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ASCO20 Update: Considerations for Checkpoint Inhibitors Moving Forward

June 01, 2020

Whereas the first portion of ASCO20 focused on cellular immunotherapies, the latter portion provided more insights into established checkpoint inhibitors that target the PD-1/PD-L1 and CTLA-4 pathways.

Special attention was paid to cancers of the bladder, kidneys, and lungs as well as melanoma. Patients with advanced stages of these cancers have historically responded relatively well to immunotherapy. There are several FDA-approved checkpoint immunotherapies for each of these cancers, and in some cases they have become the standard of care.

Despite immunotherapy’s proven benefits, questions remain over the best way to use it—both from an effectiveness and a safety standpoint. When is it best to give, and how much? When does combining different checkpoints work, and when might adding chemotherapy or radiation help? In addition to addressing these considerations, experts also unveiled preliminary data from trials with novel immunotherapy approaches.

As the cancer that claims the most lives worldwide, non-small cell lung cancer (NSCLC)—the most common form of lung cancer—has been particularly impacted by effective immunotherapy for patients with this type of cancer.

Long-term follow up data from the pivotal phase 3 CheckMate-227 trial was unveiled by Suresh S. Ramalingam, M.D., of Emory University. Patients with metastatic NSCLC who were treated with a combination of the checkpoint inhibitors nivolumab (Opdivo®) and ipilimumab (Yervoy®) continued to demonstrate durable and long-term benefits, regardless of patients’ PD-L1 expression. At three years, the survival rate for these patients was 33 and 34 percent for patients with PD-L1-positive and PD-L1-negative tumors, respectively, versus 22 and 15 percent for standard-of-care chemotherapy. Impressively, of those who responded to immunotherapy, more than one-third remained in response after three years, compared to fewer than 5 percent of patients receiving chemotherapy alone.

Adding a shortened regimen of chemotherapy to this immunotherapy combination can also be effective. At one year follow up, according to Martin Reck, M.D., Ph.D., of Lung Clinic Grosshansdorf in Germany, this strategy was associated with a 34 percent reduction in risk of death compared to chemotherapy. Here, too, the benefits were seen in patients across all PD-L1 expression levels.

Though not technically a lung cancer, mesothelioma may also respond to checkpoint immunotherapy, as shown in a phase 2 trial. Currently, patients with mesothlioma, a cancer of the chest cavity, have few effective treatment options. As shown by Patrick M. Forde, M.D., of Johns Hopkins University, 56 percent of patients with unresectable malignant pleural mesothelioma responded to the checkpoint inhibitor durvalumab (ImfinziTM) plus standard-of-care chemotherapy, and 70 percent and 44 percent were still alive at one year and two years, respectively.

The first checkpoint immunotherapy approval by the FDA, for any type of cancer, came in 2011 for metastatic melanoma. Now, CTLA-4  and PD-1/PD-L1 immunotherapies are approved, both alone and in combination, for several advanced cancers. While some patients with metastatic disease benefit from PD-1 immunotherapy alone, a phase 2 trial led by Daniel J. Olson, M.D., and involving Thomas F. Gajewski, M.D., Ph.D., both of the University of Chicago, showed that the combination of nivolumab and low-dose ipilimumab might be effective for those patients that don’t benefit from PD-1 blockade alone. When patients received the combination immediately after progressing post-PD-1 treatment, 27 percent responded compared to the 15 percent who normally respond when treated with just ipilimumab in this situation. This combination was also found to be effective in tumors that weren’t yet inflamed by T cells, and showed a better safety profile when given in this setting compared to first-line treatment.

This combination might also be beneficial prior to surgery, said Christian U. Blank, M.D., Ph.D., of The Netherlands Cancer Institute. In the phase 2 PRADO trial, 71 percent of patients experienced responses confirmed through biopsy examination, some of which weren’t picked up by scans. Reported quality-of-life data are suggestive of the benefits, but Blank cautioned that longer-term data regarding relapse-free and overall survival will be necessary before this approach rises to the level of practice-changing.

Also in melanoma, Jessica C. Hassel, M.D., of University Hospital in Heidelberg, Germany highlighted work that analyzed the self-reactive (auto) antibodies found in more than 300 metastatic melanoma patients treated with either PD-1/PD-L1 or CTLA-4 immunotherapy or both. Antibodies targeting both tumor-associated and autoimmune-related antigens were found, and some were linked to either favorable or unfavorable treatment outcomes, while others were associated with side effects. While an autoantibody prediction strategy has enormous potential, it has yet to be validated. If more about these mechanisms could be characterized, Hassel noted, perhaps it could lead to the development of a panel to predict responses and/or side effects, which would have immense value when forming treatment strategies for individual patients.

The genitourinary session focused on two talks relating to checkpoint immunotherapy in patients with metastatic and previously untreated renal cell carcinoma (RCC), the most common form of kidney cancer.

First, speaking on the Keynote-426 trial, Elizabeth R. Plimack, M.D., of Fox Chase Cancer Center, revealed that the combination of pembrolizumab (Keytruda®) and the tyrosine kinase inhibitor axitnib (Inlyta®) compared to another tyrosine kinase inhibitor alone led to improved response rates (60 versus 40 percent) and two-year survival rates (74 versus 66 percent) as well as complete response rates that were three times higher (9 versus 3 percent). Increased survival was associated with greater extent of tumor shrinkage in patients who received immunotherapy.

Second, Michael B. Atkins, M.D., of Georgetown Lombardi Comprehensive Cancer Center, presented data from a phase 2 trial, such as a 32 percent response rate, supporting the use of nivolumab alone as a first-line treatment in RCC patients. Additionally, roughly half the patients who didn’t respond to nivolumab were then treated with nivolumab plus ipilimumab—and 11 percent responded.

Immunotherapy has also transformed bladder cancer, another genitourinary cancer that afflicts more than half a million people worldwide each year, and new approvals may still be ahead. In the phase 3 JAVELIN trial, as highlighted during Sunday’s plenary session by Thomas Powles, M.D., Ph.D., of the University of London, combining avelumab (Bavencio®) with best supportive care treatment outperformed the latter alone after initial platinum-based chemotherapy in patients with advanced urothelial cancer, including those with low PD-L1 expression. In terms of overall survival, the combination was associated with increased survival at the one-and-a-half-year mark (61 versus 44 percent) and a 31 percent reduction in risk of death in the general patient population, whereas PD-L1-positive patients saw a 44 percent reduction. Complete response rates were also significantly higher—6 versus 0.9 percent in all patients, and 9.5 versus 0.6 percent in the PD-L1-positive patients—in those who received the combination, which Powles suggested should be considered the new first-line maintenance therapy in advanced bladder cancer.

In colorectal cancer, Thierry Andre, M.D., of Sorbonne University in Paris, France, discussed results from the phase 3 Keynote-177 trial. Compared to chemotherapy, pembrolizumab led to more frequent responses (44 versus 33 percent) in patients with metastatic disease that is characterized by high microsatellite instability (MSI-high). Immunotherapy responses were also more durable, with 83 percent lasting at least two years, compared to only 35 percent of those associated with chemotherapy.

Checkpoint immunotherapy also showed promise against some sarcomas, which are typically immune-resistant, when combined with radiation therapy. While not very effective against dedifferentiated liposarcomas (DDLPS), the combination of nivolumab and radiation, both with and without ipilimumab, did show clinical activity in patients with undifferentiated pleomorphic sarcoma (UPS), according to Christina L. Roland, M.D., of The University of Texas MD Anderson Cancer Center. In a phase two trial, UPS patients had significantly more tumor elimination prior to surgery, compared to historical data with other treatments.

Lastly, a number of newer immunotherapy approaches were highlighted, including several bispecific antibodies capable of engaging two different targets.

Jason J. Luke, M.D., of the University of Pittsburgh, discussed early evidence of clinical activity in a phase 1 trial of MGD013, a bispecific “DART” therapy binding two immune checkpoint pathways found on T cells: PD-1 and LAG-3. In relapsed and refractory HER-2-positive cancers, MGD013 plus an HER-2-targeting antibody led to encouraging response rates—greater than 40 percent—in tumors that express low levels of PD-L1.

Another bispecific antibody approach was highlighted by Saad Z Usmani, M.D., of Levine Cancer Institute-Atrium Health, who spoke about a phase 1 trial for patients with relapsed or refractory multiple myeloma. This bispecific antibody targets the CD3 receptor found on T cells and the BCMA protein found on myeloma B cells. Eight of the twelve patients who received the highest dose responded, with six having “very good” responses defined as at least a 90 percent disease reduction in circulating antibody levels produced by these B cells. These responses also appeared durable, with sixteen of twenty-one responses ongoing.

A pilot study discussed by Eglys Gonzalez Marcano, Ph.D., of Unifontis Clinic in Germany, involved a vaccine made of a patient’s own disrupted tumor cells. Four of the thirty-one patients treated—13 percent—had their tumors completely vanish, and an additional 6.5 percent had partial responses. Three of these complete responders were patients with breast cancer.

Check back soon for our overall ASCO20 recap as well as our exciting lineup of Cancer Immunotherapy Month (#CIM20) events in June.

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