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Blockbuster Drugs for 2015, Immunotherapy

Opdivo® (nivolumab): Bristol-Myers Squibb’s Immunotherapy for Melanoma and Lung Cancer

In my inaugural blog post, I mentioned that I was going to break down each of the top 11 blockbuster drugs of 2015 as predicted by Thomson Reuters. As promised, I will start with number one on the list – Opdivo® (nivolumab), which was first approved as second line treatment of melanoma in December of 2014.

Background

Melanoma is the fifth most common type of cancer in the United States. The National Cancer Institute estimated that 76,100 Americans were diagnosed with melanoma and 9,710 died from the disease in 2014. Although systemic therapy is essential for patients with unresectable or metastatic disease (anywhere from 4% to 16% of all diagnoses), traditional chemotherapy has been found to be particularly useless in the treatment of melanoma. Researchers had to get creative to tackle this disease.

Melanoma has long been known to be innately immunogenic in humans. Small studies as early as 1985 showed that treatment with high dose interleukin-2 (IL-2, a cytokine that stimulated the immune system via T-cell activation and proliferation) for unresectable or metastasized melanoma could cause complete remission in a small group of patients (~6% in this study). Although this was heartening, the treatment was almost as bad as the disease – patients had to be admitted to the ICU and given medications to raise their blood pressure as the high dose IL-2 regimen simulated overwhelming infection/sepsis. And almost as many patients died as were cured by the administration of the IL-2 regimen. There had to be a better way.

Harnessing the Immune System Precisely

Painstaking basic science research in immunology was necessary to understand why targeting of the immune system sometimes caused sustained remission and how this response could be improved. One mechanism cancer cells utilize to evade the immune system is by affecting immune checkpoint pathways that regulate T-cell responses. Current immunotherapies for melanoma mostly focus on the priming and effector phases of T-cell activation.

Immunotherapy with checkpoint inhibitors results in the preferential activation of T cells with specificity for cancer cells. During the priming phase, dendritic cells present tumor antigens to primed T-cell receptors (TCR) via major histocompatibility complexes (MHC). Interaction between B7 molecules on dendritic cells and CTLA-4 on T cells leads to T-cell inhibition. When CTLA-4 is inhibited by immunotherapy like ipilimumab, these B7 molecules are free to bind to CD28, thus boosting T-cell activating signals. During the effector phase, PD-1 is expressed on T cells, and when PD-1 binds to either of its ligands (PD-L1 or PD-L2) that are prominently expressed in melanoma, this also leads to decreased T-cell activity. Blockade of PD-1 receptors with immunotherapy (e.g., nivolumab, pembrolizumab) activates T cells by inhibiting their negative regulation during this phase. Adapted from N Engl J Med. 2012;366(26):2517 by onclive.com.

The groundwork for discovering key elements of the priming phase of T cells (see illustration) occurred in the laboratory of Dr. James P. Allison in the 1990s. Over the next 10 years in the lab, Matthew Krummel and Dana Leach would demonstrate the importance of CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) to retard the priming process and the efficacy of an antibody to CTLA-4 to inhibit tumor growth in animal models. Medarex, a biotech company based in Princeton, New Jersey, licensed the Allison/Krummel/Leach patent, developed ipilimumab (Yervoy®), and was bought by Bristol-Myers Squibb (BMS) in 2009. The FDA approved ipilimumab for treatment of unresectable and metastatic melanoma in 2011 based on a clinical trial showing prolonged survival in patients who had not responded or who progressed with other treatments (~23% had been treated with IL-2 previously). Ipilimumab soon thereafter became the standard of care. However, BMS/Medarex knew there was an opportunity for further immunotherapy for those patients with recurrence or in whom ipilimumab did not work.

Returning to the world of basic science research in immunology in the 1990s, the laboratory of Tasuku Honjo in Japan was discovering the importance of PD-1 for proper T-cell function in the 1990s. Further work led to the elucidation of key role of PD-1 in T-cell inhibition during the effector phase of T-cell activation (see illustration). Increased expression of PD-L1, a PD-1 ligand, has been shown in many different cancer types (e.g., melanoma [40%-100%], non-small cell lung cancer [35%-95%], and multiple myeloma [93%]), and increased expression of PD-L1 has been linked to poor clinical outcomes. Taken together, all of this evidence led to the development of the PD-1 inhibitors, nivolumab (Opdivo®) by BMS/Medarex/Ono Pharmaceuticals and pembrolizumab (Keytruda®) by Merck.

The Age of Immunotherapies: Timing Is Everything

Ipilimumab benefited greatly from entering the market in 2011 — concluding their initial clinical trial well before the PD-1 inhibitors, which were only approved by the FDA in 2014. The median overall survival was 10.1 months among patients receiving ipilimumab compared to 6.4 months among patients receiving a standard vaccine therapy (gp100). Although statistically significant, prolonging survival ~4 months is a pretty modest improvement over standard therapy, considering that ~1% of study participants died as a result of immune-related side effects of the medication. On the other hand, a recent study using a pooled analysis from multiple studies showed that overall survival of patients with metastatic/unresectable melanoma after ipilimumab treatment is ~21%, a 10% improvement over historical averages.

As ipilimumab became the standard of care in 2011, investigators had to show the efficacy of PD-1 inhibitors in ipilimumab non-responders before being able to test them in treatment-naive patients. After efficacy could be determined in this group of patients, BMS and Merck were able to obtain FDA approval for nivolumab and pembrolizumab, respectively, as second-line therapy for metastatic/unresectable melanoma. Merck was able to obtain approval for pembrolizumab in September 2014 based on results from a clinical trial showing an overall response rate of 24% and sustained response >6 months in 9% of patients treated. This study was a phase I trial so there was no actual control group making it pretty weak as far as scientific studies are concerned. Although BMS only obtained approval for nivolumab in December 2014, the study utilized for the FDA approval process was much stronger in that it was a phase III study that compared nivolumab to investigators’ choice of chemotherapy. Also, the overall response rate was 32% with a sustained response >6 months in 11% of patients treated. And since there was a control group, we can estimate that only 5 patients would need to be treated with nivolumab to see an improvement over standard therapy.

Regardless of the differences in the studies, both PD-1 inhibitors had more favorable safety profiles than ipilimumab as there were no deaths due to the drugs and even severe adverse effects were mainly reversible with supportive care and discontinuation of the medications. Now, both companies are in a race to obtain FDA approval as first-line therapy for metastatic/unresectable melanoma. Merck put out a press release in March touting their Keynote-006 phase III clinical trial which was stopped early as it met its end points showing that pembrolizumab monotherapy was superior to ipilimumab monotherapy as first-line treatment for the end points of overall survival and progression-free survival. Although not yet published, these results will be presented soon at the American Association of Cancer Research Annual Meeting in Philadelphia, April 18-22. BMS, on the other hand, will have to wait some time before they can present similar results for nivolumab as their phase III study examining nivolumab and ipilimumab head-to-head will not finish data collection until September 2016.

Beyond Melanoma Monotherapy

It might seem at this point that nivolumab will have to wait a while before seeing a bigger share of the immuno-oncology market, but the folks at BMS are quite resourceful. In March, they were able to obtain an additional indication for nivolumab as second-line treatment for squamous non-small cell lung cancer after platinum-based chemotherapy. And although they reported a very modest improvement in median overall survival compared to docetaxel (3.2 months), they have the advantage of entering a large market with a great need — in 2014, there were an estimated 224,210 new diagnoses of lung cancer and 159,260 deaths. Also, even localized lung cancer has a historical 5-year survival rate of 54% which means that nivolumab may be useful for adjuvant or neoadjuvant chemotherapy in these groups as well.

With regards to melanoma, although it may occur after 2016, nivolumab may still surpass pembrolizumab in the end. Preliminary data from the combination of therapy with nivolumab and ipilimumab is very promising. Since BMS owns both products, it will be an attractive option to market these medications as combination therapy, especially if this proves to be superior to monotherapy when the final results are reported.

Bottom Line

Hundreds of clinical trials are underway with these therapies and others like them. Time will tell which immuno-oncology therapies will prove to be the best options with the most sustained remissions in melanoma, lung cancer, and other malignancies. One thing is clear: the future of immuno-oncology is bright and full of possibilities for more effective, less toxic treatment.

Further Reading

  • This review by Kim, Amaria, et al. is quite informative about the historical research behind checkpoint inhibitors and also discusses BRAF pathway inhibitors which was beyond the scope of my blog post.
  • Although requiring subscription access, last week’s issue of Science is all about cancer immunology and immunotherapy.
  • This article and this one as well discuss the competition between Keytruda and Opdivo regarding which medication will win out in the market of PD-1 inhibitors. Opdivo’s sales stood at $3 million in February as compared to $24.8 million for Keytruda, but Opdivo had not been on the market as long as Keytruda and had not yet been approved for squamous cell lung cancer.
  • This excellent interview with Lifetech Capital’s Stephen Dunn discusses the future of immuno-oncology therapies including CAR T cells and which companies he considers to be the most attractive investment opportunities.
  • A major issue I neglected in my blog post is that of price – how is the current scheme of increasingly high prices for cancer treatment sustainable? Or ethical? This excellent piece in the Dallas Morning News addresses this point.

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