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AACR Conference – Major Highlights of Immunotherapy Clinical Trials
By Ruchi Jhonsa, Ph.D.
Immunotherapeutic treatments have become a go-to approach for multiple cancer indications. However, response to these therapies is limited with resistance from the tumor microenvironment. This demands for alternate treatment regimens and combinatorial strategies to overcome the resistance. The second immunotherapy clinical trials session of the virtual AACR conference featured some of the important improvements in the field of immunotherapy in the past year.
1) Q6W Dosage of Keytruda Bags FDA Approval
Keytruda (pembrolizumab) is Merck’s blockbuster anti-PD-1 immunotherapy drug that enhances the body’s immune response to the cancer cells by blocking the pathway that makes them invisible to the immune system. The drug has been approved globally for multiple cancer indications at a dose of 200mg or 2mg/kg every three weeks (Q3W). However, based on pharmacokinetic modeling and simulation, an alternate dosage of the drug, which requires administration of 400mg of the drug every 6 weeks, is also approved in markets including the European Union, Australia, and New Zealand. This dosing regime is preferable as it is convenient for the patient and the physician in many ways. However, there is no clinical data supporting the efficacy and safety of the Q6W regime to date.
To validate the model-based assessments as well as efficacy and safety of the Q6W regimen in the absence of any clinical data, the KEYNOTE-555 clinical trial was launched in 2018. KEYNOTE-555 is an ongoing, open-label single-arm clinical study in treatment naïve patients with metastatic melanoma designed to evaluate the dosing of pembrolizumab every 6 weeks (Q6w). The interim data from the KEYNOTE-555 trial evaluating the new 6-week regimen was discussed by Dr. Mallika Lala on the second day of the AACR virtual conference. The dosing of 400mg for the KEYNOTE trial was determined using extensive modeling and simulation analysis based on Q3w and Q2w clinical data. The interim data from 44 patients showed a similarity in the efficacy of Q6W and Q3W regimens. An overall response rate of 38.6% comparable to ORR of 35.1% for Q3W was observed for the 6-week regimen. Additionally, the safety of the Q6W regimen was found consistent with the established extensive safety profile. The interim study supports the Q6W regimen of pembrolizumab for melanoma patients making it convenient and flexible for patients and physicians.
While this data was being presented at the AACR conference, the USFDA approved this alternate dosage of pembrolizumab, across all adult indications, which also includes monotherapy and combination therapy regimens. The accelerated approval is based on the relationship of drug exposure to efficacy and safety and pharmacokinetic data, some of which were presented at the conference yesterday. This less frequent dosing regimen will be more convenient and safe, amid the COVID-19 pandemic given that patients will have to visit less frequently at the clinics for dosing. However, continued approval of this regime will depend upon its verification in clinical trials.
Roy Baynes, M.D., Merck senior vice president and head of global clinical development, said in a statement, “the important social distancing measures for COVID-19 have created a number of challenges for people with cancer, including keeping to planned treatment schedules. Today’s approval of an every six-week dosing schedule for KEYTRUDA gives doctors an option to reduce how often patients are at the clinic for their treatment.”
2) Importance of VEGF Signature for Atezolizumab, Bevacizumab Combo
Hepatocellular carcinoma (HCC) is the most common type of liver cancer that occurs predominantly in people with underlying liver diseases. Although the mainstay of HCC therapy is surgical resection, the majority of patients are not eligible because of the advanced nature of the tumor or underlying liver condition. Current treatment regimes with multikinase inhibitors like Sorafenib have been effective, but new methods are required to impede the advanced nature of cancer.
Genomic studies determining the molecular landscape of the HCC tumors show high expression of VEGF and PD-L1 biomarkers, which correlate with the hypervascular nature of HCC tumors. Blocking these markers with anti-PD-L1 drug Atezolizumab and anti-VEGF drug bevacizumab executed in the IMbrave150 trial has been effective in reducing the risk of death as well as progression-free survival in HCC patients in comparison to the standard of care drug, Sorafenib. The drug combo may soon become a new standard of care therapy for patients with newly diagnosed HCC.
At the AACR meeting on 28th April, Dr. Andrew Zhu from Massachusetts General Hospital Cancer Center presented the findings from exploratory studies preceding the GO30140 trial investigating the safety and efficacy of atezolizumab in combination with bevacizumab in patients with solid tumors. Divided into two arms, the exploratory study aimed to identify candidate biomarkers for predicting response to atezolizumab and bevacizumab combination in HCC as well as the genetic basis of the improved effectiveness of drug combo over atezolizumab alone. Through whole-genome sequencing and RNA seq analysis of the tumor extracted from patients prior to the treatment followed by correlation analysis with the clinical response to the drug combo, the group associated high PD-L1 and T-effector expression with positive clinical response and longer progression-free survival (PFS) and notch activation with treatment resistance and shorter PFS. Additionally, the authors determined that VEGF/VEGFR, Treg, and TREM1/MDSC signatures were associated with longer PFS in patients treated with the combo than in those treated with atezolizumab alone. These findings are consistent with previous clinical studies that support the role of VEGFR in immunosuppression. Dr. Zhu concluded that the addition of anti-VEGF drugs in the regular course of anti-PD-L1 therapy would be beneficial for HCC treatment.
3) Overcoming Treatment Resistance with Dual PI3K inhibitor, Duvelisib
Immune checkpoint inhibitors, such as atezolizumab or pembrolizumab, have provided meaningful clinical responses in patients with multiple cancer indications. However, resistance to the treatment from the tumor microenvironment after the initial response suggests a need for additional strategies. PI3K signaling has been shown to regulate the immune system and inhibition of the signaling has been shown to modulate the tumor immune microenvironment by relieving T-regs mediated immunosuppression.
To modulate the immune response in favor of anti-PD-1 therapy, a team of scientists from Verastem Oncology tested Duvelisib, a dual PI3K-delta/gamma inhibitor on T cells derived from human donors or chronic lymphocytic leukemia (CLL) patients for its immunity enhancing effects. Duvelisib is an FDA approved oral, dual, PI3K-delta, gamma inhibitor used as a monotherapy for treating chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma. Duvelisib regulates key immune cells in the tumor microenvironment, making it a promising candidate for combination with PD-1 blockade.
The team showed that duvelisib expanded the T cell population by 3 to 4 fold ex vivo upon inhibiting both delta and gamma isoforms of PI3K. Moreover, treatment with the drug reduced T cell exhaustion markers and enriched early memory cells, indicative of strong immune response against the tumor. The group also investigated if duvelisib could increase the efficacy of a PD-1 antibody in solid tumors and lymphoma syngeneic models. They saw a massive inhibition in tumor growth with the combination treatment (81%) in comparison to duvelisib (59%) or anti-PD-1 (49%) alone. Concurrently, 60% of mice treated with the combo were found tumor-free in comparison to just 10% in anti-PD-1 monotherapy at the end of 2 months. The tumor reduction is attributed to the reduction of immunosuppressive Tregs, M2 macrophages, and M-MDSCs in the tumor microenvironment following treatment with PI3K and PD-1 inhibitor cocktail. Together, these data show immense potential for tumor treatments combining PI3K and PD1 inhibitors and support their clinical evaluation in patients with solid tumors or hematologic malignancies.
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