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Durvalumab (Imfinzi)

A human immunoglobulin G1 kappa monoclonal antibody that blocks the interaction of PD-L1 with programmed cell death protein 1 (PD-!) and CD 80.

Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases inhibition of immune responses, without inducing antibody-dependent cell-mediated cytotoxicity.

Approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with that chemotherapy.

Approved for the treatment of patients with locally advanced, unresectable NSCLC whose disease has not progressed following platinum based chemoradiation.

Pacific Investigators randomized patients to durvalumab intravenously 10 mg per kilogram of body weight or placebo every two weeks for up to 12 months in patients with stage III NSCLC: Durvalumab resulted in significant longer overall survival than placebo.

In the above study the 24 month overall survival rate 66.3% in the durvalumab group rate compared to 55% of the placebo group, the median duration of progression free survival was 17.2 months in the durvalumab Group and 5.6 months in the placebo group, the median time to death or distant metastases was 28.3 months in the durvalumab group and 16.2 miles in the placebo group.

Durvalumab in the PACIFIC study demonstrated in patients with stage III NSCLC there was a significant benefit in survival with adjuvant durvalumab after chemotherapy compared with placebo.

In the PACIFIC  trial Standard chemotherapy/radio therapy followed by Durvalumab maintenance for one year is now the standard of care in unresectable stage III non-small cell lung cancer.

Approved durvalumab for the treatment of patients with stage III non-small cell lung cancer (NSCLC) whose tumors are unresectable and whose cancer has not progressed after chemoradiation.

Current standard of care for patients with unresectable stage III non-small cell lung cancer is a platinum-based doublet given concurrently with radiation, followed by immunotherapy with Durvalumab.

CASPIAN trial showed the combination of durvalumab and etoposide achieved significant improvement in overall survival compared to etoposide alone.

 

The FDA has approved durvalumab (Imfinzi) for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC) for use in combination with standard-of-care chemotherapy, including etoposide plus either carboplatin or cisplatin.

 

It is approved by the FDA for the treatment of patients with locally advanced, unresectable stage III non-small cell lung cancer who have not progressed following chemoradiotherapy.

Phase 3 CASPIAN trial showed maintained overall survival (OS) benefit of durvalumab treatment in combination with platinum etoposide chemotherapy vs chemotherapy alone, in newly diagnosed patients with extensive-stage small cell lung cancer (ES-SCLC) after more than 2 years of follow-up.

More than 10% of patients on durvalumab plus chemotherapy had not progressed and remained on treatment at two years vs 2.9% on chemotherapy alone.

 

It reduced  the risk of death by 27%.

After a median follow-up of 14.2 months, the addition of the durvalumab improved the median OS to 13.0 months versus 10.3 months with EP alone.

After a median follow-up of 25.1 months, the median OS was 12.9 months among patients who received durvalumab + EP compared with 10.5 months for those who received EP alone.

Overall survival favored durvalumab regardless of whether carboplatin or cisplatin was the backbone chemotherapy agent used.

 

The first treatment approved to reduce the risk of the cancer progressing in this setting.

An approved therapy that has been shown to keep the cancer from progressing for a longer time after chemoradiation,

An anti-programmed death ligand 1 (PD-L1) inhibitor and has one previous FDA approval, for certain patients with locally advanced or metastatic bladder cancer.

The new approval is based on results from the 173-patient PACIFIC trial, in which all of the patients had nonprogressive cancer after chemoradiation, and it significantly improved progression-free survival (PFS) compared with placebo; the median PFS was 16.8 months with durvalumab vs 5.6 months with placebo.

In the above study patients with stage III with unresectable NSCLC who did not have disease progression after concurrent chemo radiotherapy, durvalumab significantly increased progression free survival as compared with placebo, with median duration of 16.8 months and 5.6 months, respectively, and the median time to death or distant metastasis was 28.3 months in the Durvalumab group and 16.2 months in the placebo group.

The objective response rate was significantly higher with durvalumab than with placebo, at 28.4% vs 16.0%.

Subsequently, approval of durvalumab for metastatic bladder cancer withdrawn.

The Ventana PD-L1 Assay (Ventana Medical Systems) as a complementary diagnostic test for assessing the programmed cell death ligand-1 (PD-L1) protein in urothelial carcinoma tissue.

Urothelial cancers include carcinomas of the bladder, ureters and renal pelvis.

In a single-arm trial of 182 patients with locally advanced or metastatic urothelial carcinoma whose disease progressed after prior platinum-containing chemotherapy: Objective response rate was 17.%, and the median response duration was not reached.

Among the 182 patients, the confirmed ORR was 26.3% in 95 patients with a high PD-L1 score and 4.1% in 73 patients with a low or negative PD-L1 score.

For patients with stage III NSCLC it improved median PFS by 11.2 months compared with placebo in patients with locally advanced, unresectable disease that had not progressed after chemoradiotherapy.

The most common adverse reactions are fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, and urinary tract infection.

Serious adverse events include: Infection and immune-related adverse events, including pneumonitis, hepatitis, colitis, thyroid disease, adrenal insufficiency, acute renal injury and diabetes.

The recommended dose of durvalumab is 10 mg/kg, administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.

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