Bristol's Opdivo Enjoys IO First-Mover Advantage In Small Cell Lung Cancer

In addition to Opdivo, three other PD-1/L1 inhibitors are in late-stage development for a high-unmet need disease, including Roche's Tecentriq, which will be filed as soon as possible.

US FDA approval of Bristol-Myers Squibb Co.'s PD-1 inhibitor Opdivo in relapsed small cell lung cancer based on response rate data marks a breakthrough and gives the drug a lead in a new indication, though it's unclear for how long given that Roche's competing Tecentriq has demonstrated an overall survival benefit in an earlier line of therapy.

The FDA granted accelerated approval for Opdivo (nivolumab) in metastatic small cell lung cancer (SCLC) after progression on platinum-based chemotherapy and at least one other line of therapy on Aug. 17.

This marks the first approval of an immuno-oncology drug for SCLC.

"With this landmark approval based on the open-label Phase I/II CheckMate 032 trial, Opdivo becomes the first therapy to be approved for SCLC in nearly 20 years, introducing an entirely new treatment modality to SCLC," Biomedtracker analysts commented on the news.

The approval in SCLC adds to Opdivo's existing indications for relapsed non-small cell lung cancer, recurrent metastatic squamous cell carcinoma of the head and neck, renal cell carcinoma, melanoma, classical Hodgkin lymphoma, urothelial carcinoma and microsatellite-high or mismatch repair deficient colorectal cancer.

Opdivo has been the leading drug in the PD-1/L1 family, but Merck & Co. Inc.'s competing PD-1 inhibitor Keytruda (pembrolizumab) has assumed a dominant role in non-small cell lung cancer (NSCLC), and sales began to overtake Bristol's drug in the second quarter. (Also see "First-Line Chemo Combo Data Help Merck's Keytruda Power Past Opdivo" - Scrip, 29 Jul, 2018.) and (Also see "Roche, Bristol On The Defensive After Merck's Lung Cancer Wins At ASCO" - Scrip, 6 Jun, 2018.)

About 10%-15% of lung cancers are the SCLC type and there will be an estimated 27,000 new cases diagnosed yearly in the US. Treatment options are limited and the five-year survival rate is only 2%.

Currently, topotecan chemotherapy (Novartis’s Hycamtin and generics) represents the standard of care for SCLC.

Morningstar Research has forecast that in 2022, the NSCLC market for PD-1/L1 inhibitors will be worth $17bn versus $2bn for SCLC. With a first-mover advantage in this indication, Bristol's Opdivo is expected to take a 45% share of the market, followed by Merck with 25%, Roche with 20% and AstraZeneca with 10%, according to Morningstar projections.

Modest Efficacy In Supporting Trial

Bristol's filing was supported by data from an SCLC cohort in the Phase I/II CheckMate 032 study of cancer patients with disease progression after platinum-based chemotherapy.

The Phase III CheckMate 331 study is comparing overall survival for Opdivo versus chemotherapy and the Phase III CheckMate 451 study tests Opdivo with the company's CTLA4 inhibitor Yervoy (ipilimumab) as maintenance therapy in extensive-stage SCLC after completion of platinum-based chemotherapy. Results from both studies are expected by the end of the year (see chart below).

In CheckMate 032, out of 109 SCLC patients enrolled, 13 (12%) responded to treatment, including 12 partial responses and one complete response. This effect was not dependent on the level of expression of the PD-L1 biomarker, the company reported.

Seventeen percent of patients received Opdivo for greater than six months, and 9% of patients received Opdivo for more than one year. The median duration of response was 17.9 months.

Side effects most commonly reported included fatigue (45%), decreased appetite (27%) and musculoskeletal pain (25%).

Biomedtracker analysts noted that the efficacy results in CheckMate 032 are at best only comparable to chemotherapy in second- and later lines of therapy.

"The accelerated approval despite the open-label design, the small number of patients and modest results underscores the immense unmet need for new therapies in this area," they explained.

Most patients with SCLC relapse and median survival is typically only four or five months. In the CheckMate 032 study, the median survival was 4.4 months, which is similar to older therapies, but prescribers may want to use Opdivo due to the comparably better safety profile, Biomedtracker said.

In addition to Opdivo, three other PD-1/L1 inhibitors are in Phase III for SCLC – Roche's Tecentriq (atezolizumab), AstraZeneca PLC's Imfinzi (durvalumab) and Merck's Keytruda. All three are being tested in newly diagnosed SCLC whereas Opdivo is not being positioned for treatment-naïve patients.

Roche reported in July that Tecentriq and chemotherapy improved overall survival compared with chemotherapy alone in an interim analysis of the Phase III IMpower133 trial of first-line use in extensive-stage small cell lung cancer patients. (Also see "More Data Backs Tecentriq As IMpower133 Combo Meets Primary SCLC Endpoints" - Scrip, 25 Jun, 2018.) Data are slated for release at the International World Conference on Lung Cancer annual meeting in Toronto next month.

Roche subsidiary Genentech tells Scrip that it will file the data with the FDA and other global regulatory authorities "as soon as possible."

Keytruda is being tested with chemotherapy in the KEYNOTE 604 study and Imfinzi is being tested with AstraZeneca's CTLA4 inhibitor tremelimumab along with chemotherapy in the CASPIAN study. Both are first-line trials.

Opdivo's Lead May Be Short-lived

Commenting on the news of the Opdivo approval by email to Scrip, oncology H. Jack West noted that this is a setting where there is "no enthusiasm" for the most-evidence based treatment of relapsed SCLC – topotecan, an agent that has very modest efficacy, requires a lot of time in the clinic for patients receiving treatments and has challenging toxicity.

"Prior to the introduction of immunotherapies here, many if not most thoracic oncology specialists and community-based general oncologists alike often favored less evidence-based options despite the lack of proven benefit, based on a conclusion that the clinical value and therapeutic index of topotecan is so low that just about any marginally active alternative is sufficient," said West, who is medical director of thoracic oncology at the Swedish Cancer Institute in Seattle.

Nivolumab and the combination of nivolumab with ipilimumab both have shown very limited response rates, yet have been included in National Comprehensive Care Network guidelines, as there is a recognition that the minority of patients who do respond have a durable response, often with little or no toxicity, West noted.

"Overall, I consider the evidence to be rather weak to justify approval of nivolumab, though the main issue is the cost and value relative to the anticipated benefit, more than anticipated harm relative to other alternatives," he said.

West added that he hopes the upcoming data presentation for Tecentriq in the IMpower133 study justifies approval and that the combination with chemo becomes a first-line standard of care.

That would obviate the role of Opdivo for relapsed SCLC, except in patients who relapse after treatment for limited stage SCLC on chemo/radiation or others who did not receive immunotherapy previously for one reason or another, he said.

Upcoming Key Data Catalysts: Small Cell Lung Cancer
Sponsor/Drug	Trial Development Phase	Date Range Expected
NantWorks' aldoxorubicin	Phase IIb	Now to 9/30/2018
Bristol's Opdivo	Phase III CheckMate 331 and CheckMate 451	Now to 12/31/2018
Aeglea's Pegzilarginase and Merck's Keytruda	Phase I/II	10/1/2018 to 12/31/2018
AstraZeneca's Imfinzi and tremeliumumab	Phase III CASPIAN	1/1/2019 to 12/31/2019
PharmaMar's Zepsyre (lurbinectidin)	Phase III ATLANTIS	7/1/2019 to 12/31/2019
AbbVie's Rova-T	Phase III MERU	1/1/2019 to 12/31/2020
AbbVie's Rova-T	Phase III TAHOE	1/2/2020 to 12/31/2020
Source: Biomedtracker, Datamonitor Healthcare