumab govitecan in patients who have early-stage triple-negative breast cancer upfront and in patients with poor response to standard neoadjuvant chemotherapy.

It’s important to treat most patients who have triple-negative breast cancer with neoadjuvant therapy because you want to be able to offer them rescue therapy with additional agents on clinical trials, or course, capecitabine outside of trials. We need to understand how immunotherapy is going to interact with these new agents as we’re waiting for disease-free survival data from the KEYNOTE-522 trial, which is looking at pembrolizumab (Keytruda) in the neoadjuvant setting.

 mutations, we now have PARP inhibitors and we're waiting for the data from the Olympia trial that evaluated adjuvant olaparib.

The real lesson for me and the excitement of this approval is that we are finally beginning to make progress for the treatment of our patients who have chemotherapy-resistant triple-negative breast cancer.

In an interview with Targeted Oncology following the announcement of sacituzumab govitecan accelerated FDA approval, Hope Rugo, MD, discussed the published data from the phase 1/2 basket trial and the relevance of having sacituzumab govitecan available for the treatment of patients with metastatic triple negative breast cancer.

Sacituzumab Govitecan Brings Long-Awaited Progress in the Treatment Landscape of mTNBC

Aaron E. Katz, MD, a professor in the Department of Urology at NYU Long Island School of Medicine and chairman in the Department of Urology at NYU Winthrop Hospital, discusses a genomic test for patients with low-risk prostate cancer.

The Oncotype Dx Genomic Prostate Score (GPS) assay was validated by multi-institutional study [NCT03502213] and is included in the National Comprehensive Cancer Network guidelines for this patient population. This assay helps patient and physicians make decisions and who should be on an active surveillance program or not, according to Katz. It was developed to look at 21 genes expressed in the patient’s prostate.

The Oncotype Dx GPS goes through a number of different categories of genes and within each category, there are 2 to 4 genes. which are regulated by hormones and others which are proliferating genes. Katz says the impressive thing about it is that rather than looking under a microscope to see the cellular architecture and describing it using the Gleason Grading System, which has been used for many years, this assay gives physicians the added feature of looking at and isolating only the cancer cells and extracting the DNA. Then the assay uses a reverse transcription polymerase chain reaction to look at the expression of specific genes that are turned on in these cells, which allows the physician to come up with the GPS.

<< View more resources and information regarding prostate cancer

Aaron E. Katz, MD, discusses a genomic test for patients with low-risk prostate cancer.

Assay Shows Value for Patients With Low-Risk Prostate Cancer

Because of the strain on the health care system brought on by the novel coronavirus disease 2019 (COVID-19) pandemic, the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) have laid out guidelines to help practicing oncologists delineate the best ways to allocate limited resources.

"Health care has basically been turned upside down,” said Arjun V. Balar, MD, director of the genitourinary medical oncology program at NYU Langone’s Perlmutter Cancer Center in New York, New York, and co–editor-in-chief of Targeted Therapies in Oncology during an interview. “Our efforts in the cancer clinic have been driven by patient safety and also maintaining patient access to care. [In the age of COVID-19], those 2 things are sometimes at odds with each other."

With patients’ safety and access in mind, the NCCN issued tumor type–specific updates for the treatment of breast cancer, non–small cell lung cancer (NSCLC), prostate cancer, colorectal cancer (CRC), melanoma, nonmelanoma skin cancers, and T-cell and primary cutaneous lymphoma during the COVID-19 pandemic.

 Most of the recommendations aim to limit the number of patients who need to leave their homes for care by emphasizing the use of telehealth visits and oral systemic therapy regimens as well as outlining surgical procedures that may be temporarily delayed.

A key aspect of the recommendations for treating patients with breast cancer involves assigning patients to 3 priority levels based on urgency of care. Patients in category A are those with a life-threatening prognosis who cannot delay therapy, category B includes patients whose disease is not life-threatening but for whom treatment should not be delayed until after the pandemic, and category C comprises patients whose therapy can be deferred until after the pandemic.

In general, the guidelines recommend that all visits be conducted remotely when feasible and that most breast-focused imaging be delayed. Practitioners should defer surgical procedures in all possible scenarios for which an alternative therapy could serve as a stand-in. The 

 includes a select list of surgical procedures by priority.

Balar spoke to his concerns regarding these delays of therapy. “This has forced us in the cancer [community] to delay treatments for patients,” he said. “The definition of an elective surgery, it’s important to understand, is that it is not really elective—it just means patients are scheduled for surgery…all of these were thought to be considered elective because of the need for ventilators for patients with COVID-19."

The recommendations for breast cancer care further detail ways to reduce the number of clinic visits by delaying or dose-adjusting systemic therapy based on disease subtype. For example, the guidelines advise that patients with advanced-stage invasive breast cancer have their therapy dose and schedule adjusted to reduce the need for monitoring visits and their chances of developing treatment-related adverse effects. Notably, endocrine therapy agents are considered safe, and clinicians may continue to use them during the COVID-19 pandemic.

Because of the virus’ effect on the lungs and vulnerable populations, patients with lung cancer are at heightened risk of complications of COVID-19. As such, the NCCN outlined strategies for treating patients with NSCLC during the pandemic with the goal of reducing exposure while maintaining optimal outcomes.

Treatment interval prolongation or deferred systemic therapy doses are a reasonable option for certain patients with metastatic disease, but medical oncologists should gear efforts toward continuing therapy for most. The guidelines recommend use of oral regimens in place of intravenous agents—such as substituting oral for intravenous etoposide—when feasible to reduce clinic visits. Additionally, reliance on circulating tumor DNA testing over tissue testing may be reasonable in this setting to avoid the need for tissue harvesting.

As with the breast cancer recommendations, practitioners should evaluate surgical procedures to assess the possibility of postponement. For example, patients with clinical stage IA1 solid tumors can be deferred for 2 to 3 months, whereas patients with clinical stage IIIA (T3N1 or T4N0) should be strongly considered for surgery within 1 month.

According to the NCCN guidance on prostate cancer care, “the benefit of routine localized prostate cancer care should not be overestimated. In most instances, minimal harm is expected with delays in care or treatment of 3 to 6 months, especially when weighed against the risk of mortality of COVID-19.”

Oncologists should conduct telehealth visits with rare exceptions. They can avoid or defer routine care for most patients with prostate cancer, including delaying initiation of androgen deprivation therapy (ADT) in patients with a prostate-specific antigen doubling time of more than 9 months. For patients who need to continue on ADT, clinicians should prioritize 3-, 4-, and 6-month formulations for use over 1-month injections.

The NCCN has provided similar documents detailing recommendations for therapy in patients with various other solid tumors and hematologic malignancies.

"For patients who are on routine follow-up, we are doing much more virtual medicine,” said Balar. “Bringing patients into the health care system means putting them at risk for exposure or contracting the virus. Trying to both [treat patients and prevent disease spread] has been challenging, [but] patients [who] absolutely have to be here to receive treatment are physically present."

For example, oncologists can manage care for patients with CRC who are receiving treatment that includes capecitabine without routine laboratory assessment in the absence of symptoms and provide an alternative dosing strategy that includes the oral agent. Oncologists could consider bridging capecitabine with or without oxaliplatin in patients with stage II or III disease whose surgeries are delayed because of the pandemic.

With the exception of Merkel cell carcinoma, most nonmelanoma skin cancer excisions can be safely delayed during the pandemic, according to the NCCN.

 For patients with melanoma, systemic therapy substitution options are offered in cases of drug shortages.

"Our efforts in the cancer clinic have been driven by patient safety and also maintaining patient access to care. In the age of  COVID-19, those 2 things are sometimes at odds with each other."