The science of cancer immunotherapy has come a long way in the last decade since the approval of the first checkpoint inhibitor in 2011, as the 2021 annual meeting of the American Society of Clinical Oncology (ASCO21) highlighted this month. Just as importantly, those scientific advances have already translated into meaningful improvements in the lives of those affected by cancer, and lifesaving scientific research is unlocking more of immunotherapy’s potential each passing year.
Living Longer with Immunotherapy
With cancer, nowhere has immunotherapy’s progress been more evident than in advanced (metastatic) melanoma, which was essentially untreatable. At ASCO21, Memorial Sloan Kettering Cancer Center’s Jedd D. Wolchok, M.D., Ph.D., an associate director of the CRI Scientific Advisory Council, presented long-term patient data from the CheckMate-067 trial showing that the combination of the immune checkpoint inhibitors nivolumab and ipilimumab enabled half those treated to survive at least six years, the longest median overall survival ever seen in a phase 3 trial in advanced melanoma.
During the ASCO Book Club event, Wolchok also had a conversation with someone who is living, breathing proof of that progress: CRI ImmunoAdvocate Mary Elizabeth Williams, who has had no evidence of disease for more than a decade after Wolchok treated her with that immunotherapy combination. In sharing her story, Williams also expressed her deep appreciation for the decades of research and the thousands of scientists who contributed to this treatment breakthrough.
“I’m grateful to you and the centuries-plus of doctors and researchers who didn’t give up. Immunotherapy really has its roots in the nineteenth century. When I think about Drs. William B. Coley and Lloyd Old and the Cancer Research Institute, and everyone there who didn’t stop for decades and decades… that persistence makes all the difference in the world.”
“When [Wolchok] was talking earlier about all the amazing science,” Williams continued, “I was just thinking what a relay it is because you see all the hands along the way passing that science [along]. If at any point, someone drops that baton because they didn’t communicate well, they weren’t compassionate, they weren’t respectful, they weren’t kind, they weren’t inclusive, they didn’t try hard enough, it gets dropped, and all that great science gets ignored.”
Thanks to organizations like CRI, that baton continues to be protected and passed. But the race isn’t over. As Wolchok said, “Just because we have some medicines that work for some people doesn’t mean that the job is done.”
Even in melanoma, there remain many patients who don’t benefit from current immunotherapy approaches. To that end, a phase 3 trial led by Dana Farber Cancer Institute’s F. Stephen Hodi, M.D., a member of the CRI Scientific Advisory Council and the CRI Clinical Accelerator Leadership, found that combining nivolumab with a newer checkpoint immunotherapy—the anti-LAG-3 relatlimab—more than doubled the median progression-free survival time in melanoma patients compared to nivolumab alone. This combination also appeared beneficial when given both before and after surgery in patients with operable stage 3 melanoma, leading to major pathological responses in two-thirds of the patients treated. Thus far, with an average follow-up time of 16 months, none of the 29 patients who were treated have relapsed. Pembrolizumab, a PD-1 checkpoint immunotherapy, also demonstrated superior protection against relapse when given after surgery, lending weight to the case for its use as standard of care for patients with high-risk, operable disease.
Regarding patients who don’t respond to or relapse after PD-1 checkpoint immunotherapy, several talks at ASCO21 explored approaches to overcoming this resistance, including in melanoma. Of note, a cell therapy called lifileucel, which involves tumor-infiltrating lymphocytes, led to responses in more than a third of patients with advanced melanoma, many of which improved over time, including one patient who went from a partial response to a complete response after two years. Other talks revealed that combining pembrolizumab with either lenvatinib, a tumor blood vessel-targeting therapy, or alrizomadlin, which is designed to stimulate the tumor suppressor activity of the p53 pathway, enabled about one-quarter of immunotherapy-relapsed/refractory patients to respond to treatment.
Checkpoint Immunotherapy in Other Cancers
Checkpoint immunotherapy continues to prove itself useful in a variety of settings in lung cancer, genitourinary cancers, and breast cancer, among others.
In patients with operable lung cancer, treatment with the anti-PD-L1 immunotherapy atezolizumab combined with chemotherapy after surgery resulted in the first phase 3 trial data linked to improved disease-free survival in those with PD-L1-positive tumors compared to chemotherapy alone. Another phase 3 trial observed the usefulness of nivolumab plus chemotherapy prior to surgery, which allowed more lung cancer patients to undergo complete resection.
In bladder cancer, five-year follow-up data on patients treated with pembrolizumab in a phase 2 trial showed that those whose tumors had high PD-L1 expression were more than twice as likely to respond, and lived almost twice as long, compared to those with low PD-L1 levels. Two combinations involving checkpoint therapies—nivolumab plus chemotherapy, and the anti-PD-L1 immunotherapy durvalumab in combination with the anti-CTLA-4 immunotherapy tremelimumab and radiation—also appeared helpful while at the same time sparing patients from surgical removal of their bladders, thus enabling preservation of this important organ without compromising treatment success. Feladilimab also became the first ICOS-stimulating immunotherapy to demonstrate benefits in patients for whom prior PD-1 immunotherapy was ineffective. By itself, the treatment reduced the risk of death by roughly 70% in patients with PD-L1-positive advanced bladder cancer, compared to those with PD-L1-negative disease. PD-1 immunotherapy was also responsible for the first positive phase 3 results involving immunotherapy after surgery (nephrectomy) in kidney cancer, where pembrolizumab was associated with improved relapse-free survival.
In triple-negative breast cancer (TNBC), a phase 3 study involving the anti-PD-1 immunotherapy camrelizumab in combination with chemotherapy and the targeted therapy famitinib led to responses in more than 80% of patients, the highest ever seen for a first-line treatment against metastatic TNBC. In patients with early-stage TNBC, adding the checkpoint inhibitor durvalumab to chemotherapy improved long-term outcomes and was associated with a 76% reduction in risk of death.
Checkpoint immunotherapy advances were also highlighted in cancers of the esophagus, stomach, and the gastroesophageal junction (GEJ). In particular, data from a phase 3 trial in advanced esophageal cancer revealed that combinations of nivolumab and ipilimumab, and nivolumab plus chemotherapy, may represent potential new standards of care in this disease based on response and survival benefits compared to chemotherapy alone. Nivolumab plus chemotherapy also outperformed chemotherapy alone in terms of progression-free survival, overall survival, and durability of responses in patients with advanced GEJ cancer that doesn’t express HER2, supporting it as a first-line standard-of-care strategy. In the neoadjuvant setting, combining pembrolizumab with chemotherapy and radiation improved the major pathological response rate prior to surgery compared to historical controls, and the disease-free survival rate at one year was 100% (39 patients).
Lastly, while checkpoint immunotherapy has been relatively ineffective in advanced sarcoma, results from a phase 2 study identified tertiary lymphoid structures (TLS)—complexes which promote adaptive immune responses—as important biomarkers linked to immunotherapy responses in patients with soft tissue sarcomas who were treated with pembrolizumab and chemotherapy. At the six-month mark, 40% of the patients whose tumors had TLS remained progression-free, compared to only 5% of those without TLS.
Cellular Immunotherapy and Vaccine Advances
ASCO21 also showcased the latest breakthroughs in cellular immunotherapies, including an intriguing new cancer cell-based vaccination approach. Sticking first with sarcoma, patients with advanced synovial sarcoma or liposarcoma who received afamitresgene autoleucel—which consists of T cells engineered with anti-MAGE-A4 T cell receptors—experienced significant tumor regression across different levels of dosage and expression of proteins within the MAGE family. In lymphoma, three CAR T cell therapy trials produced promising results. In a phase 2 study, the CD19-targeting CAR T therapy tisagenlecleucel led to an 86% response rate (and a 66% complete response rate) when used as a third-line treatment in patients with follicular lymphoma. The two others, both phase 1 studies, explored the use of a CD20-targeting CAR T cell product called C-CAR066 and a bispecific CD19- and CD20-targeting CAR T cell product called C-CAR039 in patients with relapsed or refractory B cell non-Hodgkin lymphoma. The CD20-targeting C-CAR066 was evaluated in patients who didn’t have lasting benefit from CD19 CAR T cell therapy. All ten patients responded, seven of whom had complete responses. The dual-targeting C-CAR039 led to responses in 93% of patients, including complete responses in 85%. In ovarian cancer, which, like sarcoma, has also remained relatively resistant to current checkpoint immunotherapies, a treatment utilizing tumor cells—not T cells—appeared to benefit certain patients with advanced disease. In a phase 2 study, gemogenovatucel-T—a vaccine made from a patient’s own harvested tumor cells that are then engineered to reduce their expression of immunosuppressive molecules—provided significant benefit as a maintenance therapy in a subset of patients with stage 3 and 4 ovarian cancer who underwent surgery. Those patients, defined as homologous recombination proficient or HRP, experienced two- and three-year survival rates of 94% and 70%, compared to 55% and 40% for non-HRP patients.
Addressing Healthcare Disparities and Inequities
ASCO21 also focused on the disparities and inequities within the oncology world, particularly those faced by the Black community in the United States, and how to address the issues. Several studies revealed how Black cancer patients are much less likely to undergo next-generation sequencing or comprehensive genomic analysis early in their treatment journeys and are less likely to enroll in clinical trials. These delays, whether due to lack of awareness of or access to these important elements of cancer care, hamper their ability to receive optimal treatment in a timely fashion. In prostate cancer, PSA screening is associated with a lower risk of severe disease and death, and overcoming issues related to access, availability, or insurance may help improve outcomes for Black men with prostate cancer.
One productive approach to overcoming these disparities was highlighted in a study in lung cancer, where Black patients who delay treatment are more likely to suffer from longer waits for surgery that can lead to disease progression and negatively impact their survival. Here, the ACCURE intervention method—developed from a community partnership that relied on a combination of real-time electronic health record monitoring, nurse navigation, and race-based feedback—was able to drastically improve time to surgery in Black patients, and ultimately reduce racial disparities in this situation.
Another important effort, led by the University of Pennsylvania, encouraged clinical trial enrollment among Black cancer patients. Their multifaceted, community-based engagement initiative sought to build trust and establish bi-directional relationships in the Philadelphia area prior to COVID-19, organize educational efforts in Black communities, and develop programs to increase access to cancer screening and mitigate transportation barriers for patients. Overall, the effort has been successful, increasing clinical trial enrollment by 90% in adult therapeutic trials, 300% in adult non-therapeutic intervention trials, and 70% in adult non-interventional trials.
This important discussion at ASCO21 on how to help address racial disparities in cancer care has drawn leaders in the field to seek solutions quickly. Helping that effort are passionate and motivated patients who find in ASCO21 a platform not only for advocating for themselves, but also for all others who must face cancer, whether now or in the future. As Mary Elizabeth Williams noted during her ASCO Book Club event, most people don’t have her long list of privileges. That’s why she is so passionate about leveraging her experiences and her insights to help educate and empower other patients. In other words, to be “the voice… for that patient who doesn’t look like me, and for the patients who are scared, who have limited access, limited time.”