Investigational Targeted Agents for Myelopreservation Hold Potential to Improve Care

Jared Weiss, MD

Despite efforts to produce chemotherapy agents that are more effective and less toxic, most of these agents are still difficult to tolerate, especially for patients with small cell lung cancer (SCLC) and breast cancer.

“You have this landscape where myelosuppression in general is hurting patients,” said Jared Weiss, MD, associate professor of medicine in the Division of Hematology/Oncology at the University of North Carolina at Chapel Hill School of Medicine and a thoracic oncologist at Lineberger Comprehensive Cancer Center, also in Chapel Hill. “The existing armamentarium to ameliorate this is not satisfactory.”

Two agents under investigation, trilaciclib and ALRN6924, are termed myelopreservation agents because of their ability to combat the hematologic events that are commonly observed with toxic chemotherapeutics.

“It’s important to understand that [these drugs are] different [from] most of the cancer drugs we talk about,” Weiss said, explaining that their primary purpose is to decrease toxicity, not increase antitumor efficacy. When a physician is deciding whether to add another drug to a patient’s regimen, the main concern is typically safety, he said: “How much did you hurt safety, and was it worth it for the benefit to the patient?”

Chemotherapy damages hematopoietic stem and progenitor cells (HSPCs), leading to multilineage myelosuppression. Myelosuppression affects quality of life—with symptoms such as fatigue or shortness of breath caused by anemia—which can lead to critical setbacks in treatment plans, including dose reductions and skipped chemotherapy cycles. When white blood cells cannot regenerate, the patient is less equipped to fight infections, resulting in possible hospitalization and death. Fighting the adverse effects (AEs) of myelosuppression can create new difficulties, such as diarrhea caused by antibiotics. Likewise, therapy-induced thrombocytopenia can cause delays in treatment and decreased efficacy, leading to patient anxiety.

“While I do believe we’re relieving more suffering than we’re causing, we cannot ignore that we’re causing suffering with chemotherapy,” Weiss said. The desire to help his patients experience fewer AEs during oncology treatment caused him to look outside his normal research interests for an opportunity to become involved in a myelosuppression study.

Current Myelosuppression Landscape

Existing agents to treat myelosuppression are reactive instead of protective and proactive. Granulocyte colony- stimulating factor (G-CSF) can be given to prevent febrile neutropenia resulting from chemotherapy, but G-CSF treatment can cause thrombocytopenia, nausea, fever, and bone pain.¹ “It’s a reactive treatment given after the damage is done,” Weiss said. “You stimulate whatever progenitors are left to make more cells.” Erythropoiesis-stimulating agents (ESAs) for managing anemia have encountered substantial obstacles, leading to black box warnings for patients with cancer and those with kidney disease.^2,3 As a result, Weiss said, ESAs are not commonly used in the United States.

There is also emerging evidence of problems with blood transfusions. “Volume [over] load can hurt patients,” Weiss said. Allogeneic blood transfusions are potentially immunosuppressive and can increase treatment time. Moreover, he noted, blood transfusions are reactive; treatment involves giving blood after the patient receives chemotherapy. As a result, progenitor cells are not protected from this toxic treatment.

Chemoprotective agents, such as amifostine used in patients with ovarian or head and neck cancer to protect healthy tissues from some treatment-related AEs⁴ or mesna for preventing hemorrhagic cystitis caused by ifosfamide,⁵ were developed to prevent toxicities rather than treat symptoms. Targeted agents for multilineage myelopreservation are the latest chemoprotectants to gain attention in the cancer care space.

CDK4/6 Inhibition With Trilaciclib

Four phase 2 trials demonstrated that intravenous trilaciclib (G1T28), a CDK4/6 inhibitor that can induce transient G1 arrest in HSPCs,⁶ preserved immune system function during chemotherapy treatment. “Individually, each of the studies did demonstrate myelopreservation,” Weiss said.

Small Cell Lung Cancer

The G1T28-02 trial (NCT02499770) examined trilaciclib in combination with etoposide and carboplatin in patients with newly diagnosed extensive-stage SCLC (ES-SCLC). The study comprised 2 parts: a dose-finding phase 1b (n = 19) and a randomized, placebo- controlled phase 2 (n = 75).⁶ Prespecified primary outcome measures were dose-limiting toxicities and treatment-related AEs; secondary outcome measures included safety, efficacy, and pharmacokinetic parameters. The phase 2 dose of trilaciclib was 240 mg/m² given once daily before chemotherapy administration. All patients received etoposide at 100 mg/m² on days 1 through 3 and carboplatin at a target area under the plasma drug concentration-time curve of 5 on day 1 of each cycle.

Patients receiving trilaciclib showed improvements in neutrophil, red blood cell (RBC), and lymphocyte measures. Safety was improved with trilaciclib, with fewer grade 3 or greater AEs in the experimental arm (50%) compared with placebo (83.8%), mostly due to less hematologic toxicity. Additionally, no trilaciclib- related AEs of grade 3 or greater occurred.

In terms of antitumor efficacy, a numerically improved overall response rate (ORR) of 66.7% with trilaciclib was achieved versus 56.8% with placebo, but this result failed to reach statistical significance (P = .3831). Median progression-free survival (PFS) also showed numerical improvement at 6.2 months for trilaciclib versus 5.0 months for placebo (HR, 0.70; P = .1695), with longer PFS sustained across most patient subgroups. Overall survival (OS) was comparable between the 2 groups.

The results indicated that patients in the trilaciclib group had increased tolerance of chemotherapy, including improved myelopreservation across multiple hematopoietic lineages, and therefore needed fewer supportive care interventions and dose reductions. The addition of trilaciclib mitigated myelosuppression without reducing the antitumor efficacy of etoposide and carboplatin.

Another phase 2 trial in ES-SCLC, G1T28-03 (NCT02514447) included 61 previously treated patients in 2 arms receiving either topotecan alone or in combination with trilaciclib. Primary end points were the occurrence and duration of severe neutropenia, and key secondary end points were all-cause dose reductions and the rates of RBC transfusion, G-CSF administration, and platelet transfusion. Other prespecified end points included measures of antitumor efficacy, patient-reported outcomes, and AEs.⁷

Study results presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting demonstrated that patients receiving trilaciclib completed more cycles and had fewer dose reductions compared with the placebo arm. Data showed that trilaciclib did not impair chemotherapy efficacy, with comparable ORR, PFS, and OS in the placebo and trilaciclib arms.

In the critical area of myelosuppression, G1T28-03 revealed a clear benefit of trilaciclib. Trial results showed that 75.9% of patients in the placebo group experienced severe neutropenia compared with 40.6% in the treatment arm. Also, 65.5% of the placebo group received G-CSF versus 50% of the treatment arm. In terms of grade 3/4 anemia, 63% of the placebo group versus 38.7% of the treatment group experienced this toxicity. RBC transfusions were given to 41.4% of the placebo group versus 31.3% of the treatment group, and 31% of the former received platelet transfusions as opposed to 25% of the treatment group.

At the European Society for Medical Oncology (ESMO) Congress 2019, results from a cohort of patients with ES-SCLC treated with firstline etoposide/carboplatin plus atezolizumab (Tecentriq) with or without trilaciclib in the phase 2 G1T28-05 trial (NCT03041311) were reported.⁸ The main objective of the study (n = 107) was to evaluate the potential of trilaciclib to reduce chemotherapy-induced myelosuppression. The primary end points were 2 aspects of grade 4 neutropenia: its overall occurrence and its duration in cycle 1. Key secondary end points were rates of RBC transfusion beginning in study week 5, G-CSF use, and all-cause dose reductions, as well as OS.

Just below half (49.1%) of patients in the placebo group experienced grade 4 severe neutropenia compared with just 1.9% in the trilaciclib arm. Also, 47.2% of the placebo group received G-CSF versus 29.6% of the treatment arm. In terms of grade 3/4 anemia, 28.3% of the placebo group experienced this AE versus 18.5% of the treatment group. RBC transfusions were given to 20.8% of the placebo group versus 13.0% of the treatment group, and 3.8% of the former received platelet transfusions as opposed to 1.9% of the treatment group.

Study results showed that patients receiving trilaciclib had a higher relative chemotherapy dose intensity compared with the placebo group, which was due to fewer patients on trilaciclib undergoing etoposide or carboplatin dose reductions and/or cycle delays compared with placebo. Investigators also found lower frequencies of etoposide and carboplatin dose reductions over time among patients receiving trilaciclib versus placebo. The placebo group had a rate of all-cause dose reductions (per 100 cycles) of 8.5 compared with 2.1 in the treatment arm.

Based on the myelopreservation data generated in these clinical trials, trilaciclib received breakthrough therapy designation for use in patients with SCLC, and G1 Therapeutics is expected to file a new drug application in 2020.^9,10

Pooled data from the G1T28-02, -03, and -05 trials were examined to address concerns about missing safety signals in individual studies with small sizes, Weiss said. Data presented as part of the 2020 ASCO Virtual Scientific Program showed that adding trilaciclib before chemotherapy significantly and meaningfully reduced chemotherapy-induced myelosuppression and its consequences, including a substantial reduction in high-grade hematologic AEs (FIGURE).¹¹ Moreover, trilaciclib did not negatively affect PFS or OS. Because trilaciclib reduces the toxicity of chemotherapy in SCLC treatment, Weiss and colleagues suggested its potential to become a new standard of care.

Weiss said one of the most common questions he gets about trilaciclib involves survival advantage: “I would love it if it [induced] a survival advantage [in SCLC], except that misses the point that the goal of the drug is to improve quality of life.” He said his patients’ top concern is typically improving their quality of life, but clinicians are still looking for a survival advantage. “Quality of life is extremely important,” he said. “You don’t have to go further than that to show benefit."

Breast Cancer

Results from the phase 2 G1T28-04 trial (NCT02978716) of patients with metastatic triple-negative breast cancer (mTNBC) treated with gemcitabine and carboplatin with or without trilaciclib were presented at the ESMO Congress 2019 and simultaneously published in The Lancet Oncology.^12,13 The randomized trial assigned 102 patients with mTNBC to 1 of 3 treatment arms: Patients in 2 groups received trilaciclib and chemotherapy (gemcitabine and carboplatin), with the other group receiving only chemotherapy. The primary end points were duration of severe neutropenia during cycle 1 and occurrence of severe neutropenia during the treatment period. Secondary end points included antitumor efficacy measures, such as PFS and OS; pharmacokinetics; and safety.

Investigators found no significant differences in primary myelosuppression end points with trilaciclib plus chemotherapy versus chemotherapy alone. In particular, there were no significant differences (P = .70) in severe neutropenia, which occurred in 26% of patients in group 1 (chemotherapy only on days 1 and 8), in 36% of group 2 (chemotherapy and trilaciclib on days 1 and 8), and in 23% of group 3 (chemotherapy on days 2 and 9 plus trilaciclib on days 1, 2, 8, and 9). Median OS was 12.6 months, 20.1 months, and 17.8 months, respectively.

The trilaciclib regimen was generally well tolerated. The most common treatment-emergent AEs in group 1 were anemia (73%), neutropenia (70%), and thrombocytopenia (60%); neutropenia (82%), thrombocytopenia (55%), and anemia (52%); and in group 3, neutropenia (66%), thrombocytopenia (63%), and nausea (49%). The groups received a median of 4, 7, and 8 cycles of therapy, respectively. Investigators found that trilaciclib increased the duration of exposure and cumulative dose of gemcitabine and carboplatin compared with the chemotherapy alone group.

The trial’s OS results were encouraging. Hazard ratios for OS showed that responses were clinically meaningful with the addition of trilaciclib, at 0.33 (95% CI, 0.15-0.74; P = .028) for group 2 and 0.34 (95% CI, 0.16-0.70; P = .0023) for group 3.

Weiss said the primary end point results from this trial were notable. “I’m scratching my head over that,” he said, adding that achieving both statistical significance and clinical relevance in a randomized phase 2 trial can be difficult. “The weakness of randomized phase 2 compared with phase 3 data [is] a lot of the reason that we combined [the results in an analysis] in SCLC,” he said. “Unfortunately, 2 other studies don’t exist in TNBC to allow that to be done,” though further study is recommended.

Unlike in SCLC, the G1T28-04 breast cancer study found a survival advantage with the addition of trilaciclib. This suggests that by increasing the duration of chemotherapy exposure, the agent can improve outcome beyond simply enhancing quality of life, Weiss said. “Breast cancer has some of the best data [showing] that preservation of dose intensity can improve outcomes. If you’re going to find a survival advantage through myelo[preservation] leading to improved chemotherapy delivery, breast cancer is the first place you should look.”

Trilaciclib will be included in a new arm of the I-SPY 2 basket trial (NCT01042379), which will examine the agent in patients with locally advanced breast cancer with a high risk of recurrence. The trial will evaluate whether adding trilaciclib to neoadjuvant chemotherapy-based treatment, with or without immunotherapy, increases the probability of tumor disappearance prior to surgery, which would positively affect outcome and survival.¹⁴

The manufacturer of trilaciclib also plans to begin additional trials in colorectal and breast cancers this year.¹⁵

ALRN-6924

A phase 1b/2 trial of ALRN-6924, a first-in-class dual MDM2/MDMX inhibitor, for the mitigation of topotecan-induced myelosuppression is actively recruiting patients with ES-SCLC who harbor TP53 mutations (NCT04022876). In 2019, the FDA accepted an investigational new drug application for the agent in response to preclinical data showing transient, dose-dependent cell cycle arrest in TP53–wild-type ex vivo human bone marrow cells.¹⁶

ALRN-6924 works by disrupting the interaction of the p53 tumor suppressor protein with its endogenous inhibitors MDMX and MDM2. This reduces sensitivity to chemotherapy- induced cellular toxicity. The agent has no effect on the cell cycle for TP53-mutant cancer cells, so they remain vulnerable to chemotherapy.¹⁷

Results of a mouse model study presented at the 2019 American Association of Cancer Research (AACR)–National Cancer Institute–European Organization for Research and Treatment of Cancer International Conference on Molecular Targets and Cancer Therapeutics showed protection against both neutrophil depletion and gastrointestinal (GI) inflammation. The study also showed that ALRN-6924 enhanced topotecan’s antitumor effects in TP53-mutant cancer models.¹⁷ Interim dose-optimization results for 17 patients in the phase 1b/2 trial are expected midyear, with final phase 1b data expected in the fourth quarter of 2020. The schedule optimization portion of the study will involve 20 patients, with possible expansion to more. The investigators’ goal for the interim data was to show a protective effect against chemotherapy-induced thrombocytopenia and anemia.^18,19

“While the molecular target [of ALRN-6924] is quite different, the core mechanistic concept is overwhelmingly similar to trilaciclib,” Weiss said. “You’d hypothesize that holding cells in G1 isn’t going to protect cancer cells that are TP53 mutated” while sparing bone marrow that is TP53 wild type. “By holding those cells out of cycle, you’d preserve myelopreservation. That was entirely [what] the preclinical data demonstrated at AACR.” Weiss found the GI results similar to those of trilaciclib, suggesting that the agent might be able to ameliorate GI tract effects of chemotherapy treatment.

“There’s not nearly enough work being done on agents aimed at improving the quality of life of the patients directly,” Weiss said. These first-in-class targeted agents for myelopreservation represent a movement in that direction, as a way to improve quality of life during chemotherapy without reducing survival. By working proactively, these agents appear to provide an opportunity to head off AEs that could otherwise delay treatment and negatively impact doses.

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_{13. Tan AR, Wright GS, Thummala AR, et al. Trilaciclib plus chemotherapy versus chemotherapy alone in patients with metastatic triple-negative breast cancer: a multicentre, randomised, open-label, phase 2 trial. Lancet Oncol. 2019;20(11):1587‐1601. doi:10.1016/S1470-2045(19)30616-3}

_{14. Quantum Leap Healthcare Collaborative and G1 Therapeutics announce the selection of trilaciclib in the I-SPY 2 TRIAL for breast cancer. News release. Quantum Leap Healthcare Collaborative and G1 Therapeutics. January 14, 2020. https://bit.ly/3cTxVUz}

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_{16. Aileron Therapeutics announces FDA acceptance of IND for ALRN-6924 as a myelopreservation agent in patients with p53-mutant cancer treated with chemotherapy. News release. Aileron Therapeutics. June 27, 2019. Accessed June 11, 2020. https://bit.ly/2MPMbTS}

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_{18. Aileron Therapeutics announces plans to release interim results from its phase 1b/2 myelopreservation study in mid-2020. News release. Aileron Therapeutics. April 22, 2020. Accessed June 11, 2020. https://bit.ly/3cZLWAh}

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