Update on Immunotherapy and Targeted Combination Therapies

Paul A. Bunn Jr, MD

Melanoma

While the concept of cancer-specific immunotherapy is not new, it recently has been proven feasible as a rational treatment for patients with some of the most challenging and difficult malignancies.^1-5Together with the current range of cancer-specific and targeted therapies that have become available in recent years, immunotherapy soon will have the potential to be included in a range of novel combination therapies in different cancer subtypes.One of the most important developments in advanced melanoma was the approval of ipilimumab, a fully human monoclonal antibody, directed against cytotoxic T-lymphocyte associated antigen 4 (CTLA-4), a negative regulator of activated T cells.⁴Pivotal data were published in 2010 when a phase III study of previously treated patients with advanced melanoma demonstrated significant improvement in overall survival (OS) with ipilimumab in combination with a glycoprotein (gp100) peptide vaccine. A 32% relative reduction in the risk for death (P< .001) was observed for patients in the ipilimumab/gp100 group as compared with those treated with gp100 alone. Similarly, a 34% relative reduction in the risk for death (P= .003) was seen with ipilimumab alone relative to gp100 alone.⁶Although serious immune-related adverse events (AEs) were noted, in most cases they could be reversed with appropriate treatment. This study provided proof of concept for immunotherapy as a feasible treatment option in melanoma.⁶

Balazs Halmos, MD, on the Future of Immunotherapy Treatments in Lung Cancer

Halmos is the section chief of Thoracic Oncology at NewYork-Presbyterian Hospital/Columbia University Medical Center.

Since then, ipilimumab has been evaluated in combination with other targeted therapies for melanoma. Dacarbazine had been the established standard of care for advanced melanoma. But ipilimumab administered in combination with dacarbazine significantly improved OS over the use of dacarbazine alone, and AEs were not different from those typically seen with either therapy on its own.⁷Notably, however, this trial did not have an ipilimumab-alone arm, so it was not possible to assess the overall benefit of adding dacarbazine to the ipilimumab regimen.⁷

NSCLC

Vemurafenib is an orally administered inhibitor of the BRAF signaling pathway, and is also approved for use in advanced melanoma, based on trials showing improved OS.8 Because ipilimumab and vemurafenib had both been shown to improve OS in patients with advanced melanoma through differing mechanisms, the two agents were combined in a phase I study. Results of the study, however, demonstrated hepatotoxicity in patients receiving this combination therapy, and the trial was closed.⁸Commenting on these data, Jedd D. Wolchok, MD, PhD, chief of the Melanoma and Immunotherapeutics Service and the Lloyd J. Old Chair for Clinical Investigation at Memorial Sloan Kettering Cancer Center, said: &ldquo;The message here is that just because we have drugs that are approved and have distinct mechanisms of action, this does not mean necessarily that they can be safely administered together.&rdquo; On a more encouraging note, however, Wolchok pointed to the results of a trial investigating the combination of ipilimumab with nivolumab, a fully human IgG4 antibody that targets the programmed death 1 (PD-1) receptor, another inhibitory T-cell checkpoint.⁹In this study, the combination therapy was associated with manageable toxicity and an overall response rate (ORR) of 40%, with evidence of clinical activity in some 65% of concurrently treated patients.⁹The results of this trial have set the stage for a phase III study examining the combination of nivolumab and ipilimumab in patients with advanced melanoma (NCT01844505).Despite the successes of aprecision-medicineapproach using molecular profiling, and the corresponding availability of multiple-targeted agents for the treatment of non-small cell lung cancer (NSCLC), most patients will ultimately relapse, emphasizing the continued need for novel therapies that can prolong survival.³Toward this end, immunotherapies have also shown benefit in combination with various therapies for NSCLC. The use of anti-CTLA-4 antibody (ie, ipilimumab), for example, has shown promising synergistic activity over single-agent therapy when used in combination with chemotherapeutic agents in lung cancer tumor models. These studies suggested that the use of immunotherapy could induce a memory immune response in a lung cancer model, resulting in rejection of the tumor on rechallenge.¹⁰The use of cytokine-induced killer (CIK) cells, which recognize and attack tumor cells without priming in an major histocompatibility complex- (MHC-)unrestricted manner, is another immunotherapeutic approach that has been investigated in lung carcinoma models.¹¹Efficacy of CIK cells in this study was enhanced by the concomitant use of an anti-angiogenesis therapy, endostatin, raising the possibility that normalizing the tumor vasculature and reducing tumor hypoxia may provide a more favorable environment for the CIK cell therapy.¹¹The use of dendritic cell (DC)-activation has also been found to enhance the activity of CIK cells in patients with NSCLC, resulting in significantly higher (P< .05) 1-year and 2-year OS rates for patients treated with chemotherapy and DC-CIK cells, as compared to those patients treated with chemotherapy alone.¹²

Another important development in the use of immunotherapy in NSCLC occurred in 2012 when nivolumab was shown to have activity across a range of tumor types, including patients with NSCLC.¹³Among patients with NSCLC enrolled in this trial (n = 122), 94% and 34% of whom had, respectively, received prior platinum-based chemotherapy and tyrosine kinase inhibitor (TKI) therapy, the cumulative response rate was 18%, and responses were durable. Grade 3 or 4 AEs were immune related, and occurred in 14% of patients overall; although three deaths occurred, most events could be effectively managed with minimal supportive care. In this study, the expression of programmed death ligand-1 (PD-L1) in tumors was also associated with objective tumor response, raising the possibility for its use as a biomarker to selectively identify patients for PD-1 antibody therapy.¹³Efficacy and safety of nivolumab after failure of platinum-based chemotherapy in NSCLC are being compared with docetaxel in a phase III trial (NCT01673867).

Prostate Cancer

Paul A. Bunn Jr, MD, Distinguished Professor in the Division of Medical Oncology and James Dudley Chair in Lung Cancer Research at the University of Colorado, noted the potential for nivolumab and other immunotherapies (eg, anti-PDL-1 antibody) to be used in combination with a range of targeted therapies, specifically TKI used in NSCLC. Phase I trials will need to be done to show that the various therapies can be safely combined, and, thereafter, use of these combinations could be guided by molecular profiling using an approach similar to that underway in squamous cell carcinoma in the Master Protocol.¹⁴From the perspective of a patient survival curve in NSCLC, Bunn noted, it may be possible to show that &ldquo;you can influence the tail of the curve with immunotherapy, and you can influence the middle of the curve with molecular therapy &hellip; and it makes sense to combine them.&rdquo; Bunn also said, however, that while such combination studies are underway, data in NSCLC are not yet available.Castration-resistant prostate cancer (CRPC) remains a significant challenge for clinicians. Only recently have additional options become available for metastatic CRPC, in addition to the previous standard treatment of docetaxel and prednisone.^1,15Immunotherapy combinations, however, have shown great promise in this setting as well, according to James L, Gulley, MD, PhD, chief of the genitourinary malignancies branch of the Center for Cancer Research at the National Cancer Institute. Enzalutamide has been approved by the Food and Drug Administration (FDA) for treatment of CRPC, and there have been efforts to combine this agent with immunotherapy strategies.¹⁶In particular, enzalutamide has been combined with a therapeutic vaccine targeting the Twist protein, a transcription factor and mediator of epithelial-mesenchymal interactions and metastasis.¹⁶There was improvement in OS with the combination of enzalutamide and the Twist vaccine, particularly in very advanced disease.¹⁶Gulley noted that these encouraging preclinical findings have led to at least two ongoing studies in prostate cancer: (1) NCT 01875250; evaluating enzalutamide in combination with a vaccine (PROSTVAC/TRICOM) in castration-sensitive nonmetastatic prostate cancer, and (2) NCT 01867333; evaluating enzalutamide with or without PROSTVAC/TRICOM vaccine therapy in advanced prostate cancer. As in melanoma, Gulley also highlighted some new data using ipilimumab in prostate cancer treatment. In CA184-043, which compared a single dose of radiotherapy to radiotherapy with ipilimumab, no improvement in OS, the primary endpoint, was noted (hazard ratio [HR] = 0.85,P= .053), although antitumor activity was observed in other endpoints.¹⁷A subgroup analysis of this trial nonetheless suggested that there may be an OS advantage among patients with less aggressive disease features, such as those with no visceral disease and those with a hemoglobin level of 11 g/dL or greater.¹⁷Gulley noted that one obvious area of future research is to combine therapeutic vaccines with immune checkpoint inhibitors, citing a phase I study from his own group evaluating a therapeutic vaccine, PSA-Tricom, in combination with ipilimumab.¹⁵In this trial, increasing doses of ipilimumab were evaluated in combination with fixed dose of PSA-Tricom in patients with metastatic CRPC. This combination did not appear to exacerbate immune-related AEs with ipilimumab.¹⁵Moreover, the median OS observed in the trial (34.4 months) raises the possibility for prolonging OS in CRPC, and provides a rationale for the use of PSA-Tricom in combination with other immunotherapies, such as PD-1 inhibitors.¹⁵

References

1. Madan RA, Gulley JL, Fojo T, Dahut WL. Therapeutic cancer vaccines in prostate cancer: the paradox of improved survival without changes in time to progression.Oncologist. 2010;15(9):969-975.
2. Wolchok J. How recent advances in immunotherapy are changing the standard of care for patients with metastatic melanoma.Ann Oncol. 2012;23(suppl 8):viii15-viii21).
3. Heuvers ME, Aerts JG, Cornelissen R, et al. Patient-tailored modulation of the immune system may revolutionize future lung cancer treatment.BMC Cancer. 2012;12:580.
4. Wolchok JD, Hodi FS, Weber JS, et al. Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma.Ann N Y Acad Sci. 2013;1291:1-13.
5. Drake CG. Antonarakis ES. Current status of immunological approaches for the treatment of prostate cancer.Curr Opin Urol. 2012;22(3):197-202.
6. Hodi FS, O&rsquo;Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma.N Engl J Med. 2010;363(8):711-723.
7. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.N Engl J Med. 2011;364(26):2517-2526.
8. Ribas A, Hodi FS, Callahan M, Konto C, Wolchok J. Hepatotoxicity with combination of vemurafenib and ipilimumab.N Engl J Med. 2013;368(14):1365-1366.
9. Wolchok JD, Kluger H, Callahan MK,et al. Nivolumab plus ipilimumab in advanced melanoma.N Engl J Med. 2013;369(2):122-133.
10. Jure-Kunkel M, Masters G, Girit E, et al. Synergy between chemotherapeutic agents and CTLA-4 blockade in preclinical tumor models.Cancer Immunol Immunother. 2013;62(9):1533-1545.
11. Shi S, Wang R, Chen Y, et al. Combining antiangiogenic therapy with adoptive cell immunotherapy exerts better antitumor effects in non-small cell lung cancer models.PLoS One. 2013;8(6):e65757.
12. Yang L, Ren B, Li H, et al. Enhanced antitumor effects of DC-activated CIKs to chemotherapy treatment in a single cohort of advanced non-small-cell lung cancer patients.Cancer Immunol Immunother. 2013;62(1):65-73.
13. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.N Engl J Med. 2012;366(26):2443-2454.
14. The ASCO Post: &lsquo;Master Protocol&rsquo; Could Revolutionalize Trials in Lung Cancer, and Eventually Other Cancers. Available at: http://www.ascopost.com/issues/november-1,-2013/master-protocol-could-revolutionalize-trials-in-lung-cancer,-and-eventually-other-cancers.aspx. Accessed: Feb 10, 2014.
15. Madan RA, Mohebtash M, Arlen PM, et al. Ipilimumab and a poxviral vaccine targeting prostate-specific antigen in metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial.Lancet Oncol. 2012;13(5):501-508.
16. Ardiani A, Farsaci B, Rogers CJ, et al. Combination therapy with a second-generation androgen receptor antagonist and a metastasis vaccine improves survival in a spontaneous prostate cancer model.Clin Cancer Res. 2013;19(22):6205-6218.
17. Drake CG, Kwon ED, Fizazi K, et al. Results of subset analyses on overall survival (OS) from study CA184-043: ipilimumab (Ipi) versus placebo (Pbo) in post-docetaxel metastatic castration-resistant prostate cancer (mCRPC). 2014 Genitourinary Cancers Symposium.J Clin Oncol. 2014;32(suppl 4, abstract 2). Available at: http://meetinglibrary.asco.org/content/90915