5 Important Developments in Cancer – 2021 AACR Annual Meeting

The 2021 American Association for Cancer Research (AACR) Annual Meeting is largely a collection of basic research and early-stage clinical trial presentations, but some of this year's presentations contain important clinical data that could change oncology practice.

Cancer immunotherapies have entered an era in which phase 3 trials are mushrooming and researchers and their sponsors compete for high-profile sessions at major clinical oncology meetings.

In this article, we summarize 5 clinically important—or potentially important—studies presented at the AACR 2021 annual meeting.

A Practice-Changing Study in Metastatic Uveal Melanoma

Metastatic (stage 4) uveal (eye) melanoma was the setting for the first randomized controlled trial positive for overall survival, whose results were described as “practice-changing.”

This phase 3 clinical trial investigated first-line use of the experimental treatment tebentafusp (Immunocore) and its results compared with immunotherapy or chemotherapy in patients with metastatic disease.

The 378 patients enrolled were randomly assigned in a 2:1 ratio to one of two groups:

• 252 patients received tebentafusp, or
• according to investigator choice, 103 patients received pembrolizumab, 16 received ipilimumab and 7 received dacarbazine

Results

• At a median follow-up of 14.1 months, overall survival was significantly longer in patients receiving tebentafusp than in those in the investigator-choice arm: 21.7 months versus 16.0 months.
• The estimated 1-year overall survival rate was 73.2% in the tebentafusp arm and 58.5% in the standard-treatment arm (hazard ratio [HR], 0.51; P <.0001).

Target-mediated or cytokine-mediated adverse events were the most common side effects with tebentafusp. They included pyrexia/fever (76%), itching (69%) and rash (83%), which decreased in frequency and severity after the first three to four doses.

Although cytokine release syndrome was common with tebentafusp (89%), the rate of grade 3–4 cytokine release syndrome was very low (1%).

How Does Tebentafusp Work?

Tebentafusp is a protein that redirects T cells to kill gp100-expressing tumor cells. Because its T-cell receptor binding domain recognizes only a specific gp100-derived peptide presented by HLA-A*02:01, tebentafusp can be used only to treat patients with this HLA type.

The manufacturer recently described HLA-A*02:01-positive adults with unresectable or metastatic uveal melanoma as the patients for whom tebentafusp (IMCgp100) received US Food and Drug Administration (FDA) breakthrough therapy designation, according to its announcement.

Lung Cancer Disappears Before Surgery

The immunotherapy nivolumab (Opdivo) has received numerous approvals for many different advanced cancers and is now being tested, like many other anti-PD-1 and anti-PD-L1 immunotherapies in early-stage disease.

New phase 3 trial data concern nivolumab given to patients with operable non-small cell lung cancer (KHDAK) before surgery for neoadjuvant purposes, and suggest that it may be effective.

CheckMate 816 trial results show that the pathological complete response rate was much higher with nivolumab than with standard chemotherapy alone: 2.2% versus 24%.

Pathological complete response was the primary endpoint of this trial and was defined as complete regression in both the primary tumor and lymph nodes.

Improved Survival in Children With a Very Difficult Tumor

According to Dr. Howard Kaufman, director of the Oncolytic Virus Research Laboratory at Massachusetts General Hospital, Boston, Massachusetts, recurrent or progressive high-grade glioma is “a terrible disease that really does not respond to anything.”

Kaufman was asked to comment on a small trial involving herpes simplex virus type 1 (HSV-1), specifically a phase 1 study of an experimental immunotherapy containing a genetically modified version of the virus.

Known as G207, the oncolytic virus product stimulates an immune response and kills tumor cells.

In the clinical trial, this candidate cancer drug was infused directly into the brains of 12 patients aged 7-18 with glioma. The historical control patients had a median survival for comparison: median overall survival was 12.2 months, more than double the 5.3 months observed in those controls.

This study was also published simultaneously online in NEJM as a concurrent publication.

Meanwhile, an oncolytic viral therapy is already on the US market: Talimogene laherparepvec (Lmlygic), an oncolytic HSV-1 treatment, received FDA approval in 2015 for injection directly into skin lesions.

Made-to-Order Personalized Treatment for Metastatic Melanoma

Patients with metastatic melanoma whose disease continues to progress despite treatment with breakthrough immunotherapy and targeted drugs have few subsequent treatment options. One approach that might work involves cells isolated directly from tumor tissue: T cells are used in a customized cell treatment for which the name TIL therapy is used.

One such product, called Lifileucel, is made individually for each patient and uses tumor-infiltrating lymphocytes (TILs) obtained from the patient's cancerous lesions.

This approach differs from treatments using T cells collected from a patient's blood, such as CAR T-cell therapy, and other cell-based treatments.

This study of 66 patients with previously untreatable or metastatic melanoma was a phase 2 trial whose results yielded an objective response rate of 36.4%. Of the 24 responding patients, 3 had a complete response and 21 a partial response.

After a median follow-up of 28.1 months in this study, median duration of response had not been reached because more than half of the patients continued to respond to treatment. Response durations ranged from 2.2 to 35.2 months.

Customized cell therapy with TILs is not actually new—it has been investigated for melanoma treatment for more than a decade. Some researchers have reported durable responses in 25% of patients.

However, the process of producing TIL therapy is truly complex and is not fully standardized.

The current study shows that cell production can take place at a central facility with the necessary technical expertise. It also showed that TILs can be successfully produced from tumor sites other than the skin or lymph nodes.

A Healthy Lifestyle in Men at High Risk of Prostate Cancer

Adhering to a healthy lifestyle, according to results from a large US cohort study, may offset a high risk of lethal prostate cancer in patients with a high genetic risk score.

According to lead study author from Harvard School of Public Health, Boston, Massachusetts, Anna Plym, prostate cancer risk variation is approximately 58% attributable to genetic factors. Common single-nucleotide polymorphisms (SNPs) account for an important share of prostate cancer susceptibility.

A polygenic risk score combining information from 269 SNPs is “highly predictive” of prostate cancer.

The researchers used this score to measure genetic prostate cancer risk in 10,443 men enrolled in the Health Professionals Follow-up Study. The men were divided into quartiles by genetic risk.

The researchers also classified the men using a validated lifestyle score for this categorization.

Using follow-up data extending up to 22 years, the team found that adhering to a healthy lifestyle did not reduce overall prostate cancer risk in men at low genetic risk (HR, 1.01;95% CI, 0.84 - 1.22).

However, a healthy lifestyle appeared to affect men in the highest genetic-risk quartile. Men with the highest healthy-lifestyle scores, compared with those with the lowest lifestyle scores, had about half the risk of lethal prostate cancer.