Pembrolizumab shows benefit in high-risk BCG non-responsive bladder cancer

24th February 2023

Pembrolizumab therapy in patients with high-risk, non-muscle-invasive bladder cancer unresponsive to BCG treatment shows anti-tumour activity

Data presented at the 2023 American Society for Clinical Oncology (ASCO) genitourinary cancer symposium, showed that pembrolizumab monotherapy in patients with Bacillus Calmette-Guerin (BGC) unresponsive, high-risk, non-muscle invasive bladder cancer, showed notable anti-tumour activity after roughly 45 months of follow-up.

The vast majority (75 to 80%) of newly diagnosed bladder cancers are categorised as non-muscle invasive cancers (NMIBC). BCG has been used in the treatment of NMIBC for many years although in roughly half of high-risk patients, intra-vesical BCG treatment fails and NMIBC persists or recurs early. In an earlier Phase II study (KEYNOTE-057), patients with histologically confirmed BCG-unresponsive carcinoma in situ with or without papillary tumours, treated with pembrolizumab monotherapy showed that the drug was both tolerable and demonstrated promising anti-tumour activity.

The data presented at the ASCO symposium relates to a second patient cohort from KEYNOTE-057 who had papillary tumours but without carcinoma in situ. These individuals received pembrolizumab at a dose of 200 mg every three weeks for less than 35 cycles. The primary endpoint as 12-month disease-free survival (DFS) as determined by central pathology and radiology review. Other outcomes explored included the 12-month DFS of any disease, progression-free survival (PFS) to worsening of grade, stage, or death as well as PFS to muscle invasion, metastasis, or death and finally, overall survival (OS).

Pembrolizumab and disease-free survival

A total of 132 patients with a median age of 72 years were included and who had received a median of 10 prior BCG instillations. The median follow-up was 45.4 months.

The 12-month DFS rate was 43.5 % and the median DFS was 7.7 months (95% CI 6.5 – 13.6). In addition, for any level of disease recurrence, the 12 month DFS was estimated as 41.7% with a median DFS of 6 months. The 12-month PFS to either invasive or metastatic disease or death was 88.2% with a median PFS of 46.2 months and the estimated overall survival rate at 12 months was 96.2%.

The authors concluded that patients with BCG unresponsive, non-carcinoma in situ papillary high risk NMIBC may benefit from pembrolizumab monotherapy.

Citation
Necchi A et al. Pembrolizumab (pembro) monotherapy for patients (pts) with high-risk non–muscle-invasive bladder cancer (HR NMIBC) unresponsive to bacillus Calmette–Guérin (BCG): Results from cohort B of the phase 2 KEYNOTE-057 trial. Abstract LBA442, GuCS 2023

Pembrolizumab with radiotherapy equal to cetuximab for advanced head and neck SCC

25th November 2022

A pembrolizumab and radiotherapy regime was no better than cetuximab in locally advanced squamous cell carcinoma of the head and neck

Pembrolizumab and radiotherapy failed to improve tumour control and survival compared to a standard of care regime with cetuximab and radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck according to a phase II randomised study by French researchers.

Most head and neck cancers are derived from the mucosal epithelium in the oral cavity, pharynx and larynx and are known collectively as head and neck squamous cell carcinoma. Head and neck cancer is the seventh most common cancer worldwide and accounts for over 800,000 new cases annually.

Pembrolizumab is a monoclonal antibody directed against programmed cell death protein 1 (PD-1) and it has been shown that in combination with platinum and 5-fluorouracil, the drug is an appropriate first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). In addition, pembrolizumab monotherapy is also an appropriate first-line treatment for PD-L1-positive recurrent or metastatic HNSCC. However, while effective as monotherapy, the drug has also been found to significantly increase both the response and outcome in patients with metastatic non-small-cell lung cancer, when combined with radiotherapy. Many patients with HNSCC have locally advanced disease and are commonly managed with cetuximab plus radiotherapy which significantly improves overall survival at 5 years compared with radiotherapy alone, hence confirming the regime as an important treatment option in this group of patients. Nevertheless, the regime is associated with acute and late toxicities, including myelosuppression, severe nausea/vomiting, irreversible renal failure, hearing loss, and neurotoxicity, prompting the need for effective alternatives.

Based on the effectiveness of pembrolizumab and radiation therapy in patients with non-small cell lung cancer, in the present study, the French team tested this combination against cetuximab-radiotherapy in patients with non-operated stage III-IVa-b SCC of oral cavity, oropharynx, hypopharynx and larynx. Patients received once-daily radiotherapy with weekly cetuximab or 200mg Q3W pembrolizumab during RT and the primary endpoint was the loco-regional control (LRC) rate 15 months after radiotherapy.

Pembrolizumab and head and neck squamous cell carcinoma outcomes

A total of 133 patients with a median age was 65 years, 92% of whom were smokers, were randomised to either arm (67 to pembrolizumab) and followed for a median of 25 months.

The 15-month LRC rate was 59% with cetuximab and 60% with pembrolizumab, representing a non-significant difference (Odds ratio, OR = 1.05, 95% CI 0.43 – 2.59, p = 0.91). In addition, there were no significant difference between arms for progression-free survival (Hazard ratio, HR = 0.85, 95% CI 0.55 – 1.32, p = 0.47) or for overall survival (HR = 0.83, 95% CI 0.49 – 1.40, p = 0.49).

Despite the lack of difference in cancer outcomes, toxicity was lower with pembrolizumab than with cetuximab, with 74% vs 92% patients having at least one grade ≥ 3 adverse event (p=0.006) and which were mainly mucositis, radio-dermatitis and rash.

The authors concluded that compared to cetuximab with radiotherapy, pembrolizumab and concomitant radiotherapy, did not improve the tumour control and survival but appeared less toxic in unfit patients with locally, advanced, squamous cell carcinoma of the head and neck.

Citation
Toa Y et al. Pembrolizumab versus cetuximab, concurrent with radiotherapy in patients with locally advanced squamous cell carcinoma of head and neck unfit for cisplatin (GORTEC 2015-01 PembroRad): a multicenter, randomized, phase 2 trial. Ann Oncol 2022

Adjuvant pembrolizumab increases event-free survival in triple negative breast cancer

18th February 2022

Adjuvant pembrolizumab in addition to chemotherapy has been found to improve event-free survival in triple negative breast cancer patients

Adjuvant pembrolizumab added to chemotherapy post surgery significantly improves event-free survival compared to chemotherapy alone. This was the conclusion of a study by researchers from the Centre of Experimental Cancer Medicine, Barts Cancer Institute, London, UK.

Triple negative breast cancer constitutes 10-15% of female breast cancers and is a more aggressive cancer with more frequent recurrence and worse survival compared with the non-triple negative form. Clinical trial data has revealed improved disease-free survival with postoperative chemotherapy in patients with either triple-negative or HER2-positive breast cancer who had residual disease after neoadjuvant chemotherapy. Whether the addition of pembrolizumab to neoadjuvant chemotherapy would increase the proportion of patients with early triple-negative breast cancer who had a pathological complete response after surgery was unclear until publication in 2020, of the KEYNOTE-522 trial. The trial concluded that the percentage of patients with a pathological complete response was significantly higher among those who received pembrolizumab plus neoadjuvant chemotherapy than among those who received placebo plus neoadjuvant chemotherapy.

For the present study, the authors have reported on an updated analysis of the KEYNOTE-522 trial and in particular, event-free survival as well as additional efficacy and updated safety information. Participants were adults with confirmed triple negative breast cancer or those with newly diagnosed and previously untreated non-metastatic disease with primary tumour and regional lymph node involvement. During the adjuvant phase, patients with previously untreated stage II or III triple negative breast cancer, were randomised 2:1 to receive either pembrolizumab (the pembrolizumab–chemotherapy group) or placebo (the placebo–chemotherapy group), administered once every 3 weeks. After surgery, patients received either pembrolizumab or placebo and chemotherapy every 3 weeks for up to nine cycles. The primary endpoint was pathological complete response and event-free survival.

Adjuvant Pembrolizumab and event-free survival

A total of 1174 patients were randomly assigned to either arm and during follow-up, 123 (15.7%) patients assigned to the pembrolizumab arm had an event or died compared to 93 (23.8%) in the placebo-chemotherapy arm.

The estimated event-free survival after 36 months was 84.5% in the adjuvant pembrolizumab group and 76.8% in the placebo arm, giving a hazard ratio, HR, for an event or death = 0.63, 95% CI 0.48 – 0.82, p < 0.001.

Data on overall survival were described as immature at the time of the analysis and the estimated overall survival at 36 months was 89.7% in the adjuvant pembrolizumab group and 86.9% in the placebo-chemotherapy group. With respect to safety, the authors reported that the reported adverse events were consistent with the established safety profile of both pembrolizumab and chemotherapy.

The authors concluded that among those with early triple negative breast cancer, neoadjuvant pembrolizumab plus chemotherapy and then followed by adjuvant pembrolizumab after surgery, was associated with a significantly longer event-free survival than neoadjuvant chemotherapy alone.

Citation
Schmid P et al. Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer N Engl J Med 2022