In an interview with PharmaShots, Ramon Mohanlal, M.D., Ph.D., MBA, Chief Medical Officer and Executive Vice President of Research and Development at BeyondSpring share his views on the data of triple combination regimen presented at ASCO and also shed light on the impact of plinabulin on SCLC.

Shots:

• Plinabulin in combination with nivolumab and ipilimumab showed 46% ORR with one complete response in PD-1/PD-L1 naïve and failed patients with 2nd and 3rd line SCLC
• The plinabulin combination was able to re-sensitize patients who previously failed on PD-1/PD-L1 inhibitors with 43% ORR and all tumor reduction >50%, with durable response
• Plinabulin recently had positive P-III data supporting NDA applications for prevention of chemo-induced neutropenia and is in P-III trials for treatment of NSCLC

Tuba:  Highlights the key features of data presented at ASCO by BeyondSpring.

Dr. Mohanlal:  The study results being presented at this year's ASCO conference related to the poster titled,  A Phase I Trial of Plinabulin in Combination with Nivolumab and Ipilimumab in Patients with Recurrent Small Cell Lung Cancer (SCLC), describes an investigator-initiated Phase 1 study where plinabulin was combined with nivolumab and ipilimumab in the treatment of 2nd and 3rd line small cell lung cancer (SCLC) in a total of 16 patients.

It highlights preliminary data demonstrating potent and potentiating anti-cancer effects of the combination of plinabulin, nivolumab, and ipilimumab, with an overall 46% objective response rate (ORR) in 13 evaluable patients with PD-1/PD-L1 naïve or resistant tumors in 2nd and 3rd line SCLC. The nivolumab/ipilimumab IO combination was recently withdrawn from the market, due to lack of efficacy in a trial designed to confirm its efficacy in SCLC. By adding plinabulin to nivolumab/ipilimumab, we observed a highly impactful improvement in anticancer efficacy that was not seen before with the nivolumab and ipilimumab alone. We demonstrated this impactful benefit with plinabulin in a small Phase 1 trial, and seek to confirm this in a larger Phase 2 trial that already has been initiated.

Early-efficacy data included that the ORR was 50% for the six patients receiving the triple IO combination as second-line therapy after platinum. Three patients had partial responses (PR), with the best tumor reduction at target lesions of 100%, 53%, and 45%, respectively. Also, the ORR was 43% for the seven patients receiving the triple IO combination as third-line therapy, who had either failed or had not responded to platinum and PD-1/PD-L1 inhibitors. Three patients had PRs, with the best tumor reductions at target lesions of 78%, 75%, and 52%, respectively. The duration of therapy for these three PR patients was 18 months, five months (still on treatment), and three months, respectively.

An additional endpoint of the trial was to evaluate whether the addition of plinabulin to nivolumab + ipilimumab would reduce Immune-Related Adverse Events (IR-AEs). IR-AEs are inflammatory responses caused by overstimulation of the immune system. The principle of IO treatment is to stimulate the immune system, which at times may cause overstimulation of the immune system. IR-AEs are the most predominant limitations to immunotherapy, and if it reaches Grade 3 or 4, it leads to permanent discontinuation of these IO agents. This not only represents a loss of effective treatment options to the patient but also a loss of revenues to BMS, the manufacturer of these agents. Plinabulin potentially has the ability to reduce IR-AEs, because it inhibits an inflammation-pathway called PDE4. It is very gratifying to see that the Grade 3/4 IR-AE frequency in the study with plinabulin + nivolumab + ipilimumab was 12.5%, whereas with nivolumab + ipilimumab alone was reported to be 37% with nivolumab + ipilimumab alone.

Tuba:  Discuss the impact of plinabulin on patients with SCLC.

Dr. Mohanlal:  SCLC continues to represent an area of unmet medical need. By adding plinabulin to nivolumab + ipilimumab, we enhance both antigen generation and antigen presentation to the T-cell repertoire, resulting in an expected superior anticancer efficacy compared to nivolumab + ipilimumab, which as we now know was shown to be ineffective. The preliminary observation that Plinabulin also decreases IR-AEs caused by the nivolumab + ipilimumab combination represents collectively a very powerful product offering with adding plinabulin to a PD1/PD-L1+CTLA4 combination. To offer patients the promise of living longer at reduced toxicity is our common holy grail. If this comes with an increased return to the pharmaceutical industry represents a win-win scenario for all parties involved.  We consider this trial in SCLC  as a proof-of-concept study, and if it will work here, this concept will work in many other cancer types.  We look forward to reporting the data from Phase 2, which just started, in a larger number of patients.

Tuba:  Discuss the key features of the poster to be presented at the lung cancer poster session?

Dr. Mohanlal:  This was discussed in detail in the answer to Question 1.

Tuba: Plinabulin is a potent agent to mature and activate dendritic cells. Shed some light on this statement.

Dr. Mohanlal:  Through a number of independent studies we demonstrated that the principal mechanism by which Plinabulin exerts its anticancer effect, is though enabling dendritic cells to better activate helper and cytotoxic T-cells, which latter can be viewed as the foot soldiers that go out and kill cancer cells in an antigen-specific manner. Two seminal peer-reviewed publications from 2019 helped shed light on the unique mechanisms of action of plinabulin, including its effects on the maturation and activation of dendritic cells. The first, La Sala et al., 2019 Chem, highlights tubulin-binding properties of plinabulin which act as a precursor to activation of GEF-H1. The second publication, Kashyap et al., 2019 Cell Reports, highlights the required link between GEF-H1 signaling and the dendritic cell activation and maturation that is specific to antigen cross-presentation, T cell activation as well as anti-tumor activity. A third study from the 2020 AACR conference demonstrated that plinabulin leads to activation of antigen-presenting dendritic cells and that combinations with anti-PD-1 and radiation therapies showed further activation of the immune system, in preclinical cancer models.

Additional MOA publications resulting from a multi-year collaboration with the University of Basel, Fred Hutchinson Cancer Research Center, and Mass General Hospital further elucidated plinabulin's mechanisms which also include 1) delaying neutrophil cell death to complement the actions of granulocyte cell-stimulating factor treatments like pegfilgrastim (supporting the recent NDA acceptance by the U.S. FDA for plinabulin in combination with pegfilgrastim for prevention of chemotherapy-induced neutropenia) and 2) Direct cancer cell killing effects through JNK activation.

Tuba:  What is plinabulin? How does it work?

Source: BeyondSpring

Dr. Mohanlal:  Simply put, we consider plinabulin as an agent to agent that exerts a broad defense strategy to insults attacking the host (the patient), which insult includes cancer cells. Plinabulin is a selective immunomodulating microtubule-binding agent (SIMBA), a first-in-class small drug treatment with multiple mechanisms of action supporting its broad 'pipeline in a product' potential as a treatment that can help prevent chemotherapy-induced neutropenia (in combination with pegfilgrastim), as well as having a potential direct anti-cancer activity (being tested in the ongoing Phase 3 DUBLIN-3 study of plinabulin in non-small cell lung cancer, which is expected to produce topline data in mid-2021) and immuno-oncology activity, as validated in the current posted being presented at ASCO 2021. Further details about plinabulin's mechanism of action are mentioned in the answer to Question 4.

Tuba:  How has BeyondSpring made tremendous growth in the field of oncology?

Dr. Mohanlal:  Immuno-oncology therapy has demonstrated its worth as the biggest advancement in oncology in the last decades. While acknowledging the impact that IO therapy made in oncology, it is equally fair to point out that the current IO strategies work but are not the Silver bullet. Much more work needs to be done to bring out the full potential of current IO treatment, and that is where plinabulin comes in. With the SCLC data, we demonstrated that adding plinabulin to IO makes nivolumab + plinabulin work better as anticancer agents, and also improves their safety by reducing IR-AEs.

BeyondSpring's strategy is in general, not to go where everyone is going, but important to look at future trends and at limitations of current IO approaches and to complement and improve on those trends.

Tuba:  When you are expecting the first approval for plinabulin?

Dr. Mohanlal:  On June 1, we announced that the FDA had accepted, for Priority Review, the NDA for plinabulin in combination with pegfilgrastim for the prevention of chemotherapy-induced neutropenia (CIN) and set a Prescription Drug User Fee Act (PDUFA) target action date for November 30, 2021. Neutrophils are our first line of Innate Immunity defense to foreign insults such as bacteria and fungi. CIN is an indication that hasn't had an approved drug in over 30 years. A matching NDA is also under review with the China NMPA. We are focused on working with regulators on these submissions and, if all goes well, hope to announce approvals before the end of 2021.

Tuba:  Are you open to collaborations for the commercialization of plinabulin?

Dr. Mohanlal:  Yes, we are open to collaborations for commercialization and/or co-development in all regions.

Tuba:  Can you provide a glimpse of your robust pipeline?

Dr. Mohanlal:  As indicated before, BeyondSpring's strategy is to carefully analyze and address the future trends in the IO space, with the aim not to compete with current approaches, but to make current approaches better, in terms of both efficacy and safety. In addition to CIN and SCLC, plinabulin is in a Phase 3 trial in non-small cell lung cancer (NSCLC), the DUBLIN-3 trial, with topline data expected in mid-2021. This means that in addition to the Phase 1 IO activity presented at ASCO and the NDAs being reviewed for prevention of CIN, there's a chance that plinabulin also shows direct anti-cancer activity in NSCLC. We are also advancing a pipeline with a novel new Phase 1 trial, that we cannot disclose at this time, and with developing a novel targeted protein degradation platform (TPD) class of therapies with our subsidiary Seed Therapeutics which is developing novel agents for undruggable targets. This technology was partially validated by our $800M collaboration deal that we received last year with Lilly.  

Image Source: Healthline

About Ramon Mohanlal:

Dr. Mohanlal has served on the Board of Directors of BeyondSpring since January 2020. He also serves as Executive Vice President of Research and Development and has served as Chief Medical Officer since October 2015. Dr. Mohanlal earned his M.D. and Ph.D. in Experimental CV Pharmacology from the University of Leiden University in The Netherlands and his M.B.A. from the American Intercontinental University in Illinois.

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