The NIH and National Cancer Institute have made large strides in preventing and combating cancer. Aggressive research efforts have proved to be a boon to the discovery of cancer drugs in the private sector, according to the American Institute for Cancer Research.

Here is a look at four potentially practice-changing clinical trials that are garnering attention.

 

High hopes for HER2-low patients

Previously, patients with low levels of human epidermal growth factor receptor 2 (HER2) amplification or those with overexpression of HER2 were not considered for HER2-directed therapy. That changed following a phase 3 DESTINY-Breast04 trial, according to research published by the New England Journal of Medicine.

Modi S, Jacot W, Yamashita T, et al., DESTINY-Breast04 Trial Investigators. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9–20.

T-Dxd has been approved by the FDA for HER2 low and is a category 1 NCCN recommendation for use in this setting.

 

Trastuzumab deruxtecan (T-Dxd) was approved by the FDA in 2019 to treat HER2-positive, metastatic breast cancer in patients who are no longer sensitive to other HER2 treatments. This antibody-drug conjugate not only blocks tumor growth signals sent by HER2 but also delivers a chemotherapy payload. This payload makes the drug much more powerful, as per the Memorial Sloan Kettering Cancer Center (MSKCC).

FDA approves first targeted drug to treat HER2-low breast cancer: Trastuzumab deruxtecan (T-DXd). MSKCC. August 5, 2022.

 

In a phase 3 trial, MSKCC researchers administered T-Dxd to patients with HER2-low metastatic breast cancer who had received one or two previous lines of therapy. Patients were randomly assigned 2:1 to receive either T-Dxd or the physician’s choice of therapy.

The cohort included 557 patients; 88.7% had HER2-positive disease and 11.3% had HER2-negative disease. In the HER2-positive patients receiving T-Dxd, the median progression-free survival was 10.1 months versus 5.4 months in those who received the physician’s choice of treatment. Overall survival was 23.9 months and 17.5 months, respectively.

Shanu Modi, MD, the study’s first author, reflected on this trial.

The results of this trial are practice-changing and redefine how a large population of patients with metastatic disease will be treated.

“Although this trial focused on patients with breast cancer, we believe that these results could also have implications for the future treatment of people with other types of cancer that express HER2 at low levels,” Dr. Modi added.

Based on the statistically significant and clinically meaningful improvement in overall survival noted in this trial, the FDA has approved fam-trastuxumab deruxtecan for patients who meet the study criteria, according to an article published by New England Journal of Medicine.

Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022; 387:9.

 

Participants were individuals with unresectable or metastatic HER2-low (IHC 1+ or 2+/ISH-negative) breast cancer patients who had received prior chemotherapy in the metastatic setting or who developed disease recurrence during or within 6 months of completing adjacent therapy. The NCCN also designated this a category 1 preferred therapy in this setting.

 

Immunotherapy alone for metastatic rectal cancer

 

It’s rare that a treatment is 100% effective, especially in the field of metastatic rectal cancer. But that was the takeaway when the preliminary results of a phase 2 study in patients with locally advanced mismatch repair-deficient rectal cancer were presented at the ASCO 2022 Annual Meeting.

According to The ASCO Post, in the study, 14 patients experienced complete clinical responses after 6 months of treatment with the anti–PD-1 agent dostarlimab-gxly. To date, these patients didn’t need chemotherapy, radiation, or surgery.

“Since mismatch repair deficient colorectal cancer is responsive to PD-1 blockade in the metastatic setting, we hypothesized that locally advanced mismatch repair deficient rectal cancer is sensitive to checkpoint blockade and may alter the requirements for chemoradiotherapy and surgery,” wrote the authors of an article published by Journal of Clinical Oncology.

Astellas announces zolbetuximab meets primary endpoint in phase 3 SPOTLIGHT trial as first-line treatment in claudin 18.2 positive, HER2-negative locally advanced or metastatic gastric and gastroesophageal junction (GEJ) cancers. PR Newswire. November 16, 2022.

 

 

Benefits in gastric cancer

Zolbetuximab is a first-in-class monoclonal antibody that binds CLDN18.2 and yields tumor cell death via antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. CLDN18.2 is expressed in gastric cancers and gastric metastases. And although CLDN18.2 is normally concealed in the tight junctions of gastric mucosal cells, it becomes exposed—and thus targetable—in cancer cells.

The SPOTLIGHT phase 3 trial involved 566 patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, according to an article published by Annals of Oncology.

Sahin U, Türeci Ö, Manikhas G, et al. FAST: A randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma. Ann Oncol. 2021;32(5):609–619.

 

Researchers announced that the trial met its primary endpoint of progression-free survival in patients treated with zolbetuximab plus mFOLFOX6 versus placebo plus mFOLFOX6. This novel immunotherapy could expand treatment options for gastric and GEJ cancers, of which there are few, as reported by PR Newswire.

Cercek A, Lumish MA, Sinopoli JC, et al. Single agent PD-1 blockade as curative-intent treatment in mismatch repair deficient locally advanced rectal cancer. JCO. 2022;40(17_suppl):LBA5–LBA5.

 

 

 

Alternative to bladder surgery

In January 2022, US investigators released phase 2 results involving the safety of UGN-102, a mitomycin-containing reverse thermal gel used to treat low-grade intermediate-risk, non-muscle-invasive bladder cancer (LG IR NMIBC), according to research published by The Journal of Urology.

Chevli KK, Shore ND, Trainer A, et al. Primary chemoablation of low-grade intermediate-risk nonmuscle-invasive bladder cancer using UGN-102, a mitomycin-containing reverse thermal gel (Optima II): A phase 2b, open-label, single-arm trial. J Urol. 2022;207(1):61–69.

Typically, this recurrent cancer requires that transurethral resection of bladder tumor be performed at recurrence.

 

Of 63 patients with LG IR NMIBC who received one or more doses of UGN-102, 65% achieved complete response at 3 months, with 61% remaining disease-free at 12 months.

Nonsurgical primary chemoablation of LG IR NMIBC using UGN-102 resulted in significant treatment response with sustained durability.

“UGN-102 may provide an alternative to repetitive surgery for patients with LG IR NMIBC,” the authors added.

Phase 3 trials are currently underway.