Durvalumab Approved by FDA for Reducing NSCLC Progression

The FDA recently approved durvalumab (Imfinzi) for the treatment of patients with stage 3 non-small cell lung cancer (NSCLC) whose tumors are unresectable and whose disease has not progressed following treatment with chemoradiation, according to a press release. This application was previously granted priority review and breakthrough therapy designations.

“This is the first treatment approved for stage 3 unresectable non-small cell lung cancer to reduce the risk of the cancer progressing, when the cancer has not worsened after chemoradiation,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA Center for Drug Evaluation and Research.

Lung cancer is a leading cause of death in the United States and a majority of diagnoses are the NSCLC subtype. Stage 3 NSCLC is characterized by metastases in the lymph nodes or other nearby parts of the body. Durvalumab is a checkpoint inhibitor that works by blocking the PD-1/PD-L1 pathways, which is thought to bolster the body’s defense against cancer, according to the FDA.

The new approval was based on positive findings from a clinical trial including 713 patients with NSCLC whose disease had not progressed following chemoradiation. The study evaluated progression-free survival (PFS) for durvalumab versus placebo. The researchers found that the median PFS for patients taking durvalumab was 16.8 months compared with only 5.6 months for those taking placebo, according to the release.

Common adverse events associated with durvalumab in patients with NSCLC include cough, fatigue, pneumonitis/radiation pneumonitis, upper respiratory tract infections, dyspnea, and rash. The FDA warns that durvalumab comes with serious risks. These risks include immune-mediated adverse events, in which the immune system attacks cells or organs, such as the lungs, liver, colon, hormone-producing glands, and kidneys. Other serious risks include infection and infusion-related reactions, according to the release. In 2017, durvalumab was granted accelerated approval by the FDA for the treatment of patients with advanced or metastatic bladder cancer.

“For patients with stage 3 lung cancer that cannot be removed surgically, the current approach to prevent progression is chemoradiation. Although a small number of patients may be cured with the chemoradiation, the cancer may eventually progress,” Dr Pazdur said. “Patients now have an approved therapy that has been shown to keep the cancer from progressing for a longer time after chemoradiation.”

This article originally appeared on Specialty Pharmacy Times.

News digest – ‘Ultra-processed’ foods, clinical trials boost, ovarian cancer risk and… tiny DNA robots?

  • Ultra-processed’ foods were linked with cancer this week following a large study. Researchers defined ready meals, packaged cakes, sugary drinks, and more as ‘ultra-processed’. As we told the BBC, it’s difficult to untangle whether the increased cancer risk is caused by the foods themselves or their effects on bodyweight. Sky News and the Guardian also have more on this one.


  • Clinical trials are crucial for bringing new treatments to cancer patients. That’s why we’re investing £45 million into our network of clinical trials’ units across the UK. Check out our press release and Express coverage for details on how the cash will be spent.
  • Pancreatic cancer survival remains stubbornly low. In a bid to develop better treatments for the disease, we announced £1.5m in funding to scientists at the University of Liverpool. They’ll be studying how pancreatic cancer spreads in the hope of identifying new ways to tackle the disease. The BBC has the details.
  • New research suggests that newly discovered gene faults that may raise the risk of ovarian cancer could be passed down from a father to his daughters. The research could lead to a better understanding of ovarian cancer risk in people with a family history of the disease. The BBC, Telegraph and others picked up this story.
  • Scientists have created an anti-cancer vaccine in mice using stem cells. Human cancers are complex though, so it’s too soon to say whether it could prevent the disease in healthy people as some reports suggested.
  • Chemicals used in an array of products, including non-stick cooking utensils and food packaging, have been linked with weight gain by new research. While the chemicals have been studied for other health conditions before, it’s too soon to say that they can affect bodyweight, reports the Guardian.
  • More on obesity: could eating slowly help tackle bodyweight? New research has suggested so, at least in people with type 2 diabetes. The Guardian and Daily Mail report that scientists have discovered a link between slower eating speeds and both a lower BMI and slimmer waist. But there are other factors playing a role too, so it’s not clear how big an impact the pace people eat might have on bodyweight.
  • Two important cancer drugs have been given the green light for use in the NHS in Scotland, one for advanced bladder cancer and another for a type of skin cancer. Read our news report for why the decision has been hailed as ‘fantastic news‘.

And finally

  • Much more than folding paper cranes, scientists have used ‘DNA origami‘ to create tiny ‘robots‘ that deliver a drug directly to tumours. They’ve shown that a blood-clotting molecule can cut off a tumour’s blood supply in mice when delivered by the DNA nanorobot, causing the tumour to shrink and helping mice live longer. Drugs already exist that are designed to starve tumours of blood, but they’ve shown mixed results in cancer patients. This approach might have great potential if explored with different treatments in the future.


FDA OKs Durvalumab (Imfinzi) for Reducing Risk for NSCLC Progression

The US Food and Drug Administration (FDA) today approved durvalumab (Imfinzi, AstraZeneca) 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.

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

“For patients with stage III lung cancer that cannot be removed surgically, the current approach to prevent progression is chemoradiation. Although a small number of patients may be cured with the chemoradiation, the cancer may eventually progress. Patients now have an approved therapy that has been shown to keep the cancer from progressing for a longer time after chemoradiation,” Richard Pazdur, MD, acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research commented in a news release.

Durvalumab is 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. In the randomized study, durvalumab significantly improved progression-free survival (PFS) compared with placebo; the median PFS was 16.8 months with durvalumab vs 5.6 months with placebo (hazard ratio, 0.52; P < .0001).

The objective response rate was significantly higher with durvalumab than with placebo, at 28.4% vs 16.0% (P < .001).

The findings were presented last year at the European Society for Medical Oncology annual meeting and were simultaneously published online in the New England Journal of Medicine.

Various lung cancer experts have commented that these results change the treatment paradigm because they show — for the first time — that an immunotherapy is beneficial at an earlier stage of lung cancer (ie, locally advanced unresectable stage III NSCLC). All the previous trials with immunotherapy in lung cancer have been in later-stage disease: advanced and metastatic NSCLC.

In the pivotal trial, grade 3/4 adverse events were slightly more common with durvalumab than with placebo, seen in 29.9% vs 26.1% of patients, with adverse events leading to discontinuation experienced by 15.4% of durvalumab patients and 9.8% of placebo patients.

Grade 3/4 immune-related adverse events were recorded in 3.4% of durvalumab patients vs 2.6% of patients given placebo. In contrast, any grade immune-related events were seen in 24.2% and 8.1% of the respective patient groups.

“This is an important advance,” commented Michael Boyer, MD, clinical professor of medicine at the University of Sydney, Australia, last year at the World Conference on Lung Cancer, as reported by Medscape Medical News, where he acted as a meeting discussant of trial quality-of-life data. Numerous previous trials have attempted to improve outcomes in this patient population, and all have failed, he observed.

Follow Medscape senior journalist Nick Mulcahy on Twitter: @MulcahyNick

For more from Medscape Oncology, follow us on Twitter: @MedscapeOnc

Pembrolizumab Update Solidifies Survival Benefit in Bladder Cancer

Joaquim Bellmunt MD, PhD
Joaquim Bellmunt MD, PhD

In patients with locally advanced or recurrent urothelial cancer, pembrolizumab (Keytruda) sustained its improvement in overall survival (OS) compared with chemotherapy in a 2-year update of the phase III KEYNOTE-045 trial presented at the 2018 Genitourinary Cancers Symposium.

The KEYNOTE-045 update showed a median OS of 10.3 months after a median follow-up of 27.7 months for patients treated with pembrolizumab.1 This was in comparison with 7.3 months for those treated with chemotherapy (HR, 0.70; P =.00017). Previously reported results for the study showed that median OS was 10.3 months with pembrolizumab versus 7.4 months for chemotherapy (HR, 0.73, P = .0022).2

In an interview with OncLive, lead KEYNOTE-045 investigator Joaquim Bellmunt, MD, PhD, director of the Bladder Cancer Center, Dana-Farber Cancer Institute, discussed the updated pembrolizumab findings, as well as the future of immunotherapy in bladder cancer.

OncLive: Can you give some background on KEYNOTE-045?

Bellmunt: Presently, we have 5 drugs that are approved for treating second-line patients with bladder cancer. Pembrolizumab was shown to be effective in a phase I trial, and then we decided to jump to a phase III study because of the positive results observed in the phase I trial. We started to accrue patients in 2014 and, after 1 year, the trial was completed. A total of 550 patients who failed on first-line platinum-based chemotherapy in the setting of metastatic disease were randomized to receive pembrolizumab or chemotherapy.

Chemotherapy was the standard of care being used at that time; it could have been docetaxel, paclitaxel, or vinflunine in Europe. The main endpoint of this trial was OS and PFS in the overall patient population, as well as in patients who had PD-L1 staining of more than 10% based on composite positive score that was defined by Merck for pembrolizumab. After 1 year of accrual, the first readout of this trial was in September 2016 and was presented at the 2016 SITC Annual Meeting. It was published in the New England Journal of Medicine in March 2017. 

What were the updated results?

At the time that the trial was published, the median follow-up was 14 months. What we presented at the 2018 Genitourinary Cancers Symposium are the updated results after a median follow-up of 27 months. We believe that the trial is now mature, and we can see if the benefits observed at the time of publishing are maintained, and whether there are any concerns in terms of toxicity.

Importantly in this update, we see that 27% of patients who received pembrolizumab are alive, compared with only 14% in patients assigned to receive chemotherapy. Compared with the previously published study, the hazard ratio decreased from 0.73 to 0.70, meaning there is a 30% reduction in the risk of death in patients receiving pembrolizumab. In terms of response rate, this trial has shown that pembrolizumab had a superior response rate to chemotherapy, with 21% compared with 11%.

We have some additional complete responses with subsequent follow-up, and one important thing is that the responses that have been observed are durable. At 2 years, the median duration of response in the pembrolizumab arm has not been reached—but it’s close to 50%—meaning responses are durable. Meanwhile, the median duration of response for the chemotherapy arm is 4.5 months. The main benefit is that the responses achieved are durable. 

Additional data that we have observed are that the duration of response may be even better in patients who are PD-L1 positive based on the composite positive score. Also, an important thing is that the toxicity favors the use of pembrolizumab compared with chemotherapy, and with this long-term follow-up, we have not seen any unexpected toxicities appearing in the long term. What we can conclude is that the results seen with pembrolizumab in the second-line treatment of patients with metastatic bladder cancer who have failed platinum-based chemotherapy are more or less similar to what has been seen in tumors like melanoma, where we see a survival curve that is stable after 2 years. This percentage of patients who responded might have a long-term benefit with pembrolizumab.

Bristol-Myers Squibb Gains NKTR-214 Access in Nektar Collaboration

Dr. Giovanni Caforio
Giovanni Caforio, MD

Bristol-Myers Squibb and Nektar Therapeutics have announced plans to jointly develop and market combinations of the CD122-biased cytokine NKTR-214 with nivolumab (Opdivo) or nivolumab plus ipilimumab (Yervoy) across for 20 indications in 9 tumor types. Under the terms of the agreement, Bristol-Myers Squibb will pay $1.85 billion to Nektar.

Currently, NKTR-214 is being examined in combination with the PD-1 inhibitor nivolumab in a phase I/II study for patients with a variety of advanced or metastatic cancers (NCT02983045). Additionally, a separate phase II study is already looking at the agent in combination with nivolumab for patients with locally advanced or metastatic sarcoma (NCT03282344).

In addition to these existing trials, pivotal studies looking at NKTR-214 with nivolumab or nivolumab and the CTLA-4 inhibitor ipilimumab are planned for patients with melanoma, renal cell carcinoma (RCC), non–small cell lung cancer (NSCLC), bladder cancer, and triple-negative breast cancer. Studies for RCC and melanoma are expected to open in the middle of this year, according to the companies. Most of the costs associated with these trials (78%) will be paid by Bristol-Myers Squibb.

“We are excited to bring our leading capabilities and expertise in developing cancer therapies together with Nektar’s innovative science to jointly develop and commercialize NKTR-214 in combination with Opdivo and Opdivo plus Yervoy,” Giovanni Caforio, MD, chairman and CEO, Bristol-Myers Squibb, said in a statement.

“Bristol-Myers Squibb has established Opdivo plus Yervoy as the only approved immunotherapy combination for cancer patients and built a robust oncology pipeline,” Caforio continued. “With this commitment to the development of NKTR-214, an investigational therapy designed with a unique approach to harnessing the full potential of the interleukin-2 pathway, we now have a third validated I-O mechanism that has demonstrated a clinical benefit in patients, and holds significant potential to expand the benefits that these immuno-oncology agents can bring to patients with cancer.”

Early findings for the combination of NKTR-214 and nivolumab from the phase Ib PIVOT-02 trial were presented in November at the 2017 SITC Annual Meeting. This dose escalation trial included patients in the first- or second-line setting with advanced NSCLC (n = 5), RCC (n = 22), and melanoma (n = 11). Across all cohorts, the median age of patients was 61 years, 68.4% were treated in the frontline setting, and most had an ECOG performance status of 0 (65.8%).

Across all groups, the combination of NKTR-214 and nivolumab resulted in a reduction of target lesions for 72% of patients with advanced cancers. In treatment-naive patients with melanoma (n = 11), the objective response rate (ORR) by RECIST was 64% and by irRECIST it was 73%. In the efficacy-evaluable treatment-naive RCC group (n = 13), the ORR by RECIST was 46% in those with ≥1 post baseline scan (n = 13) and it was 60% for those with ≥2 post baseline scans (n = 10). In the NSCLC group (n = 4), the ORR was 75%.

This study, which was the basis for future clinical trials, identified a recommended phase II dose for NKTR-214 of 0.006 mg/kg with nivolumab at 360 mg. Both medications were given every 3 weeks. At this dose, just 1 patient experienced grade 3 or 4 treatment-related AEs (TRAE; 4%). The most common grade 1 and 2 TRAEs were fatigue (68%), flu like symptoms (60%), rash (52%), pruritus (32%), headache (32%), diarrhea (32%), arthralgia (24%), and decreased appetite (12%).

“NKTR-214’s ability to grow tumor infiltrating lymphocytes (TILs) in vivo and replenish the immune system is critically important as many patients battling cancer lack sufficient TIL populations to benefit from approved checkpoint inhibitor therapies,” Howard Robin, president and CEO of Nektar, said in a statement. “This strategic collaboration allows us to very quickly develop NKTR-214 with the leading approved PD-1 immune checkpoint inhibitor in numerous registrational trials. We look forward to our continued relationship with Bristol-Myers Squibb as we work together to advance cancer treatment for patients around the world.”

In addition to trials of NKTR-214 in combination with nivolumab, the agent is also being explored with the PD-L1 inhibitor atezolizumab (Tecentriq) or the PD-1 inhibitor pembrolizumab (Keytruda) for patients with advanced or metastatic solid tumors. This phase I study, known as PROPEL, plans to enroll 60 patients, with an estimated completion date of December 2018 (NCT03138889).

In preclinical research, NKTR-214 is being examined in combination with agents from Takeda Oncology. This collaboration, which was entered in May 2017, was focused on the exploration of NKTR-214 with 5 different Takeda compounds, including a SYK inhibitor and proteasome inhibitor, in tumor models for lymphoma, melanoma and colorectal cancer.

Diab A. Pivot-02: Preliminary safety, efficacy and biomarker results from dose escalation of the Phase 1/2 study of CD-122-biased agonist NKTR-214 plus nivolumab in patients with locally advanced/metastatic melanoma, renal cell carcinoma and non-small cell lung cancer. Presented at: SITC 32nd Annual Meeting; National Harbor, MD; November 8-12, 2017. Session 207.7.