American Society of Clinical Oncology Names Immunotherapy "Cancer Advance of the Year"

The American Society of Clinical Oncology (ASCO) has named immunotherapy as its "Cancer Advance of the Year." These agents are designed to block PD-1/PD-L1 immune checkpoint across a vast array of tumor types.

The announcement was made as part of ASCO’s release on Thursday of its annual update on oncology treatment advances: Clinical Cancer Advances 2016: ASCO's Annual Report on Progress Against Cancer. The report, which explores key advances across cancer care, from prevention, to treatment, to survivorship, was published in the Journal of Clinical Oncology.

"No recent cancer advance has been more transformative than immunotherapy. These new therapies are not only transforming patient lives, they are also opening intriguing avenues for further research," said ASCO president Julie M. Vose. "Advances like these require bold ideas, dedication and investment in research. If we are to conquer cancer, we need to invest more as a nation to support a strong biomedical research enterprise."

Melanoma

The report states that PD-1/PD-L1 agents were approved by the FDA in 2015 to treat the most common forms of advanced melanoma, lung cancer and renal cell carcinoma which are otherwise resistant to existing therapies.In melanoma, 2015 already began with three approvals of checkpoint inhibitors: Yervoy (ipilimumab), Opdivo (nivolumab), and Keytruda (pembrolizumab).

By the end of the year, FDA had expanded the approval for single-agent Opdivo to include the frontline treatment of patients with BRAF wild-type advanced melanoma.

Most recently, in January 2016, the FDA expanded its frontline approval of Opdivo again, this time as a single agent and in combination with Yervoy to include BRAF V600 patients.

The expansion is based on phase 3 data from the three-arm CheckMate-067 study, in which the combination of Opdivo and Yervoy reduced the risk of progression by 58 percent compared with Yervoy alone in patients with advanced melanoma. Single-agent Opdivo reduced the risk of progression by 43 percent versus Yervoy. Outcomes were similar regardless of BRAF mutation status.

Keytruda also had an expanded frontline approval as a single agent to include the frontline treatment of patients with advanced melanoma regardless of BRAF status, based on improvements in progression-free and overall survival (OS) compared with Yervoy in the phase 3 KEYNOTE-006 trial. The PD-1 inhibitor reduced the risk of disease progression by greater than 40 percent and the risk of death by greater than 30 percent, according to the study.

The label for Keytruda was also updated to include the treatment of patients with Yervoy-refractory melanoma, based on a greater than 43 percent reduction in the risk of death versus chemotherapy in the phase 2 KEYNOTE-002 trial. In October 2015, the FDA expanded Yervoy's indication to include adjuvant treatment of patients with stage 3 disease with pathologic involvement in regional lymph nodes greater than 1 mm who have undergone complete resection including total lymphadenectomy.

Lung Cancer

PD-1/PD-L1 agents aside, the FDA approved the first-in-class oncolytic immunotherapy Imlygic (talimogene laherparepvec; T-VEC) in October 2015 as a local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery. The approval was based on findings from the phase 3 OPTiM study, in which a 4.4-month extension in OS compared with GM-CSF was demonstrated.In the field of squamous non—small cell lung cancer (NSCLC), Opdivo was approved by the FDA as a therapy for patients whose disease progresses after platinum-based doublet chemotherapy in March 2015. By October that year, the approval was expanded to include patients with nonsquamous NSCLC or EGFR- or ALK-targeted agents in patients harboring those mutations.

The approval was based on data from the phase 3 CheckMate-057 trial, in which second-line Opdivo reduced the risk of death by 27 percent versus docetaxel in patients with nonsquamous NSCLC, including a 60 percent risk reduction among patients with the highest levels of PD-L1 expression.

In September 2015, Keytruda was given accelerated approval as a treatment for patients with advanced, PD-L1 positive NSCLC who had received prior therapies.

The approval was based on data from the phase 1 KEYNOTE-001 trial, in which the overall response rate (ORR) with the drug was 41 percent among a subgroup of 61 patients with pretreated PD-L1—positive advanced NSCLC as determined by the 22C3 pharmDx diagnostic test.

Atezolizumab, another PD-1 blockade, was granted a breakthrough therapy designation in February 2015 for the treatment of patients with PD-L1—positive NSCLC that progresses after platinum-based chemotherapy.

In the phase 2 BIRCH trial, more than 61 percent of responses were ongoing after a minimum follow-up of six months in patients with stage 3b/4 or recurrent NSCLC who received atezolizumab.

The phase 2 POPLAR study, which compared atezolizumab with docetaxel, found that patients with the highest level of PD-L1 expression experienced a median OS with atezolizumab of 15.5 months versus 11.1 months with docetaxel.

PD-1/PD-L1 Agents Expanding in Multiple Tumor Types

Atezolizumab is currently being investigated in an ongoing phase 3 study in patients with NSCLC who are PD-L1—positive.The treatment paradigm for metastatic renal cell carcinoma also saw an FDA approval of Opdivo in November 2015. The approval, which is indicated for patients who have had prior anti-angiogenic therapy, was based off of findings from the phase 3 CheckMate-025 study.

In the study, Opdivo reduced the risk of death by 27 percent versus Afinitor (everolimus), representing a 5.4-month improvement in median OS.

In bladder cancer, atezolizumab was granted a breakthrough therapy designation in 2014 for its phase 1 IMvigor210 data. Updated phase 2 findings, published in January 2016, showed that patients with locally advanced or metastatic urothelial carcinoma who received second-line atezolizumab had a median OS of 11.4 months. Eighty-four percent of patients had ongoing responses, regardless of PD-L1 status. Early findings from a study looking at Opdivo in patients with metastatic hepatocellular carcinoma (HCC) demonstrated that nearly 20 percent of patients had marked tumor shrinkage in response to the agent. Additionally, 62 percent of patients treated with Opdivo were alive at one year.

T-Cell Therapies, Vaccines Showing Promise in Hematologic Malignancies

Keytruda is showing early promise in patients with head and neck cancer. Results of an early-phase study showed that 25 percent of patients who received Keytruda had tumor shrinkage.Other immunotherapeutic approaches are making a mark in hematologic cancers. Blincyto (blinatumomab), for example, an anti-CD19 immunotherapy, was approved by the FDA in December 2014 for the treatment of patients with Philadelphia chromosome-negative relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL), described by ASCO as a patient population that is uncommon but aggressive tumor type.

Another advancement, chimeric-antigen receptor (CAR) T-cell therapy for patients with hematologic malignancies, has shown promise in clinical trials examining the therapy in patients with relapsed ALL and diffuse large B-cell lymphoma, among other difficult-to-treat hematologic malignancies, the report lists.

Therapeutic cancer vaccines, specifically Rintega (rindopepimut), are showing potential as a treatment for patients with relapsed glioblastoma, as seen in preliminary findings from a phase 2 study. Rintega, the report explains, works with the EGFRvIII mutation, which is said to contribute to uncontrolled growth of brain tumors.

"Increasingly, we're seeing that immunotherapy is able to control cancer growth longer, and may be easier for some patients to tolerate than traditional chemotherapies and targeted drugs," said Clinical Cancer Advances 2016 co-executive editor Don S. Dizon. "The next challenge is to expand the benefits of immunotherapy to more people with cancer."

Dizon DS, Krilov L, Cohen C, et al. Clinical Cancer Advances 2016: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology [published online February 4, 2016]. J Clin Oncol. doi: 10.1200/JCO.2015.65.8427.