Originally published in Life Science Leader.
Spread around the big table, the players make their bets. The game calls for some cards showing, others hidden, and with each round more of the players’ cards lie face up. One contestant in particular seems to have the hot hand, so it is almost unsurprising when the next card that player lays down, along with a hefty ante to the pot, causes a stir among all the others. To stay in this game, everyone will have to ante up. This imagined scene fairly represents the situation in the immuno-oncology (IO) space right now — and it’s an accurate metaphor for this, our annual immuno-oncology update for 2018.
This time around, the IO update is more compact because the essential story has contracted. It is still complex in many ways, with hundreds of development candidates and companies involved industrywide, as well as many new therapeutic mechanisms yet to be fully tested. But the story centers on the critical moment when the entire game jumps to a higher scale and the odds of success shift dramatically and disparately among the various players — all due to one player’s achievement.
In the IO space, that player is Merck & Co. (MSD outside North America). Last year, Merck led; this year, Merck rules. Its PD-1 inhibitor, Keytruda (pembrolizumab), in combination with standard chemo, scored unprecedented numbers in overall survival (OS) and progression-free survival (PFS) in a Phase 3 clinical trial for treating non-small cell lung cancer (NSCLC). The trial, dubbed Keynote-189, raised the ante for Keytruda itself and for every other drug in this space. As Keytruda also achieves record results from pivotal trials in a growing number of other cancers, the response to its raised ante sweeps across the table.
WHAT KEYTRUDA HATH WROUGHT
Merck has sponsored dozens of Keytruda trials — and is providing drug for more than 900 — many or most in combination with other drugs and regimens. Keynote- 189 tested how much additional benefit resulted when NSCLC patients received Keytruda combined with the standard chemotherapy of pemetrexed and platinum. The trial used the gold-standard OS and PFS endpoints, with outstanding results. Essentially, the addition of Keytuda to standard chemo increased OS at 12 months by about 20 percent and median PFS by about 29 percent. As one result, Keytruda plus chemo will become first-line therapy for NSCLC, replacing all remaining first-line use of chemo alone.
Keytruda is already approved as first-line therapy for NSCLC patients who express a “tumor proportion score” of 50 percent or more for the presence of PDL1 antigens in a tumor biopsy. Keytruda also has won FDA approval for treating any solid tumors showing the genetic marker for microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). For most patients at 50 percent-plus PD-L1 levels, anti-PD-1 drugs alone clearly outperform chemo; for those with less than a 50-percent score, far fewer to none see significant benefits from anti-PD-1 alone. But Keynote-189 treated patients with all levels of PD-L1, on the theory that the chemo portion would have immunogenic effects that complement Keytruda’s PD-1 blockade. Once more, with Keynote-189, clinical results supported two now widely accepted hypotheses: PD-L1 is a reliable predictor of anti-PD-1 response, and chemo is an effective immune enhancer, stimulating tumor-antigen expression, T-cell production, and other elements of immunity that increase anti-PD-1 response.
Few people believe chemo makes the best possible therapeutic complement to anti-PD-1 drugs such as Keytruda. But Keynote-189 has plainly vindicated Merck’s strategy of focusing on combinations with chemo first while also testing Keytruda with other possible cotherapies in a host of clinical trials. Yet the higher ante Keynote- 189 has imposed applies not only to competitors, but also to Keytruda itself, in all of its other combinations. To win adoption into practice treating NSCLC or potentially other solid cancers, any configuration of Keytruda with other agents will have to match or exceed the clinical-trial results of Keytruda/chemo.
Last year, we observed how immuno-oncology had climbed to the top of oncology more quickly than even its early supporters imagined. We also predicted IO combinations would win adoption in practice based on continuing research into immune mechanisms alongside a massive effort in clinical development. At the same time, we described how Merck was running combination trials both to understand the therapeutic mechanisms involved and to discover which combos work empirically. But now, these questions naturally follow: Will the IO field get stuck on the an-ti-PD-1/chemo standard, when it might do much better? Could complements more powerful than chemo be lost in the shuffle because their developers failed to anticipate a trendsetter like Keynote-189 in clinical planning or trial design?
By the sales data, the new status quo is holding strong. Sales for Keytruda and BMS’s Opdivo (nivolumab) are dramatic, generally exceeding analysts’ expectations. In most cases, the sales are not for single-agent immuno-oncology, but for anti-PD-1 combined with chemo, often in second-line use. Although Merck did not absolutely put a stake in the ground with Keytruda plus chemo, it is making big wins with that combination, which will continue to expand in first-line use against solid tumors.
Of course, other companies with IO drugs in development, especially the Big Pharmas conducting large late-stage trials, may have even more reason to be worried. Previously, when most IO developers aimed mainly for relatively small improvements over standard therapies, they may have designed their trials to explore any number of other scientific and therapeutic questions. Now they must judge whether they are prepared to meet or exceed the new standard set by Merck. Hereafter, to any company developing a new IO drug, the FDA will say, “Wait a minute; have you designed your trial to see the same response rates, PFS, and OS improvement as did Keytruda and chemo in combination?”
In this new game, the first line of losers will likely be those who climbed on the IO bandwagon merely by repositioning products in another class — primarily, pathway-targeted drugs — as having immunotherapeutic effects, alone or in some combination with checkpoint inhibitors. The most informed guess is, for most of those companies, the belated shift to an IO strategy never took into account how well standard chemo might complement the Keytruda class. By the time they complete pivotal trials in one indication, off-label use of Keytruda/chemo will have naturally spread to most other major cancers. Unless newer agents or combinations perform even better, persuading clinicians to change practice will be difficult to impossible.
From a business perspective, this new test may be a hard pill to swallow. Ordinarily, many IO developers, up to Phase 2, would have the flexibility to adjust for the higher ante in Phase 3. But it has become a normal practice with FDA encouragement for oncology-drug developers to make their Phase 2 trials pivotal studies for NDA submission. Pivoting to a different design at that point, especially if the “pivotal” Phase 2 trial reports a less-than-stellar response rate, is an awkward and expensive proposition. And considering the rush to the new first-line standard, companies may find it relatively unrewarding to stick with a less-ambitious plan and eventually need to settle for a second- or third-line indication.
Keynote-189 may also make it largely counterproductive to develop single IO agents in underdeveloped nations outside the United States, which is a solution small drug developers tend to seek. Although the FDA officially abandoned the Declaration of Helsinki (DoH) ethical guidelines for non-U.S. clinical trials more than a decade ago, other countries and regulatory bodies still honor them. By DoH principles, conducting trials in underdeveloped jurisdictions where no regular treatment is available, only to avoid the work and expense of meeting high U.S. standards of care, is unethical; that is, unless the trials meet the DoH terms, such as the requirement for sponsors to continue supplying the product free to the subject patients posttrial. Technically, adhering to DoH ethical standards would be voluntary, but the ensuing reaction to nonadherence would, at the least, put an additional negative spotlight on trials that also fell short of the U.S. standard of care.
An additional evolving concern related to DoH is that many developed countries, particularly in Europe, simply will not adequately pay for new drugs. DoH is very specific in that, once a drug is approved, it must be made available in any country where trials have been conducted. Many countries are thus becoming practically unavailable as trial venues.
Meanwhile, in the United States and other advanced countries, the new standard established with anti- PD-1 therapy will grow ever stronger, reinforced not just with new clinical results, but also by the interaction of patients and their support groups with physicians. If your significant other is diagnosed with metastatic NSCLC, and the doctor doesn’t prescribe Keytruda plus pemetrexed and platinum, you will demand them. No wonder Keytruda sales have gone up (and now exceed Opdivo’s).
Fallout in the ranks of IO developers is inevitable. Surely but hypothetically, as I write this, an investor is putting a fork in (cancelling) a deal for a company developing an “immunotherapy” drug. Why? The company has announced a Phase 1 trial design for the drug as a single agent. Despite the company’s confidence the drug will perform spectacularly all by itself, its own timeline places possible approval at the far end of 2023. By then, as the investor knows, Keytruda will have won approvals in nearly all major cancer indications and thus be difficult to dislodge as the dominant player, even by a single agent with remarkable results, albeit in a single trial. These are some of the defining moments for biopharma innovation — the potential breakthroughs that don’t happen, not because of science alone, but because of business strategy informing drug development, or not.
CROWD IN A CLOUD
Not that predicting the future, including the outcomes of clinical trials in humans, is easy. We are still largely in the dark about the science as well as the business of IO. Last year, during the oncology convention season, even the exceptionally incredulous among the conventional wizards of industry prognostication could not contain their excitement over IDO (indoleamine-2,3-dioxygenase) inhibitors, on which companies such as BMS, Pfizer, and, yes, Merck had placed billion-dollar scale bets.
As we reported last year, IDO inhibitors were star candidates for improving response rates in checkpoint blockade. IDO is a “rate-limiting” enzyme in the tryptophan (TRP) to kynurenine (KYN) metabolic pathway, which keeps a lid on immunity. A Phase 3 trial of Incyte’s epacadostat plus Keytruda caused an apparent collapse, though not complete loss, in IDO-related development. Merck has shut down three of its five trials with epacadostat. Incyte stock has gone through the floor, and the company has shifted its plans away from the IDO focus. NewLink Genetics has stopped one of its IDO-related trials, not based on data from the trial but on the failed Merck trial. However, after partially positive results in a Phase 2 trial in June and a complete corporate downsizing, NewLink has just announced a refocus on IDO.
Another plentifully hyped phenomenon in immuno-oncology this year was CAR-T and its variants in cell-based therapy. Cell therapies have been the darling of personalized medicine fans, even among the normally skeptical trade press, because they have shown real efficacy in some patients. But in the United States where the technologies have advanced the furthest, the breaks have not gone their way. Their inherent handicaps of complexity and expense have dogged them at every step in the wake of all the goodwill.
Last spring, the CMS established a policy that puts hospitals at risk for covering a large portion of the treatment plus related care costs when the final infusion happens in an in-patient rather than out-patient setting. The prospect of incurring such costs reportedly caused many institutions to delay opening their CAR-T centers. Since then, the two main commercial cell-therapy products, Novartis’s Kymriah (tisagenlecleucel) and Gilead’s Yescarta (axicabtagene ciloleucel) have continued to experience slow sales as they struggle with reimbursement and manufacturing issues.
By setting reported wholesale prices of $475,000 and $373,000, respectively, the product sponsors ensured costs would be an issue, though both companies believe new indications and market expansion will eventually boost sales. But unless CMS removes or softens the risk for hospitals, and perhaps authorizes a special “new technology add-on payment” for related in-patient care, the pace of sales and adoption in practice will likely continue to lag. Many of the big IO companies — notably Merck and Pfizer — have specifically avoided ventures into autologous cell therapies, betting on the success of allogeneic or other off-the-shelf approaches that significantly lower both production and treatment costs.
There are so many new IO approaches under development in this industry — cancer vaccines, viral targets, gene editing, and much more — some people will rightfully fault me for not exploring them all in more detail here. One example is the sudden surge of interest in better delivery of IO drugs (small molecules, antibodies, nucleic acid constructs, and oncolytic viruses) to tumors and particularly across the blood-brain barrier. This may have an interesting effect on IO overall, since the success of some of these methods may change the efficacy mix of both approved and experimental therapies. But whatever your approach may be, you will have to ante up to the high stakes now placed in play by Keytruda and Keynote-189.
Special thanks to Dr. Llew Keltner for his extensive input and help with this article.
In addition to the specific cancer indications listed below, Keytruda (pembrolizumab) also has won the first FDA approval for a cancer drug based on a genetic biomarker, spotlighting its potential for treating cancer regardless of the organ or tissue site. (See Milestones.)
October 2015: Metastatic non-small cell lung cancer (NSCLC). Approval for the treatment of metastatic NSCLC in patients whose tumors express PD-L1 and who have failed treatment with other chemotherapeutic agents.
August 2016: Recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Accelerated (conditional) approval for treatment of recurrent or metastatic HNSCC, regardless of PD-L1 staining, following progression on a platinum-based chemotherapy. Accelerated approval was based on objective response rates (ORR) in the Phase 1b Keynote-012 study. Final approval later confirmed based on the overall survival (OS) results of the Phase 3 Keynote-040 study ending January 2017. Even though the 19-percent OS rate achieved in the trial fell short of goal, the FDA considered the OS clinically significant.
May 2017: Unresectable or metastatic solid tumor with DNA mismatch repair deficiencies or a microsatellite instability-high state. Accelerated approval for treating any unresectable or metastatic solid tumor with DNA mismatch repair deficiencies or a microsatellite instability-high state (or, in the case of colon cancer, tumors that have progressed following chemotherapy). First FDA approval based on a genetic mutation. There is no specified site or tissue type in the approved label. The approval was based on a clinical trial of 149 qualified patients, for whom the ORR was 39.6 percent, 36 percent in colorectal cancer patients, and 46 percent in patients with the other tumor types, including 11 complete responses and partial responses in all others. With such a small clinical trial, Merck must conduct postmarketing studies to confirm the results.
June 2018: Advanced cervical cancer for PD-L1 positive patients, and adult and pediatric refractory primary mediastinal large B-cell lymphoma (PMBCL). The FDA approved pembrolizumab for use in both advanced cervical cancer for PD-L1 positive patients and for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed aft er two or more prior lines of therapy.