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Over the past 2 decades, non–small cell lung cancer (NSCLC) has become a poster child for precision oncology. The identification of oncogenic driver mutations to inform targeted therapy selection is the bedrock of clinical practice in this disease, with current estimates suggesting that more than half of patients harbor an actionable mutation.

Yet lung cancer is a genomically complex malignancy and there is significant heterogeneity in the clinical behavior of tumors defined by the same oncogenic driver. As investigators have begun to unravel this complexity, co-occurring mutations have emerged as a potential explanation for some of the intradriver heterogeneity, particularly in patients with KRAS-mutant NSCLC, a notoriously “undruggable” subtype.

The tumor suppressor gene STK11 is mutated across numerous cancer types,4 but has attracted significant attention in recent years as one of the most commonly co-mutated genes observed in KRAS-mutant NSCLC.

 Mutations in the STK11 gene are thought to promote metabolic rewiring in cancer cells, which not only enhances tumor growth and survival but also may be a key driver of therapeutic resistance.

Mutations in another gene involved in regulating metabolic pathways, KEAP1, are closely linked to loss of liver kinase B1 (LKB1); somatic mutations in STK11 and KEAP1 commonly co-occur with each other and with KRAS mutations in NSCLC.

 Although the roles of these co-mutations as prognostic biomarkers and predictors of treatment response remain controversial,7 their presence could guide novel therapeutic options.

The glutaminase inhibitor telaglenastat (CB-839) is designed to target the metabolic rewiring common in cancer cells, including those with STK11 or KEAP1 mutations. Ongoing phase 2 trials of telaglenastat are examining its potential as a treatment for patients with NSCLC and other solid tumors with STK11 and/or KEAP1 mutations. Telaglenastat is among several novel agents being evaluated in clinical trials in biomarker-defined subsets targeted to these mutations (

Found on chromosome 19, the STK11 gene encodes LBK1, a serine/threonine kinase member of the calcium calmodulin family, which is ubiquitously expressed. LKB1 is activated via a phosphorylation-independent allosteric mechanism through the formation of a heterotrimeric complex with 2 accessory proteins, STRAD and MO25. Its activity is fine-tuned through a number of other interaction partners and post-translational modifications that remain poorly understood.

LKB1 is implicated in a range of cellular processes, including cell cycle control, cell polarity, and the DNA damage response, but its best characterized role is in maintain-ng cellular energy homeostasis through activation of AMPK and at least 12 AMPK-related kinases.

In conditions of energy deprivation, LKB1 activates AMPK, which shifts the balance of metabolic activity away from adenosine triphosphate (ATP)–consuming anabolic activities, such as lipid and protein synthesis, toward ATP-generating catabolic processes. Activated AMPK does this by phosphorylating a plethora of key proteins involved in these metabolic pathways. AMPK also directly (through phosphorylation of the Raptor component of the mTORC1 complex) and indirectly (through phosphorylation of TSC2) modulates the activity of a master regulator of cell growth, mTOR, linking cell metabolism to growth control.

STK11 was first identified more than 20 years ago when germline mutations in this tumor suppressor gene were shown to be responsible for Peutz-Jeghers syndrome,11 an inherited disorder characterized by benign gastrointestinal (GI) polyps, skin hyperpigmentation, and an increased risk of several types of cancer, including GI tract, gynecologic, breast, and lung cancers.

With the advent of next-generation sequencing, somatic alterations in the STK11 gene have been identified in approximately 3% of cancers and several hundred different STK11 mutations have been described, although the functional relevance of many of them is not yet known.

 Although rare in most cancer types, STK11 alterations are notably enriched in some, such as lung adenocarcinoma, in which STK11 is the third most commonly mutated gene (approximately 30% of cases).

In addition to loss-of-function mutations in the STK11 gene, other mechanisms can promote LKB1 activity. Because epigenetic events that affect LKB1 at the protein level are not often investigated, LKB1 loss may actually occur in an even greater percentage of lung cancers than is currently assumed.

LKB1 is an unusual oncogene kinase in that the inactivation, rather than the activation, of its kinase activity drives tumorigenesis. Its role as a tumor suppressor is incompletely understood but is thought to be related to the aberrations in AMPK signaling that result from loss of LBK1, impacting cell growth and reprogramming cellular metabolism.

Altered cell metabolism has long been recognized as a hallmark of cancer.14 Metabolic alterations in cancer include the process by which tumor cells derive energy from glucose. In normal cells, glucose is converted into pyruvate in the cytoplasm. The pyruvate is then typically transported into mitochondria, which use oxidative phosphorylation to produce energy in the form of ATP. In contrast, cancer cells instead favor using pyruvate to produce lactate through glycolysis, even when oxygen is plentiful. This method is much less energy efficient and to compensate, cancer cells ramp up their glucose and glutamine uptake.

Loss of LKB1/AMPK activity relieves the inhibition of mTORC1 by AMPK, allowing aberrant activation of mTORC1, which promotes cellular growth and tumorigenesis. In addition, downstream of mTORC1, expression of HIF1α is increased; in turn, this increases expression of the glycolytic enzymes and transporters that shift cancer cell metabolism toward aerobic glycolysis.

Recent study results have suggested that, at least in KRAS-mutant NSCLC, the tumor-suppressive functions of LKB1 may be mediated by the AMPK-related kinases SIK1 and SIK3, rather than AMPK.17 Further, research has suggested that AMPK may play a conditional oncogenic role, in some cases actually conferring a survival advantage to cancer cells as a result of its ability to promote cell survival under conditions of stress.

In lung adenocarcinomas, STK11 mutations frequently occur alongside other driver mutations. STK11 is among the most commonly co-mutated genes in patients with KRAS-mutant NSCLC. According to a recent analysis of KRAS-mutant NSCLC tumor samples, more than half had at least 1 additional mutation, and approximately 20% had a co-occurring mutation in STK11.

STK11 co-mutations have begun to attract considerable attention in recent years as evidence has emerged that they define a unique subset of KRAS-mutant NSCLC. STK11 mutations have been shown to be associated with a more aggressive form of the disease, yielding poorer patient prognosis with significantly reduced survival.

Furthermore, studies have shown that STK11 mutations, either alone or co-occurring with KRAS mutations, may drive resistance to immune checkpoint inhibitor (ICI) treatment of NSCLC; this has been found in patients with single STK11 mutations as well as in those harboring KRAS mutations and is thought to result from the effects of LKB1 loss on the tumor microenvironment. In several studies STK11 mutations were found to be associated with a lack of PD-L1 expression, as well as depletion of tumor-infiltrating lymphocytes and accumulation of immunosuppressive cells and cytokines, suggesting that LKB1 loss promotes an immunologically “cold” microenvironment.

The prognostic and/or predictive role of STK11 mutations remains a topic of debate, as other studies have not been able to confirm these effects. This may be due to overlap between patients with concurrent alterations in the STK11 and KEAP1 genes. When a multivariate analysis was performed to tease apart the impacts of co-mutations in these 2 genes in KRAS-mutant NSCLC, the results revealed that KEAP1, not STK11, was associated with reduced overall survival and poor outcomes with ICI therapy.

KEAP1 is part of an E3 ubiquitin ligase complex that targets the NRF2 protein for proteasomal degradation. NRF2 is a transcription factor that acts as a master regulator of the antioxidant response, activating the expression of hundreds of genes, including NFE2L224, that function to protect the cell and promote survival under conditions of oxidative stress.

STK11 and KEAP1 or NFE2L2 are often found co-mutated with one another and/ or with KRAS in lung adenocarcinomas (FIGURE24), suggesting a synergistic effect of the lack of these 3 proteins in the promotion of tumor progression.2 The frequent occurrence of the triple co-mutation suggests that this condition may satisfy selective pressures as the tumor evolves. For example, it has been proposed that NRF2 pathway upregulation represents a bottleneck in tumors harboring STK11 and KEAP1 mutations; the metabolic stress created by these mutations requires enhanced antioxidant capacity that can be satisfied by KEAP1 loss.

The role of both STK11 and KEAP1 as potential biomarkers, particularly of response to therapy, continues to be evaluated. In the phase 1/2 KRYSTAL-1 trial (NCT03785249), the KRAS G12C inhibitor adagrasib (MRTX849) is being evaluated in cohorts of patients with pretreated KRAS G12C–mutant solid tumors. In the ongoing phase 2 portion of the study, adagrasib is administered at 600 mg twice daily.

At the 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, KRYSTAL-1 investigators presented data from 79 patients with NSCLC (18 from phase 1/1b and 61 from phase 2). In an exploratory analysis of a subset of these patients, the objective response rate was 64% in patients with STK11 co-mutations compared with 33% for patients with wild-type STK11. Meanwhile, there was no apparent trend for response rate among patients with KEAP1 co-mutations.

The identification of STK11 mutations as common oncogenic drivers in certain cancer types has prompted efforts to therapeutically exploit these defects, particularly in patients with KRAS-mutant NSCLC, for whom treatments are currently limited.

Several strategies have been proposed, but evaluation of them has largely been limited to preclinical studies. Given the effects of the LKB1/AMPK pathway on mTOR, investigators have tested commercially available mTOR inhibitors in patients with STK11 mutations, yielding mixed results.

 The ongoing single-arm phase 2 BUNCH basket trial (NCT04518137) is evaluating the dual TORC1/TORC2 inhibitor onatasertib (ATG008) in patients with advanced solid tumors that harbor specific genetic alterations, including STK11 and KEAP1 mutations.

LKB1 also has been shown to play a role in the DNA damage response, and STK11-mutant cancer cells are more susceptible to drugs targeting DNA repair, such as PARP inhibitors.

 The combination of the PARP inhibitor talazoparib (Talzenna) and the ICI avelumab (Bavencio) is being evaluated in patients with STK11-mutant NSCLC in the LUNG-MAP treatment trial (NCT04173507). In addition, a phase 2 trial (NCT03375307) of the PARP inhibitor olaparib (Lynparza), for treating advanced or metastatic urothelial cancer is enrolling patients with DNA-repair defects, including STK11 mutations.

Both STK11 and KEAP1 mutations appear to rewire the metabolism of cancer cells, including increasing their dependence upon glutamine. As a result, drugs that block glutamine production represent a promising strategy.

The glutaminase inhibitor telaglenastat is being tested in combination with pembrolizumab (Keytruda) and chemotherapy as frontline therapy for patients with KEAP1- or NRF2-mutant NSCLC in the phase 2 KEAPSAKE trial (NCT04265534), in which patients are stratified according to STK11 status. Meanwhile, the phase 2 BeGIN trial (NCT03872427) is examining telaglenastat in patients with STK11- or KEAP1/NRF2-mutant advanced solid tumors.

Telaglenastat also has been explored in renal cell carcinoma (RCC), although not in biomarker-specific populations. In the phase 2 CANTATA study (NCT03428217), the combination of telaglenastat plus cabozantinib (Cabometyx) was compared with cabozantinib alone in patients with advanced or metastatic RCC. The combination regimen failed to meet its primary end point of improving progression-free survival (HR, 0.94; P = .065), according to findings disclosed in January 2021 by Calithera Biosciences Inc, the company developing telaglenastat. The company is now focusing on advancing the novel therapy in the KEAPSAKE trial.

Another drug candidate in this class, sirpiglenastat (DRP-104), is a glutamine inhibitor that inhibits all known enzymes involved in glutamine metabolism, not just glutaminase.32 It was granted fast track designation for the treatment of STK11-, NRF2-, or KEAP1mutant NSCLC by the FDA in October 2020.

 A first-in-human clinical trial (NCT04471415) was recently initiated to examine sirpiglenastat alone and in combination with the ICI atezolizumab (Tecentriq) in patients with advanced solid tumors, including STK11-, NRF2-, or KEAP1-mutant NSCLC.

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Articles

The identification of oncogenic driver mutations in non–small cell lung cancer to inform targeted therapy selection is the bedrock of clinical practice in this disease, with current estimates suggesting that more than half of patients harbor an actionable mutation.

Bad Company: Concurrent Mutations  Define Unique Subsets of NSCLC

Five new therapies for the treatment of patients with cervical cancer are in late-stage development that could potentially change clinical practice and set the stage for 2021 to be a banner year for FDA approvals for this malignancy, according to Robert L. Coleman, MD. 

“This is going to be really exciting,” said Coleman, noting that there have been only 2 new drug approvals for cervical cancer in recent years: bevacizumab (Avastin) plus chemotherapy in 2014 and pembrolizumab (Keytruda) for PD-L1 positive disease in 2018.

 award winner in the gynecologic malignancies category, identified the following therapies as among the most promising in the cervical cancer pipeline: lifileucel; balstilimab as a single agent and in combination with zalifrelimab; tisotumab vedotin; cemiplimab-rwlc (Libtayo); and pembrolizumab (Keytruda) in combination with chemotherapy (

Table. Emerging Therapies for Cervical Cancer

®, Coleman discussed key data for these therapies and touched on emerging developments concerning new therapies in ovarian and endometrial cancers. Coleman, a longtime clinical investigator and leader of the Gynecologic Oncology Group Foundation, became chief scientific officer of The US Oncology Network in March 2020.

Lifileucel, formerly known as LN-145, uses autologous tumor-infiltrating lymphocytes (TILs) harvested from tumor fragments to create a patient-specific immunotherapy. In November 2020, Iovance Biotherapeutics, Inc, which is developing the adoptive cell transfer therapy, said the last patient has been dosed in the pivotal cohort of the phase 2 C-145-04 trial (NCT03108495) in patients with recurrent, metastatic, or persistent cervical cancer. The company is discussing assays to define TILs with the FDA and plans to submit a biologics license application (BLA) to the agency this year.

In early findings from the pivotal trial, lifileucel demonstrated a 44% objective response rate (ORR) among 27 patients, including 3 complete responses (11%) and 9 partial responses (33.3%), for an 85% disease control rate, according to data presented at the 2019 American Society of Clinical Oncology Annual Meeting.

 TIL persistence was observed at 6 months in the peripheral blood mononuclear cells of 20 participants available for analysis, suggesting that memory T cells in the TIL therapy can be long lived, investigators said in a poster presented at the European Society for Medical Oncology Virtual Congress 2020 (ESMO 2020).

Another treatment moving forward in the regulatory process is balstilimab, an anti– PD-1 monoclonal antibody. In September 2020, Agenus Inc, the drug’s developer, started a rolling BLA with the FDA for use of balstilimab in recurrent or metastatic cervical cancer based on findings from a single-arm phase 2 trial (NCT03104699).

 The study enrolled patients with squamous cell, adenosquamous, or adenocarcinoma of the cervix who had relapsed or progressed on or after platinum-based treatment.

Balstilimab monotherapy resulted in a 14% ORR among 160 patients in the intentionto-treat population, with a median duration of response (DOR) of 15.4 months (range, 1.1+ to 15.4), according to findings presented at ESMO 2020. The ORR was 19% among participants with PD-L1–positive tumors (19 of 99 patients).

In a separate phase 2 trial (NCT03495882), balstilimab administered in combination with zalifrelimab, a CTLA-4 inhibitor, resulted in an ORR of 22% among 143 patients, with the median DOR not reached (range, 1.3+ to 16.6+ months). The ORR was 27% among those with PD-L1–positive disease (21 of 79 patients).

 The combination is being developed under an FDA fast track designation.

Tisotumab vedotin, another therapy on the horizon, is an antibody-drug conjugate that targets tissue factor, part of the coagulation network, which is highly prevalent in cervical cancer and other solid tumors. Coleman and colleagues presented data at ESMO 2020 from the phase 2 innovaTV 204 trial (NCT03438396) evaluating tisotumab vedotin as monotherapy, if appropriate, in patients with recurrent or extrapelvic metastatic cervical cancer that progressed during or after doublet chemotherapy with bevacizumab.

The ORR was 24% (95% CI, 15.9-33.3) among 101 patients who received tisotumab vedotin, including 7 patients (7%) with a complete response and 17 patients (17%) with a partial response. After a median follow-up of 10 months, the median DOR was 8.3 months (95% CI, 4.3-not reached). The median time to response was 1.4 months (range, 1.1-5.1), with activity generally observed within the first 2 treatment cycles.

Plans call for the phase 3 innovaTV 301 trial (NCT04697628) to start enrolling patients in January 2021. The study will evaluate tisotumab vedotin monotherapy versus physician’s choice of 1 chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed) as second- or third-line treatment for patients with recurrent or metastatic cervical cancer. The trial aims to enroll 482 participants.

Several immune checkpoint inhibitors approved in other indications also are being investigated for cervical cancer. Cemiplimab, a PD-1 inhibitor approved for patients with metastatic or locally advanced cutaneous squamous cell carcinoma, is being evaluated in a phase 3 trial (NCT03257267) as monotherapy versus physician’s choice of chemotherapy in patients with recurrent or metastatic platinum-refractory cervical cancer with squamous cell histology.

In November 2020, investigators reported data from expansion cohorts from a phase 1 trial (NCT02383212) that evaluated cemiplimab as a monotherapy or in combination with hypofractionated radiation therapy in patients with recurrent or metastatic cervical cancer. One of the 10 patients in each cohort achieved a partial response for an ORR of 10% (95% CI, 0.3%-44.5%); both responders had squamous histology. The DOR was 11.2 months and 6.4 months in the monotherapy and combination cohort, respectively.

“In cervix cancer recurrence, if the cemiplimab trial is positive, that would replace chemotherapy with an immune checkpoint inhibitor. We’re monitoring these phase 3 studies that could be reporting in 2021,” Coleman said.

These studies include the phase 3 KEYNOTE-826 trial (NCT03635567), which is testing the PD-1 inhibitor pembrolizumab in combination with investigator’s choice of chemotherapy (paclitaxel plus either cisplatin or carboplatin) with bevacizumab, if appropriate, versus chemotherapy with bevacizumab alone as first-line treatment for patients with persistent, recurrent, or metastatic cervical cancer. Pembrolizumab currently is approved for PD-L1–positive recurrent or metastatic cervical cancer that has progressed on or after chemotherapy.

In the ovarian cancer space, Coleman said, the results of the TRUST trial (NCT02828618) could be practice changing. The trial is comparing primary debulking surgery followed by 6 cycles of standard chemotherapy versus 3 cycles of neoadjuvant chemotherapy followed by interval debulking surgery in patients with newly diagnosed invasive stage IIIB to IVB epithelial ovarian cancer. The study, which is designed for an enrollment of nearly 800 patients, is taking place at 20 centers with a high level of surgical expertise in ovarian cancer.

“This trial is going to be really important from a practice-changing standpoint because if it validates that there is no difference between those 2 modalities, then neoadjuvant chemotherapy will become an even bigger standard. If it refutes it, then it is going to change the way people look at surgical candidacy in ovarian cancer, and that will be practice changing,” Coleman said. 

Coleman also is anticipating the results of the phase 3 ATHENA trial (NCT03522246), which is testing the combination of the PD-1 inhibitor nivolumab (Opdivo) plus the PARP inhibitor rucaparib (Rubraca) as maintenance therapy for patients who have responded to frontline platinum-based chemotherapy and have completed cytoreductive surgery. The study, which aims to enroll 1000 patients, has 4 arms: intravenous (IV) nivolumab plus oral rucaparib or placebo, rucaparib plus IV placebo, and an oral placebo plus an IV placebo. The primary end point is progression-free survival, and secondary end points include overall survival, ORR, and DOR.

“There are a lot of drug combinations that are working their way through [the pipeline], as well as novel treatments, including tumor treatment fields to novel biologics to gene therapy. PARP inhibitors will continue to roll out. We’ll have OS data starting to emerge on some of the mature trials. The exciting story for PARP inhibitors in 2021 is combinations,” Coleman said.

In endometrial cancer, Coleman hopes to see data this year from the phase 3 LEAP-001 trial (NCT03884101), which is studying the combination of pembrolizumab plus lenvatinib (Lenvima) versus the chemotherapy regimen of paclitaxel plus carboplatin. 

“This will be important to see if we can replace chemotherapy in the metastatic, recurrent space,” he said.

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FDA approves pembrolizumab for advanced cervical cancer with disease progression during or after chemotherapy. FDA. Updated June 13, 2018. Accessed January 15, 2021. https:// bit.ly/3qnCXQf 

Iovance Biotherapeutics reports third quarter and year-to-date 2020 financial results and corporate updates. News release. Iovance Biotherapeutics Inc. November 5, 2020. Accessed December 8, 2020. https://bit.ly/2JF681I 

Jazaeri AA, Zsiros E, Amaria RN, et al. Safety and efficacy of adoptive cell transfer using autologous tumor infiltrating lymphocytes (LN-145) for treatment of recurrent, metastatic, or persistent cervical carcinoma. J Clin Oncol. 2019;37(suppl 15):2538. doi:10.1200/JCO.2019.37.15_suppl.2538 

Jazaeri AA, Gontcharova V, Blaskovich M, et al. In vivo persistence of Iovance tumor-infiltrating lymphocytes LN-145 in cervical cancer patients. Ann Oncol. 2020;31(suppl 4):S642. doi:10.1016/j. annonc.2020.08.1012 

Agenus initiates rolling BLA submission of balstilimab for recurrent/ metastatic cervical cancer. News release. Agenus Inc. September 18, 2020. Accessed December 8, 2020. https://bit.ly/39NQuM2 

O’Malley DM, Oaknin A, Monk BJ, et al. Single-agent anti-PD-1 balstilimab or in combination with anti-CTLA-4 zalifrelimab for recurrent/metastatic (R/M) cervical cancer (CC): preliminary results of two independent phase II trials. Ann Oncol. 2020;31(suppl 4):S1142-S1215. https://www.annalsofoncology.org/article/ S0923-7534(20)42346-4/pdf 

Agenus receives fast track designation for balstilimab & zalifrelimab in advanced cervical cancer. News release. Agenus, Inc. March 12, 2020. Accessed December 8, 2020. https://bit.ly/3lZnUtm 

Coleman RL, Lorusso D, Gennigens C, et al. Tisotumab vedotin in previously treated recurrent or metastatic cervical cancer: results from the phase II innovaTV 204/GOG-3023/ENGOT-cx6 study. Ann Oncol. 2020;31(suppl 4):S1142-S1215. doi:10.1016/j. annonc.2020.08.2262 

Rischin D, Gil-Martin M, González-Martin A, et al. PD-1 blockage in recurrent or metastatic cervical cancer: data from cemiplimab phase I expansion cohorts and characterization of PD-L1 expression in cervical cancer. Gynecol Oncol. 2020;159(2):322-328. doi:10.1016/j.ygyno.2020.08.026

Robert L. Coleman, MD, discusses key data for these therapies and touched on emerging developments concerning new therapies in ovarian and endometrial cancers. 

Coleman Looks Forward to a Big Year for New Cervical Cancer Therapies

Multiple myeloma (MM) IS generally considered an incurable malignancy, although a proportion of patients may achieve long-term disease-free survival with a comprehensive and aggressive treatment approach.

 The therapeutic armamentarium has rapidly expanded in recent years because of the approval of novel drugs such as carfilzomib (Kyprolis), ixazomib (Ninlaro), pomalidomide, daratumumab (Darzalex), and selinexor (Xpovio). Others, such as melflufen, likely will come to market in the near future. These drugs have especially improved the treatment options for relapsed disease, with some agents now also being used as frontline therapy. As a result, outcomes for patients with newly diagnosed and relapsed disease continue to improve with prolongation of median survival to greater than 7 years from diagnosis.

Immunotherapy holds great promise for the treatment of MM following the trends seen with developments in the lymphoma field. The addition of the anti-CD20 monoclonal antibody rituximab (Rituxan) to cyclophosphamide, doxorubicin hydrochloride (Adriamycin), vincristine sulfate (Oncovin), and prednisone has greatly improved the prognosis of lymphoma. Additionally, the antibody-drug conjugate (ADC) brentuximab vedotin (Adcetris) has had a similar impact on Hodgkin lymphoma. Innovative immunotherapeutics also are finding their way into the MM field and are set to have a transformative effect on the prognosis of both patients with transplant-eligible and ineligible MM with the possibility of the elusive goal of cure within the reach of many more patients in the not-too-distant future.

Immunotherapy for MM comprises exciting new agents, such as chimeric antigen receptor (CAR) T cells, “naked” antibodies, bispecific antibodies, ADCs, vaccines and new immunomodulatory agents such as the cereblon E3 ligase modulators (CELMoDs). Herein, the focus will be on the development of monoclonal antibody therapeutics.

The anti-CD38 monoclonal antibody daratumumab is approved as frontline therapy for patients with MM who are eligible based on data from the phase 3 Cassiopeia trial (NCT02541383). Investigators evaluated daratumumab (D) in combination with bortezomib, thalidomide, and dexamethasone (D-VTd) versus VTd alone. Patients treated with D-VTd (n = 543) achieved a more frequent stringently defined complete remission compared with those treated with VTd (n = 542) at rates of 39% versus 26%, respectively. Patients also had higher rates of minimal residual disease negativity (64% vs 44%, respectively).

In the GRIFFIN study (NCT02874742), investigators evaluated daratumumab with the lenalidomide, bortezomib, dexamethasone backbone (RVd) as induction and consolidation therapy in patients who were candidates for high-dose therapy with melphalan followed by stem cell transplantation. Overall, patients treated with D-RVd achieved a more frequently stringent complete response compared with those receiving standard RVd (62.6% vs 45.4%, respectively). Patients with standard cytogenetic risk (n = 79) were the principal beneficiaries of therapy with daratumumab (stringent complete response, 49.4%; OR, 2.03; 95% CI, 1.05-3.85).

Data from the ongoing phase 3 PERSEUS registration study (NCT03710603) will determine whether subcutaneous formulation of daratumumab and hyaluronidase human-fihj (Darzalex Faspro) in combination with RVd improves progression-free survival (PFS) in patients with transplant-eligible newly diagnosed MM. It seems likely that the quadruplet regimens of D-RVd and D-VTd will become the new standards of care as upfront therapy in MM. Daratumumab is approved for nontransplant-eligible disease in combination with lenalidomide and dexamethasone; bortezomib, melphalan, and prednisone; as well in the relapse setting in combination with bortezomib, lenalidomide, or pomalidomide.

A second anti-CD38 monoclonal antibody, isatuximab-irfc (Sarclisa), which has a somewhat different mechanism of action and recognizes a different epitope, was approved in 2020 for patients with relapsed/refractory MM based on data from the ICARIA-MM study (NCT02990338). Patients treated with isatuximab, pomalidomide, and dexamethasone had superior PFS compared with those who received pomalidomide and dexamethasone (11.5 vs 6.5 months, respectively).

Elotuzumab (Empliciti) is a monoclonal antibody recognizing the cell surface glycoprotein SLAMF7 or CS1 that was approved for relapsed/refractory MM in combination with lenalidomide and dexamethasone.10 Data from the randomized phase 3 ELOQUENT-3 study (NCT02654132) showed that elotuzumab performed particularly well in combination with pomalidomide and dexamethasone (EPd). Patients in the EPd arm (n = 60) had significantly higher overall response rates (53% vs 26%) and prolonged PFS (10.3 vs 4.7 months) compared with those who received Pd alone (n = 57).

A common theme of this class of antibodies is that these agents are generally well tolerated with manageable toxicities, are easily combined with existing agents, and can be given to elderly patients. It is also important to note that monoclonal antibodies such as daratumumab are used as an adjunct to melphalan-based stem cell transplantation in newly diagnosed patients. Future studies are needed to clarify whether these novel combinations can safely permit delayed transplantation or even avoid transplantation altogether.

A large number of bispecific antibodies are in clinical development for relapsed/ refractory MM.12 Bispecific T-cell engagers (BiTEs) have dual antigen specificity. BiTEs bind to and activate T cells via the CD3/Tcell receptor complex and link activated immune T effectors to MM cells by binding to a MM-associated tumor antigen. In comparison with CAR T cells, bispecific antibodies have advantages such as off-the-shelf use (which eliminates the need for a cellular manufacturing), immediate availability of the drug, and lack of need for lymphodepleting chemotherapy.

A disadvantage of bispecific antibodies is that they are ill-suited for heavily treated patients since their activity is critically dependent on the fitness of the patient’s immune cells. In addition, the short half-life requires continuous infusion and has been an issue in some studies. As with CAR T cells, bispecific antibodies can have significant adverse effects, including cytokine release syndrome and neurotoxicity. Most bispecific antibodies are directed at B-cell maturation antigen (BCMA); however, other targets are under investigation, including CD56, CD38, Fc receptor-like protein 5 (FCRL5), and G-protein coupled receptor family C group 5-member D (GPRC5D).

Data from a phase 1 clinical trial (NCT02514239) investigating the BiTE molecule AMG 420 that targets BCMA showed a response rate of 70% at the maximum-tolerated dose of 400 mg/day with 5 of 10 patients achieving a stringently defined complete response.

 Investigators are evaluating AMG 701, a BiTE molecule modified to have a longer half-life, in a successor clinical trial (NCT03287908).

ADCs are monoclonal antibodies that target a cytotoxic cargo to MM cells. Upon binding to the target antigen, the ADC complex is internalized, and then the cytotoxic molecule is released. The ADC class of monoclonal antibodies is attractive because the agents can be safely used in patients with a high disease burden without the risk of cytokine release syndrome or neurotoxicity. Belantamab mafodotin-blmf (Blenrep) is an ADC that targets BCMA and is conjugated to the microtubule poison monomethyl auristatin F. The agent was recently approved for relapsed/ refractory MM based on data from the DREAMM-2 study (NCT03525678) in which it demonstrated responses in patients who had received a median of 7 prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.

Corneal keratopathy was the principal adverse effect observed. Belantamab mafodotin is administered under a risk evaluation and mitigation strategy program. Studies of the agent in combination with MM backbone drugs are ongoing.

Monoclonal antibodies have made a significant impact on the treatment landscape of MM. Current and future studies will define how best to incorporate these agents into the developing treatment stratagems for patients with both newly diagnosed and relapsed MM.

Barlogie B, Mitchell A, van Rhee F, Epstein J, Morgan GJ, Crowley J. Curing myeloma at last: defining criteria and providing the evidence. 

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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. 

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

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Facon T, Kumar S, Plesner T, et al; MAIA Trial Investigators. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. 

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Mateos MV, Cavo M, Blade J, et al. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. 

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Palumbo A, Chanan-Khan A, Weisel K, et al; CASTOR Investigators. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Eng J Med. 2016;375(8):754-766. doi:10.1056/ NEJMoa1606038

Dimopoulos MA, Oriol A, Nahi H, et al; POLLUX Investigators. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. 

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Chari A, Suvannasankha A, Fay JW, et al. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. 

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Attal M, Richardson PG, Rajkumar SV, et al; ICARIA-MM study group. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. 

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Lonial S, Dimopoulos M, Palumbo A, et al; ELOQUENT-2 Investigators. Elotuzumab therapy for relapsed or refractory multiple myeloma. 

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Blenrep. Prescribing information. GlaxoSmithKline; 2020. Accessed January 7, 2021. https://www.accessdata.fda.gov/ drugsatfda_docs/label/2020/761158s000lbl.pdf

Novel drugs have especially improved the treatment options for relapsed myeloma, with some agents now also being used as frontline therapy. As a result, outcomes for patients with newly diagnosed and relapsed disease continue to improve with prolongation of median survival to greater than 7 years from diagnosis.

Monoclonal Antibodies Prove to Be   Novel Therapeutics for Myeloma 

Relugolix (Orgovyx) rapidly suppresses testosterone (T) levels in men with advanced prostate cancer with a markedly lower risk of cardiovascular events than leuprolide, paving the way for a new hormonal therapy for this population. In December 2020, the drug became the first oral gonadotropin-releasing hormone (GnRH) receptor antagonist to gain FDA approval.

The FDA approved relugolix based on data from the phase 3 HERO trial (NCT03085095) in men who required at least 1 year of androgen deprivation therapy (ADT) with either prostate cancer recurrence following radiation or surgery or newly diagnosed castration-sensitive advanced disease. Participants were randomly assigned to a loading dose of oral relugolix 360 mg on the first day followed by daily doses of 120 mg or 22.5 mg of leuprolide, a luteinizing hormone-releasing hormone (LHRH) agonist, administered via subcutaneous injection every 3 months for 48 weeks.

Investigators found that 96.7% (95% CI, 94.9%-97.9%) of patients who received relugolix (n = 622) achieved and maintained serum T at castration levels (< 50 ng/dL) through 48 weeks compared with 88.8% (95% CI, 84.6%-91.8%) of those who received leuprolide (n = 308).

 Further, relugolix was associated with a significant reduction in major adverse cardiovascular events (MACE) compared with leuprolide in patients with advanced disease after 48 weeks of treatment (2.9% vs 6.2%, respectively).

Currently available medical ADT options, which include LHRH agonists such as leuprolide and goserelin, have been a mainstay of treatment for men with advanced prostate cancer but are only available in injectable formulations and are associated with an elevated risk of cardiovascular disease, according to an FDA reviewed of the relugolix application. Degarelix (Firmagon), the only GnRH receptor antagonist available for prostate cancer treatment in the United States before the relugolix approval, also is an injectable formulation.

, Neal D. Shore, MD, lead investigator for the HERO trial, explained how relugolix could affect the standard of care for men with advanced prostate cancer. Shore is medical director of the Carolina Urologic Research Center in Myrtle Beach, South Carolina. In early January 2021, he prescribed relugolix for the first time post approval to treat a 77-year-old man with advanced disease who displayed cardiovascular risk factors.

: What is the clinical utility for relugolix compared with standard-of-care LHRH agonists?

At the end of 48 weeks, we looked at testosterone recovery in roughly 184 patients in both arms who finished treatment. Fifty-three percent of the relugolix patients were back to normal testosterone levels, ostensibly eugonadal, and only 3% of the LHRH agonist patients were back to being eugonadal at 90 days. This is really a nice advantage—the faster recovery for patients who may consider intermittent ADT or who may be on a shorter course of 6 to 12 months for adjuvant/neoadjuvant radiation therapy strategies.

Neal D. Shore, MD, discusses the FDA approval of relugolix in prostate cancer.

Vol. 22/No. 03 | Oncology Live®

Bad Company: Concurrent Mutations Define Unique Subsets of NSCLC

Coleman Looks Forward to a Big Year for New Cervical Cancer Therapies

Monoclonal Antibodies Prove to Be Novel Therapeutics for Myeloma

Oral Hormonal Therapy Breaks New Ground in Prostate Cancer

Cancer Staging and Toxicity Framework Should Be Overhauled for the Modern Era

Harnessing the Potential of Cell and Gene Therapy

Seribantumab May Hold Pan-Tumor Potential in Cancers With NRG1 Fusions