Targeting the PI3K and AKT Pathways in Solid Tumors

The Journal of Targeted Therapies in Cancer, June 2013, Volume 1, Issue 7

The next-generation PI3 kinase (PI3K) inhibitor GDC-0032 has shown signs of efficacy in patients with advanced cancers that were mutated for the PI3K alpha gene.

PI3K alphagene.1According to Dejan Juric, MD, attending physician and investigator at the Termeer Center for Targeted Therapies at Massachusetts General Hospital in Boston and lead investigator of the first-in-human trial, the drug’s safety profile was favorable and the side effects manageable. Side effects that occurred in 10% or more of the patients included fatigue, diarrhea, nausea, loss of appetite, vomiting, and hyperglycemia. One grade 4 case of hyperglycemia at the highest dosage level tested (16 mg daily) occurred during the trial.

Hyperglycemia is a side effect that signals that the drug is hitting its targets since the PI3K pathway is necessary in glucose metabolism, Juric said.

As of August 1, 2012, 34 patients with advanced solid tumors were enrolled in the trial in one of five dosing cohorts. A total of 5 patients had a clinical partial response while on treatment. Four of the 6 patients withPI3K alpha-mutated breast cancer, as well as 1 patient with lung cancer, also harboring a mutation inPI3K alpha, had partial responses. A patient with HER2-positive breast cancer had an unconfirmed partial response.

As many as 40% of hormone receptor-positive breast cancers, as well as many other cancer types, harbor a mutation in thePI3K alphagene. The phase I GDC-0032 trial is ongoing and enrolling patients with advanced solid tumors, as well as a separate cohort of patients with hormone-positive breast cancer for treatment in combination with endocrine therapy.

Another oral targeted agent, ARQ 092, which targets the AKT pathway, was shown to be active in a spectrum of different solid tumors including colorectal, endometrial, and neuroendocrine tumors, and the drug demonstrated a manageable sideeffect profile.2

Drug Combination Shows Activity in BRCA-Mutated Tumors

AKT inhibitors generally have two types of dose-limiting toxicities that relate to on-target effects of the drug: hyperglycemia and skin toxicity. In the case of ARQ 092, the researchers observed a pattern of a rise in blood sugar prior to the emergence of skin toxicity that may be a differentiating feature of this AKT inhibitor. The researchers did not observe any dose-limiting skin toxicity, and they were able to treat the hyperglycemia, allowing patients to continue the experimental treatment. This may mean that compared with other AKT inhibitors, ARQ 092 may be better tolerated at higher, more therapeutically active levels. The trial is ongoing to determine the maximum tolerated dose (MTD) and to test for efficacy.Two oral therapies, given sequentially, showed promising results for patients who haveBRCA-mutated tumors.3Defects in either the geneBRCA1orBRCA2results in deficiency in DNA repair. Germline mutations in the two genes are linked to a susceptibility to both breast and ovarian cancers.

Geoffrey Shapiro, MD, PhD

The combination of sapacitabine, an oral nucleoside analogue that can induce single-stranded breaks in DNA, and seliciclib, an inhibitor of cyclin-dependent kinases (CDKs), has been shown to work synergistically in preclinical models, providing rationale for the phase I combination trial.BRCA-deficient tumors should be sensitive to sapacitabine alone due to their DNA repair defects, and adding a CDK inhibitor should further cripple the ability of theBRCA-mutated tumor cells to repair their DNA, leading to cell death.

Of 38 patients enrolled, 4 patients—with pancreatic, breast, or ovarian cancer—had confirmed ongoing partial responses, and 3 more patients experienced partial responses. An additional 8 patients had stable disease for at least 12 weeks, including a patient with ovarian cancer who had stable disease for 64 weeks.

An MTD of sapacitabine 50 mg and seliciclib 1200 mg both twice daily resulted in reversible transaminase elevations and neutropenia. Most adverse events were mild to moderate, according to Geoffrey Shapiro, MD, PhD, director of the Early Drug Development Center at the Dana- Farber Cancer Institute in Boston.

PLK1-Targeting RNA Interference Has Some Therapeutic Activity

The trial is continuing to enroll patients. Other sequential schedules, aside from the sapacitabine for 7 days followed by seliciclib for 3 days reported here, are under evaluation.Using RNA interference (RNAi) to target the polo-like kinase 1 (PLK1) gene, was shown to be tolerable and to have some therapeutic activity in one patient with colon cancer experiencing stable disease, and in another with a carcinoid tumor having a partial response, both lasting at least 6 months.4

PLK1 can drive cell cycle progression, is overexpressed in a variety of different tumor types, and is a known negative prognostic indicator of outcome for patients. This study explored the use of the drug TKM-080301, which is a small interfering RNA (siRNA) against PLK1 that is encapsulated in a lipid nanoparticle.

Antibody-Drug Conjugate for Ovarian Cancer

Joyce F. Liu, MD

Because RNAi technology could potentially allow targeting of any protein involved in cancer inititation and progression, it is seen as a promising modality among cancer researchers.The novel antibody-drug conjugate (ADC) DMUC5754A, which combines a targeted antibody against the MUC16 protein and a toxin resulting in targeted cell-killing of MUC16-expressing ovarian tumor cells, has shown a promising level of activity and was well tolerated.5This is the first ADC study focused on ovarian cancer and could represent a new drug type for this type of cancer if further validated.

MUC16 expression level may serve as a useful predictive biomarker: patients who had the highest MUC16 expression were more likely to respond to the treatment.

One complete response and four partial responses were documented among the 44 patients with advanced, recurrent, platinum-resistant ovarian cancer enrolled in the trial. Six other patients had a minor response.

Michael Birrer, MD, PhD

ADCs are a relatively novel treatment modality that can target potent toxins directly to the tumor without affecting surrounding nontumor tissue. According to presenter Joyce F. Liu, MD, an instructor of Medicine at Harvard Medical School in Boston, and researcher at Dana-Farber Cancer Institute, there is potential to treat earlier-stage patients with DMUC5754A as MUC16 expression is typically present at initial diagnosis.

Immunotherapy Shown Safe and Efficacious in Multiple Tumor Types

“[These are] encouraging responses, especially in MUC16-expressing tumors,” said Michael Birrer, MD, PhD, of Massachusetts General Hospital Cancer Center, one of the study researchers. “If this is validated in future trials then it could be a new and novel therapeutic [for ovarian cancer].”The engineered antibody MPDL3280A, which targets the programmed death-ligand 1 (PD-L1), was found to be well tolerated and effective in a variety of tumor types, including lung, kidney, colon, and stomach cancers.6MPDL3280A is an immune checkpoint blockade antibody in development. Others in development include nivolumab (anti-PD-1), BMS-936559 (anti-PD-L1), and MK-3475 (anti-PD-1).

Michael S. Gordon, MD

“All of the agents seem to have exciting activity in patients with metastatic solid tumors, and the remaining question is whether some of these outstanding responses will be long-lasting” said Michael S. Gordon, MD, research director at Pinnacle Oncology Hematology in Scottsdale, Arizona, who presented the trial results.

Of 30 patients enrolled in the phase I dose escalation trial, 6 patients had partial responses, including a patient with stage IV non-small cell lung cancer (NSCLC) who had a 95% reduction in his tumor volume. All patients who responded continue to respond, with some responses lasting more than 12 months. There were also 10 cases of stable disease.

Three patients have had toxicities of grade 3 or 4, but no patient has had to interrupt treatment. No pneumonitis was reported.

Phase IB trials of MPDL3280A in combination with bevacizumab and chemotherapy are ongoing, and a phase II trial in NSCLC is starting soon.

References

  1. Juric D, Krop I, Ramanathan RK, et al. GDC-0032, a beta isoform-sparing PI3K inhibitor: results of a first-in-human phase Ia dose escalation study. Presented at: AACR Annual Meeting 2013; April 6-10, 2013; Washington, DC. Abstract LB-64.
  2. Saleh M, Papadopoulos K., Arabnia A, et al. First-in-human study with ARQ 092, a novel pan AKT-inhibitor: results from the advanced solid tumors cohorts. Presented at: AACR Annual Meeting 2013; April 6-10, 2013; Washington, DC. Abstract LB-197.
  3. Shapiro GI, Hilton J, Cleary JM, et al. Responses to sequential sapacitabine and seliciclib in patients with BRCA-deficient solid tumors. Presented at: AACR Annual Meeting 2013; April 6-10, 2013; Washington, DC. Abstract LB-202.
  4. Ramanathan RK, Hamburg SI, Borad MJ, et al. A phase I dose escalation study of TKM- 080301, a RNAi therapeutic directed against PLK1, in patients with advanced solid tumors. Presented at: AACR Annual Meeting 2013; April 6-10, 2013; Washington, DC. Abstract LB-289.
  5. Liu J, Moore K, Birrer M, et al. Targeting MUC16 with the antibody-drug conjugate (ADC) DMUC5754A in patients with platinum-resistant ovarian cancer: a phase I study of safety and pharmacokinetics. Presented at: AACR Annual Meeting 2013; April 6-10, 2013; Washington, DC. Abstract LB-290.
  6. Gordon MS, Hamid O, Powderly J, et al. A phase I study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors. Presented at: AACR Annual Meeting 2013; April 6-10, 2013; Washington, DC. Abstract LB-288.