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Up to 20% men with advanced prostate cancer will develop castration-resistant prostate cancer (CRPC) within approximately 5 years of follow-up, with more than 84% having metastases at the time of CRPC diagnosis.

Among those with nonmetastatic CRPC at diagnosis, 33% are likely to develop metastatic CRPC (mCRPC) within 2 years. Despite advances in treating CRPC, 5-year overall survival (OS) remains low (median OS for CRPC, 9-30 months).

, a panel of experts in advanced prostate cancer provided their insights on how best to employ 6 therapies that are enabling men with mCRPC to live longer: docetaxel (Taxotere), cabazitaxel (Jevtana), sipuleucel-T (Provenge), abiraterone acetate (Zytiga), enzalutamide (Xtandi), and radium-223 dichloride (Xofigo). “We have obtained a plethora of life-prolonging agents since 2010…Some of us on the panel are old enough to remember when it was very nihilistic for patients with metastatic disease,” said moderator Neal Shore, MD.

Taxane-Based Chemotherapy: Docetaxel and Cabazitaxel

In 2004, the microtubule inhibitor docetaxel became the first life-prolonging therapy approved by the FDA for patients with mCRPC. It remained the only agent with this distinction until 2010.

 “Docetaxel has 2 phase 3 trials published in the 

 that show an OS benefit,” said panelist Pedro C. Barata, MD, MSc.

The first study compared 12 mg of mitoxantrone per m

 of body surface area (BSA) every 3 weeks with 75 mg of docetaxel per m

 of BSA every 3 weeks or 30 mg of docetaxel per m

 All study participants (N = 1006) received 5 mg of prednisone twice daily. Compared with the men in the mitoxantrone group, those given docetaxel every 3 weeks had a hazard ratio for death of 0.76 (95% CI, 0.62-0.94; 

 = .009 by stratified log-rank test) and those given weekly docetaxel had an HR for death of 0.91 (95% CI, 0.75-1.11; 

 = .36). The median OS was 16.5 months, 18.9 months, and 17.4 months in the mitoxantrone, docetaxel every 3 weeks, and docetaxel weekly groups, respectively. Compared with mitoxantrone, docetaxel every 3 weeks also led to improvements in the study’s secondary end points of pain, prostate-specific antigen (PSA) levels, and quality of life.

The second study randomly assigned 674 men to a docetaxel plus estramustine arm (n = 338; 280 mg of estramustine 3 times daily on days 1 through 5, 60 mg of docetaxel per m

 of BSA on day 2, and 60 mg of dexamethasone in 3 divided doses before docetaxel) or a mitoxantrone plus prednisone arm (n = 336; 12 mg of mitoxantrone per m2 of BSA on day 1 plus 5 mg of prednisone twice daily), with each arm receiving treatment in 21-day cycles.

 In an intention-to-treat analysis, the median OS was 17.5 months in the docetaxel plus estramustine arm and 15.6 months in the mitoxantrone plus prednisone arm, a finding that reached statistical significance (

 = .02 by the log-rank test). The corresponding HR for death was 0.80 (95% CI, 0.67-0.97). The secondary end points of progression-free survival (PFS), objective response rate, and posttreatment declines of at least 50% in serum PSA levels were also improved in the docetaxel plus estramustine arm.

Like docetaxel, cabazitaxel is a microtubule inhibitor. It was approved by the FDA in 2010.

 “[Cabazitaxel] is a cousin of docetaxel with a different safety profile, and it is approved for use after docetaxel,” Barata said. It has been associated with a low rate of grade 3 peripheral neuropathy, which has been noted to be an important aspect of its profile because patients previously treated with docetaxel may have some residual chemotherapy- induced peripheral neuropathy.

 The most common adverse effects associated with both agents are summarized in the 

Figure. Most Common Adverse Effects Associated With Docetaxel and Cabazitaxel

Cabazitaxel showed an OS benefit in the TROPIC trial (NCT00417079), which randomly assigned 755 men to receive intravenous (IV) cabazitaxel 25 mg/m

 every 3 weeks (n = 378) or IV mitoxantrone 12 mg/m

 every 3 weeks (n = 377), with both cohorts receiving 10 mg oral prednisone daily.

 The cabazitaxel plus prednisone arm had a median OS of 15.1 months, whereas the mitoxantrone arm had a median OS of 12.7 months (HR for death, 0.7; 95% CI, 0.59-0.83; 

 < .0001). Median PFS was also improved in the cabazitaxel group (2.8 vs 1.4 months; HR, 0.74; 95% CI, 0.64-0.86; 

Sipuleucel-T is an autologous cellular immunotherapy that is designed to stimulate T cells to respond to cancer cells by targeting prostatic acid phosphatase, an antigen expressed in more than 95% of all prostate cancers.

 In 2010, it became the first therapeutic cancer vaccine to be approved by the FDA.

 It is indicated for men with asymptomatic or minimally symptomatic mCRPC.

Approval was based on 3 phase 3 studies involving 737 patients.

 Among these was the pivotal IMPACT trial (NCT00065442), which included 512 patients who were randomly assigned 2:1 to receive IV sipuleucel-T (n = 341) or matched placebo (n = 171) given every 2 weeks, for a total of 3 infusions.

 Patients in the sipuleucel-T arm experienced an improvement in median OS of 4.1 months compared with the placebo arm (25.8 vs 21.7 months; HR for death, 0.78; 95% CI, 0.61-0.98; 

 = .03). No difference in time to objective disease progression was observed between the 2 groups.

A subanalysis of the IMPACT trial that examined the prognostic and predictive value of baseline variables found that patients with the lowest baseline PSA values (≤22.1 ng/mL) had the greatest survival benefit with sipuleucel-T.

 The estimated improvement in median OS ranged from 13.0 months in the patients in the lowest baseline PSA quartile to 2.8 months in the highest quartile (>134 ng/mL).

AR-Targeted Therapy: Abiraterone Acetate and Enzalutamide 

“Androgen receptor [AR]–targeted therapies, most people would agree, are the standard of care for most patients with mCRPC, whether [the agent is] abiraterone or enzalutamide. This is because of the preponderance of evidence, the quality of the evidence, and, for most of our patients, the tolerability of the drugs and the way in which they work,” said panelist William K. Oh, MD.

Abiraterone acetate is an oral, once-daily treatment for men with mCRPC. In 2011, it was approved for use in combination with prednisone in men with mCRPC previously treated with docetaxel, based on data from the phase 3 COU-AA-301 study (NCT00638690).

 In 2012, the FDA expanded this indication to include men with chemotherapy-naïve mCRPC, based on data from the phase 3 COU-AA- 302 study (NCT00887198).

COU-AA-301 randomly assigned 1195 patients previously treated with docetaxel in a 2:1 ratio to 1000 mg of abiraterone acetate (n = 797) or placebo (n = 398), with both arms also receiving 5 mg of prednisone twice daily.

 After a median follow-up of 12.8 months, the OS was 14.8 months in the abiraterone arm and 10.9 months in the placebo arm (HR, 0.65; 95% CI, 0.54-0.77; 

 < .0001). All secondary end points, including PSA progression, PFS, and PSA response rate, also favored abiraterone treatment.

COU-AA-302 randomly assigned 1088 asymptomatic or mildly symptomatic patients with chemotherapy-naïve prostate cancer stratified by ECOG performance status (0 vs 1) in a 1:1 ratio to abiraterone acetate 1000 mg once daily plus prednisone 5 mg twice daily (n = 546) or matching placebo plus prednisone (n = 542).

 The final OS analysis showed a significantly longer median OS in the abiraterone arm than in the placebo arm (34.7 vs 30.3 months; HR, 0.81; 95% CI, 0.70-0.93; 

 = .0033). A subanalysis of the study found abiraterone plus placebo similarly increased OS in all patients with mCRPC, regardless of their pain, baseline PSA levels, and Gleason score at primary diagnosis.

Like abiraterone acetate, enzalutamide is a once-daily oral treatment. It was approved in 2012 based on data from the phase 3 AFFIRM trial (NCT00974311) as a treatment for patients with mCRPC who have previously received docetaxel.

 In 2014, enzalutamide’s indication was expanded to include men with chemotherapy- naïve mCRPC, based on data from the phase 3 PREVAIL trial (NCT01212991).

The AFFIRM trial stratified 1199 men with mCRPC after chemotherapy according to ECOG performance status and pain intensity, then randomly assigned them 2:1 to enzalutamide 160 mg daily (n = 800) or matching placebo (n = 399).

 The median OS was 18.4 months in the enzalutamide arm compared with 13.6 months in the placebo arm (HR for death in enzalutamide group, 0.63; 95% CI, 0.53-0.75; 

The PREVAIL trial randomly assigned 1717 men with chemotherapy-naïve mCRPC to receive enzalutamide 160 mg daily or matched placebo.

 A total of 626 patients (72%) in the enzalutamide group and 532 patients (63%) in the placebo group were alive at the data cutoff date, indicating a 29% reduction in the risk of death with enzalutamide (HR, 0.71; 95% CI, 0.60-0.84; 

“An important thing I learned is not to forget about osteoporotic fractures. We’re all focused on cancer, cancer, cancer. But what happens is this adjunctive therapy is leading to some real morbidity in these patients,” Oh cautioned. “If you’re on any of these combinations—on radium-223 plus any AR-targeted therapy, or even if you’re on AR-targeted therapy alone— there’s a much higher rate of osteoporotic fractures than we appreciated, up to a third. If you’re just on AR-targeted therapy, it’s still up to 5% to 10%.” Consequently, Oh recommends undertaking bone density tests and placing patients with bone disease on bone-protecting agents like zoledronic acid or denosumab.

Radium-223 dichloride is a radioactive isotope that causes irreversible DNA doublestrand breaks, ultimately leading to tumor cell apoptosis. It is a calciummimetic agent that specifically targets bone lesions. It was approved in 2013 for men with mCRPC and symptomatic bone metastases but no known visceral involvement.

 “It’s the first bone-targeted agent to show a survival benefit in that space, which is quite remarkable and, for some of us, a little unexpected,” Barata said.

Radium-223 dichloride was approved based on data from the pivotal phase 3 ALSYMPCA trial (NCT00699751), which included 921 patients who had received, were not eligible for, or had declined docetaxel, and randomly assigned them 2:1 to receive 6 injections of radium-223 or matching placebo; the injections were administered once every 4 weeks.

 Patients also received the best standard of care, which included agents like ketoconazole, estramustine, and other oral therapies. Radium-223 was associated with significantly improved median OS compared with placebo (14.9 vs 11.3 months; HR, 0.70; 95% CI, 0.58-0.83; 

 < .001). Radium-223 was also associated with benefit over placebo in all secondary end points, including time to the first symptomatic skeletal event and various biochemical end points.

“If we want to use radium-223, we really want to commit the patient to 5 or 6 cycles because we know they perform better. Fit patients and those with ECOG performance status 0 to 1 do better. We exclude patients who have nodal involvement with a lymph node greater than 3 cm or visceral disease. The more recent and important data that we have indicate that adding radium-223 to abiraterone has a negative safety signal, so we want to stay away from that,” Barata said.

Although abiraterone should be avoided, the panelists noted that other agents could be added. “It’s very reasonable to consider enzalutamide plus radium-223 and to start them at the same time…If you want, sandwich in some sipuleucel-T before you use both of those,” said panelist Nancy Ann Dawson, MD. She noted that the enzalutamide enables PSA reduction, which the panelists explained does not occur with radium-223 alone.

“A lot of us get concerned because we’re giving a treatment to our patient for half a year and we can see PSA continue to rise and we might see more disease on the scans. That creates a lot of pressure—for patients, too, because they don’t want to see PSA rising,” Barata said. Subsequently, he said he uses an AR–directed therapy first.

The panelists discussed the interesting finding that racial discrepancies in OS have been observed among men treated with radium-223. “We have real-world data showing a signal for survival favoring African Americans—a huge difference in survival compared with Caucasians,” Barata said. A study that reviewed the charts of all men in the Veterans Affairs system who received radium-223 found that black race was associated with a decreased risk of mortality from the time of radium-223 initiation (HR, 0.75; 95% CI, 0.57- 0.99; 

 = .045), despite black men receiving this treatment later in their disease course than nonblack men.

 Subsequently, Barata said this is a factor he considers when determining the best treatment for his patients, acknowledging that sometimes multiple treatments of equal benefit are available.

Few data are available to guide treatment selection and sequencing of the 6 available life-prolonging therapies for mCRPC, but the panelists shared their insights on how they make such decisions. “If I used chemotherapy in the upfront setting, then I certainly can use cabazitaxel in the mCRPC setting, but I also have the option of using 1 of the androgen receptor–directed therapies,” said panelist Alicia K. Morgans, MD, MPH. She explained that she always thinks about what the patient was treated with before, whether in the nonmetastatic CRPC setting, the metastatic hormone-sensitive setting, or the mCRPC setting. “I always think about changing the mechanism of action. That’s what we need to do and what we find is most effective: not necessarily chemotherapy to chemotherapy, but particularly with the AR-directed therapies…Changing mechanism of action and not sequencing AR therapy after AR therapy is a key tenet to the way I think through things and the way I talk to patients,” she said.

Shore concurred, adding that data indicate a lot of AR–AR sequencing still happens in clinical practice, despite its not being an ideal streategy. “It may just be because it’s convenient. It’s exchanging 1 oral therapy for another oral therapy,” he said. The panelists proceeded to discuss the CARD trial (NCT02485691), which examined this issue and garnered a lot of attention at the 2019 European Society for Medical Oncology (ESMO) Annual Congress.

The CARD trial assessed the efficacy and safety of cabazitaxel versus the AR-therapy abiraterone or enzalutamide in 255 patients with mCRPC who were previously treated with docetaxel and had progression within 12 months of initiating the alternative inhibitor (ie, abiraterone, enzalutamide).

 “In this trial, cabazitaxel had a very demonstrable benefit in terms of radiographic progression–free survival, as well as overall survival, in this trial as compared with second AR-targeted agent,” Morgans said. Trial outcomes are summarized in the 

Table. Primary and Secondary Outcomes of the CARD Trial

Morgans explained that data from the PROfound study (NCT02987543), which were also presented at 2019 ESMO, showed similar results with the PARP inhibitor olaparib (Lynparza) versus enzalutamide or abiraterone in men with mCRPC selected for 

 gene mutations who had progressed on prior treatment with either enzalutamide or abiraterone.

 She said a 3.5-month improvement in PFS was observed with olaparib. “To me, this just drives home the message that AR after AR, which is what [many] do at this point, is just not the right thing to do,” she said.

Dawson pointed out that data indicate that quality of life will also be improved by switching to a treatment with another mechanism of action, rather than swithcing between AR-targeted therapies. “Even though the response rate to the second [AR-targeted therapy] is 15% at best, we still did it because patients were saying, ‘I don’t want to get chemotherapy—isn’t there another oral drug you can give?’ Now you can go to the patient [and say,] ‘We could do that, but your response rate, your quality of life, and your pain will be better if we go straight to the chemotherapy.’ They’re assuming that their quality of life is going to be worse. And now we can say, ‘No, we have data. Not only is your response rate going to be higher, but the quality of your life is going to be better,’ ” she said.

The panelists concluded by discussing some emerging therapies about which they were particularly excited. The PARP inhibitors olaparib and rucaparib (Rubraca) were both of interest and still pending FDA approval at the time of the Peer Exchange, but in May 2020, both were approved just days apart. Rucaparib received accelerated approval for men with deleterious 

 mutations (germline and/or somatic) associated with mCRPC previously treated with AR-targeted therapy and a taxane-based chemotherapy.

 mutations (germline and/or somatic) associated with mCRPC that progressed following prior treatment with an AR-targeted therapy.

 Although only a small number of patients have such mutations (≤20%), Shore emphasized the importance of testing for these mutations early because they open the door to additional powerful treatments that may improve OS for a certain subset of patients with mCRPC.

Morgans expressed excitement over radiopharmaceuticals, which are still in clinical trials, including the phase 3 VISION study (NCT03511664), which has completed enrollment and is comparing 177 lutetium-PSMA-617 plus best supportive/standard care with best supportive/standard care alone in men with mCRPC.

 “The trial will hopefully give us some data in the next year or so,” she said.

Although immunotherapy treatments have generally been disappointing in patients with prostate cancer, Barata said studies are starting to tease out who may benefit from them. “I’m thinking [about] the 2% to 3% of patients with microsatellite instability…In data that were presented at ESMO, we learned that 

 is not a good biomarker for PARP inhibition, but it might be something to pay attention to in terms of immunotherapy.” The retrospective study found a PSA reduction of at least half among 33.3% of men with 

-altered mCRPC who were treated with a PD-1 inhibitor in the fourth to sixth line (n = 9).

 These men also demonstrated a median PFS of 5.4 months, which was longer than the PFS interval observed with some treatments used in earlier lines.

Oh concluded the panel by saying that the most exciting thing to him is that the nuances of prostate cancer are being increasingly unraveled. “We’re starting to take the science and look at individual patients, and not just view prostate cancer as 1 disease, because it’s too heterogeneous [to do that]. We’re starting to define it molecularly, which will enable us to treat patients in a targeted way,” he said.

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Articles

Features

During a recent OncLive Peer Exchange, a panel of experts in advanced prostate cancer provided their insights on how best to employ 6 therapies that are enabling men with mCRPC to live longer. 

Experts Focus on 6 Life-Prolonging Treatments for mCRPC

Investigators are working on a new generation of therapies that activate CD40, an immune checkpoint that helps promote an antitumor response by boosting T-cell–stimulatory signals. Although efforts to hit this target have often proved disappointing in clinical trials over the past 2 decades, recent strategies focusing on new drug designs and novel combinations are reviving hopes for success.

Ongoing clinical efforts are directed at exploring combinations that could expand the impact of immunotherapy into immunologically “cold” tumors by exploiting complementary mechanisms of action.

In preliminary clinical trial results, APX005M, a CD40-directed monoclonal antibody (mAb) being developed by Apexigen, showed promise for treating notoriously immunotherapy-resistant pancreatic ductal adenocarcinoma (PDAC) in combination with chemotherapy and with or without the anti-PD–1 mAb nivolumab (Opdivo).

Other pharmaceutical companies are follow-ing Apexigen’s lead and pursuing similar combinations in PDAC with the goal of providing immunotherapeutic inroads into this challenging tumor type.

At least 10 novel agents are being tested in clinical trials, frequently in combination with chemotherapy or immune checkpoint immunotherapy, according to a search of the ClinicalTrials.gov website (Table).

Table. Clinical Development of CD40 Agonists

CD-40 is a member of the tumor necrosis factor receptor (TNFR) superfamily, a group of structurally related receptors and their ligands that provide critical communication signals between various cell types, including immune cells, where they play key roles in innate and adaptive immune responses.

). The goal of therapeutically targeting CD40 is to activate CD40+ antigen-presenting cells (APCs) to boost the antitumor immune response by stimulating tumor-specific cytotoxic T cells.

Figure. Targeting CD40 in the Immune System

CD40 is a transmembrane receptor that is constitutively expressed predominantly on APCs, such as macrophages, dendritic cells (DCs), and B cells, but it is also found on plate-lets and some nonhematopoietic cells.

 CD40 expression has also been shown on malignant cells across a variety of cancer types, including bladder cancer, melanoma, lung cancer, colorectal cancer, and several B-cell malignancies, and has frequently been associated with improved outcomes.

The CD40 ligand, CD40L (also known as CD154), is also a transmembrane protein whose expression is induced on the surface of activated CD4+ T cells, B cells, and natural killer (NK) cells, among others.

 Interestingly, this receptor-ligand localization pattern is unique within the TNFR superfamily and reflects the early role of CD40 in the adaptive immune response, as the TNF ligand (not the receptor) is typically expressed on the APC.

CD40L naturally assembles into trimers at the cell surface, and their binding to CD40 receptor molecules leads to receptor clustering and the formation of a signaling complex that is required for intracellular signal transmission via the recruitment of TNFR-associated factors (TRAFs). Depending on the specific TRAFs and other cytoplasmic adapter proteins that are engaged, CD40 activation can trigger a number of downstream signal-ing cascades, including the MAPK, PI3K, and NFκB pathways.

The physiological outcomes of CD40 path-way activation are varied and complex, but one of its central functions is as a major molecular mediator of the capacity of CD4+ helper T cells to trigger tumor cell–specific cytotoxicity.

It does this by licensing DCs to activate CD8+ cytotoxic T cells via upregulation of DC-surface expression of major histocompatibility complex molecules (to facilitate antigen presentation) and other costimulatory molecules, which provide the secondary signal for T-cell activation. CD40 pathway activation also promotes the production of proinflammatory immunostimulatory cytokines that further modulate T-cell activity.

In the absence of CD40, unlicensed DCs drive T-cell exhaustion and the generation of immunosuppressive regulatory T cells. CD40 plays similar roles in B- and NK-cell activation; thus, its effects span innate and adaptive immune responses, as well as cellular and humoral immunity.

Giving the Antitumor Immune Response a Push

As an immune costimulatory molecule, CD40 is targeted with agonistic compounds. From a pharmacological perspective, agonists are much more challenging to develop than antagonistic agents. Although the major focus has been on CD40 mAbs, the first drug to enter development in the early 2000s was a recombinant form of CD40L. In a first-in-human study, 32 patients with advanced solid tumors or non-Hodgkin lymphoma (NHL) were treated with trimeric recombinant human CD40L. 

There were 2 objective responses, including a durable complete response (CR) in a patient with head and neck squamous cell carcinoma. The maximum-tolerated dose was defined by grade 3/4 elevated transaminase levels,

 which are now known to be a class effect of CD40-targeted therapies.

The clinical development of agonist CD40 mAbs began a few years later, but they had already demonstrated significant promise in preclinical trials.

 Unfortunately, that did not necessarily translate into success in human patients; clinical activity with single-agent CD40 mAbs was modest.

The most extensive clinical experience has been with Roche’s selicrelumab (formerly known as RO7009789 and CP-870,893), with development ongoing. In a first-in-human single-dose study (NCT02225002), selicrelumab produced partial responses (PRs) in 27% of patients with advanced melanoma. One patient continued to receive selicrelumab every 1 or 2 months for a year (NCT02157831) and achieved complete remission, which is ongoing 15 years later without additional therapy. Among patients with other solid tumors, however, the best response to single-dose selicrelumab was stable disease (SD).

 In a subsequent trial, weekly infusions of selicrelumab produced no objective responses, even among patients with melanoma.

 Development is now moving forward with combinatorial strategies. 

Preclinical and clinical studies have revealed new insights into the role of the CD40 pathway in normal physiology and the potential antitumor activity of CD40 agonists; this knowledge is informing ongoing research. In addition to their effects on the immune system, CD40 agonists can directly target CD40-expressing tumor cells and have been shown to directly inhibit tumor cell proliferation and trigger apoptotic cell death.

CD40 also has an important T-cell– independent function in monocyte differentiation, preferentially driving the development of the proinflammatory, tumoricidal (M1) type of macrophages, which could also contribute to the antitumor activity of CD40targeted drugs.

Importantly, because CD40 mAbs are bivalent, CD40 cross-linking facilitated by Fcγ receptors (FcγRs) is thought to be required for their agonist activity, as clustering of the CD40 receptor triggers intracellular signaling. Engagement of FcγRs promotes several effector functions of mAbs, including antibody-dependent cellular cytotoxicity, thus representing an additional mechanism by which some CD40 agonists might mediate target cell elimination.

Although FcγR-mediated cross-linking is required for the mouse mAbs used in preclinical development, ongoing debate exists over its importance for the human mAbs in clinical development.

Selicrelumab is an immunoglobulin G2 (IgG2) mAb that has been shown to have very low binding affinity to human FcγRs and to have FcγR-independent agonist activity as a result of structural features.

 Other authors, however, have concluded that all human CD40 mAbs require FcγR-mediated cross-linking for optimal activity and that the IgG2 design of selicrelumab is the major impediment to its antitumor efficacy.

 Meanwhile, some investigators argue that limiting FcγR-mediated cross-linking and the associated enhancement of mAb activity could help mitigate the toxicity of CD40 agonists.

This debate and the search for new CD40targeted drugs that strike an optimal balance between antitumor efficacy and toxicity are the driving forces behind ongoing drug development. 

Some drug companies have pursued IgG2 mAbs similar to selicrelumab and attempted to reduce agonist activity, following the logic that the toxicity associated with very potent agonists means they must be administered at low doses. This might not achieve saturation of CD40 on target APCs because of off-target binding to nonimmune cells with systemic administration.

CDX-1140 (Celldex Therapeutics) is a fully human IgG2 mAb with lower in vitro agonist activity compared with selicrelumab. In a preclinical study, its effects on immunological parameters were not significantly different from those of selicrelumab, and there was no evidence of clinically meaningful toxicity was observed in cynomolgus monkeys.

Results from a phase 1 clinical trial (NCT03329950) in patients with advanced solid tumors or NHL were presented at the annual meeting of the Society for Immunotherapy of Cancer in 2019. Among 62 patients (38 with activity assessments available), 6 treated with CDX-1140 monotherapy at doses ranging from 0.01 to 3 mg/ kg and 2 participants who received CDX-1140 plus CDX-301, a DC growth factor, experienced immune SD lasting up to 5.4 months. The most common treatment-related adverse events (TRAEs) were arthralgia, nausea, and fatigue; serious TRAEs included fatigue, cytokine release syndrome (CRS), pneumonitis, nausea, and pyrexia.

Most companies are developing IgG1-based mAbs, and many are modifying the Fc region of the antibody to enhance FcγR binding in a bid to exploit the activity boost conferred by CD40 cross-linking. Additionally, the absence of a core fucose molecule in the Fc region has been shown to increase IgG1 Fc binding affinity to an FcγR that is involved in antibody-dependent cellular cytotoxicity19; thus, strategies to enhance the potency of CD40 mAbs have included the development of nonfucosylated varieties.

Among these is SEA-CD40 (Seattle Genetics), which investigators are evaluating in an ongoing phase 1 study (NCT02376699), and interim results were presented at the American Society for Clinical Oncology Annual Meeting in 2018. At the time of presentation, 48 patients with advanced solid tumors had received a median of 2 cycles of SEA-CD40 monotherapy at doses ranging from 0.6 to 60.0 µg/kg on day 1 (n = 38) or 30 µg/kg on days 1 and 8 (n = 10) intravenously every 3 weeks. 

Dose-limiting toxicities (DLTs) consisted of infusion-related reactions (IRRs) in 5 patients, and the most common treatment-emergent AEs were IRRs, chills, fatigue, nausea, vomiting, dyspnea, and headache. One patient with basal cell carcinoma had a PR, and 10 patients achieved SD.

 Despite being an Fc-modified IgG1 mAb, SEA-CD40 is still reportedly at the weaker end of the agonist spectrum.

At the other end of that spectrum is APX005M, a humanized rabbit IgG1 Fc-engineered mAb. APX005M also binds the CD40L binding site and is the most similar, in terms of its molecular features and pharmacodynamics, to the mouse mAbs used in preclinical development.

In a first-in-human clinical trial, APX005M was administered every 3 weeks at doses ranging from 0.0001 to 1.0 mg/kg in 30 patients with advanced solid tumors. Five patients experienced prolonged SD. Most AEs were mild to moderate in severity, with a DLT of grade 3 and higher CRS observed at doses of at least 0.6 mg/kg.

An Fc-engineered version of selicrelumab is also in development. Investigators at The Rockefeller University in New York, New York, introduced point mutations into the selicrelumab Fc domain to increase FcγR binding and agonist activity. In a mouse model, a V11 Fc variant had improved antitumor activity compared with selicrelumab; higher doses led to even greater activity enhancement but also increased toxicity.

To reduce the toxicity of CD40 mAbs, investigators are exploring alternative dosing strategies. In a mouse model, directly injecting the V11 Fc variant into the tumor site led to a significantly lower tumor burden compared with systemic administration. Moreover, no substantial toxicity was observed, and many mice displayed long-term survival.

 The anti-CD40 agonist, now called 2141-V11, is being evaluated as an intratumoral injection in patients with skin lesions associated with their cancer in a small phase 1 clinical trial (NCT04059588). 

Using recombinant CD40L bypasses the issue of FcγR-mediated cross-linking, and several companies are returning to the idea of designing improved versions of this strategy. AstraZeneca is developing MEDI5083, a fusion protein composed of a trivalent but single-chain CD40L receptor–binding domain linked to a human IgG, thereby generating a hexavalent molecule. Such higher-order receptor/ligand multimers have been shown to be superior at transmitting TNFR signals.

Gene therapy is also being explored, with oncolytic viruses used for tumor-specific introduction of immunostimulatory transgenes. As the virus replicates inside the cancer cells, it produces the transgene- encoded proteins at the tumor site. This technology was described as turning “tumor cells into drug factories” by John Beadle, MD, CEO of PsiOxus, a UK-based company developing NG-350A, which delivers a transgene encoding an agonist CD40 mAb.

 Lokon Pharma is pursuing a similar strategy; LOAd703 carries transgenes expressing CD40L and a second TNF superfamily ligand, 4-1BBL, to activate an antitumor immune response.

Irrespective of mechanism of action, by far the most promising avenue for CD40 agonists is in combination therapy, and this is where most ongoing clinical efforts are focused. Based on preclinical studies that have demonstrated synergistic activity, the major strategies are combining CD40 agonists with chemotherapy, which may increase neoantigen availability; other T-cell–activating drugs, predominantly those inhibiting PD-1 or its ligand; and antiangiogenic drugs.

The rationale for the latter is that, in addition to blocking aberrant angiogenesis and normalizing the tumor vasculature (which can also improve drug access to the tumor), antiangiogenic drugs can help to relieve immunosuppression and boost T-cell infiltration into the tumor. The combination could make immunotherapy more effective in tumors that are typically immunologically cold and therefore unresponsive.

In several phase 1 clinical trials, selicrelumab was combined with various forms of chemotherapy, yielding objective response rates (ORRs) of 20% to 40%, depending on the specific type of chemotherapy and the cancer type.27-29 Selicrelumab was also tested in combination with the immune checkpoint inhibitor (ICI) tremelimumab, which targets CTLA-4, in 22 patients with immunotherapy-naïve metastatic melanoma, yielding an ORR of 27.3%, including 2 CRs and 4 PRs (NCT01103635). Nine patients displayed long-term survival (≥3 years).

Preliminary results from an ongoing phase 1/2 trial of intratumoral injection of LOAd703 in combination with nab-paclitaxel (Abraxane) and gemcitabine in patients with PDAC who are not candidates for complete surgical resection were recently presented (NCT02705196).

 Among chemotherapies, nab-paclitaxel has the added advantage of potentially exerting its own immunostimulatory effects.

 At the time of presentation, 13 evaluable patients had been treated at a dose of 5 × 1010 (n = 3), 1 × 1011 (n = 4), or 5 × 1011 virus particles (n = 6). The best response at the lowest dose was SD, but 6 patients receiving the higher doses experienced PRs. TRAEs were transient and largely grade 1 or 2, most commonly fever, chills, nausea, and increased transaminase levels.

In a mouse model of pancreatic cancer, the most significant antitumor efficacy resulted from combining a CD40 agonist with both chemotherapy (nab-paclitaxel and gemcitabine) and ICIs. This strategy led to complete rejection of established tumors and long-term survival in a significant number of mice.

These findings prompted a flurry of clinical trials evaluating this type of triplet therapy in patients with PDAC, a notoriously hard-to-treat and immunotherapy-resistant form of cancer, in addition to other cancer types. 

Promising preliminary data from an ongoing trial of APX005M in combination with nab-paclitaxel and gemcitabine, with or without nivolumab, in patients with previously untreated PDAC (NCT03214250) were presented at the American Association for Cancer Research meeting in 2019. 

Patients were enrolled in 4 cohorts, all of which received gemcitabine plus nab-paclitaxel as well as APX005M. The APX005M dose was 0.1 mg/kg for cohorts B1 and C1 versus 0.3 mg/kg for B2 and C2. Additionally, cohorts C1 and C2 received nivolumab. At the time of presentation, 24 patients were evaluable for DLTs (6 per cohort), and median follow-up was 32.2 weeks. Fourteen patients experienced PRs (11 confirmed), and 8 achieved SD. There were 2 DLTs: grade 3 and 4 febrile neutropenia in the B2 and C1 cohorts, respectively. Ten patients experienced a serious TRAE, and 2 patients died as a result of AEs (sepsis and septic shock in the setting of neutropenia).

Meanwhile, the ongoing phase 1 study of SEA-CD40 has been expanded to include a new cohort that is testing the combination of SEA-CD40 with gemcitabine, nab-paclitaxel, and pembrolizumab (Keytruda) as a frontline treatment for patients with metastatic PDAC.

Vonderheide RH. CD40 Agonist antibodies in cancer immunotherapy. 

Investigators are working on a new generation of therapies that activate CD40, an immune checkpoint that helps promote an antitumor response by boosting T-cell–stimulatory signals.

Vol. 21/No. 13 | Oncology Live®

Experts Focus on 6 Life-Prolonging Treatments for mCRPC

Novel Combos May Jumpstart the CD40 Immune-Stimulating Checkpoint

Neoadjuvant Apalutamide May Shrink Prostate Tumors

Beyond Cancer Type: New Pan-Tumor Targets Emerge

Adoptive Cell Therapy Aims to Improve Outcomes in Metastatic Melanoma

Palliative Care Builds Bridges in Oncology Practice

Olaparib Plus Bevacizumab Combination Expands Options in HRD+ Cancer

Regimen Doubles Down on Immunotherapy to Improve NSCLC Outcomes

Precision Medicine Should Play a Role in Population-Based Health Care