CAR-T Outlook

Chimeric antigen receptor T-cell (CAR-T) therapies promise to transform treatment of many cancers but have been slow to gain wide use. We argue that the CAR-Ts’ high costs ought to be thought of in light of the many years of life they can add over standard therapy. Even amortizing CAR-T costs over two years puts them in a similar cost-benefit zone as many other highly innovative cancer therapies. Pay-for-performance schemes, such as some being used for CAR-Ts in Europe to reduce payer risk, offer another path to more acceptable costs.

Marketed CAR-Ts are indicated only for hematological malignancies, but there are many developmental programs targeting solid tumors. Moreover, efforts are under way to extend the technology beyond the current autologous approach to include allogeneic solutions, which could ease the cost and complexity of treating with CAR-T therapies. 

In this post we analyze the commercial outlook for CAR-Ts, given their unique characteristics, especially:

• dramatic clinical improvement (near-cures in approximately 40% of treated patients) and

• very high prices (typically north of $400,000 to treat a single patient)

We have analyzed several CAR-T therapies through the lens of our Disease Target Assessment (DTA) framework, which provides (1) an objective and comparable basis for quantifying the magnitude of clinical improvement offered by a therapy, and (2) a measure of clinical benefit compared to price – is the benefit/cost ratio similar to other new oncology drugs that have achieved good market access?

Yescarta

Yescarta (axicabtagene ciloleucel) won its first FDA approval in 2017 and can be considered a moderate commercial success. Its clinical innovation, notably its efficacy, puts it in what has historically been breakthrough territory by our measures. In third-line-plus diffuse large B cell lymphoma (3L+ DLBCL), Yescarta boosted median overall survival to 25.8 months from 6.3 months for Rituxan regimens, with similar improvements in progression-free survival and response rates. Importantly, five-year survival with Yescarta was 42.6%--reflecting a fat tail to the survival curve.

Entering these results and other clinical information in our framework puts Yescarta’s clinical innovation over the Rituxan regimen as 21.5%.  This figure is well above the 10% threshold that we observe for new drugs that achieve dominant patient share. Yescarta clearly delivers substantial clinical improvement, on par with other commercially successful new drugs. Yescarta shows nearly identical clinical innovation in the newer 2L+ DLBCL population, suggesting strong share potential in that patient group. 

Benefit vs. Cost

To address the question of how a drug’s price affects its outlook, our techniques measure the ratio of “Clinical Benefit” vs. cost; through empirical observation we have shown there is a clear benefit/cost relationship among oncology drugs that have achieved favorable market access (see figure below). Priced upwards of $400K, Yescarta is much more expensive than Rituxan regimens in DLBCL, which average ~$20K annually. CAR-Ts incur substantial ancillary costs for apheresis, bridging therapy, conditioning therapy, infusion and post-infusion, along with hospitalization, ICU stays, and ER visits. Patients with life-threatening adverse events such as high-grade cytokine release syndrome (CRS) incur higher than average costs. All told, the total direct costs of CAR-T therapy can reach ~$650K in DLBCL. In contrast to more conventional drug therapies, all of that cost is incurred up-front. 

Because costs are front-loaded while the benefits are durable, we believe these costs should be amortized. We consider a two-year horizon reasonable (i.e., cutting first-year costs in half). Using that assumption, Yescarta’s benefit to cost ratio in 3L+ DLBCL is in line with other novel oncology therapies that have achieved good market access. This is also true for Yescarta in the 2L+ DLBCL population).

Other Approved CAR-Ts

BMS’s Breyanzi has similar clinical characteristics to Yescarta’s in both 3L+ and 2L+ DLBCL, and although launched several years after Yescarta, it is seeing reasonably good uptake. Still more recent is Janssen’s Carvykti in 5L+ multiple myeloma; this agent has even more impressive clinical innovation (40%), and also offers a good clinical benefit to price ratio. Given those results, we think Carvykti will be successful as it gains approvals in earlier lines of therapy.

Barriers to Use

Factors aside from clinical benefit and price also affect CAR-T share. CAR-Ts are only available at authorized treatment centers (ATCs). While there are over 110 ATCs in the United States, their uneven geographical distribution poses challenges. The elapsed time between sampling a patient’s T-cells and reinfusing treated cells limits CAR-T use to patients who have enough time to benefit from it. Ancillary costs are high and may face uncertain reimbursement.

Key Questions Affecting the Outlook for a New CAR-T Program

Equinox conducted this analysis to investigate the extent to which our analytical tools can help development teams anticipate the commercial potential for CAR-T (and other regenerative medicine therapies) programs. Our preliminary conclusion is that the same metrics we have applied for years to more traditional oncology therapies seem to provide similar insight even in the special case of cell therapies. Evidence so far confirms that the level of clinical improvement and its relationship to price remain important factors.

Enhertu shows high clinical innovation in second-line metastatic breast cancer

Conclusion: Enhertu achieves impressive clinical innovation versus Kadcyla, the current SOC, in second-line HER2+ metastatic breast cancer, and in the newly defined HER2-low metastatic breast cancer population at second or later lines of therapy versus chemo.

Enhertu (trastuzumab deruxtecan, AstraZeneca) was approved[1] in December 2019 for HER2+ unresectable or metastatic breast cancer patients who have received multiple prior anti-HER2 treatments. In May 2022 the FDA approved Enhertu in second line HER2+ breast cancer, based on results from the DESTINY-Breast03[2] trial, which show impressive efficacy in the second-line setting in HER2+ unresectable or metastatic breast cancer.

In these patients, Enhertu boasts a significant increase in progression-free survival compared to the current standard of care (SOC), trastuzumab emtansine (Kadcyla) (25.1 vs. 9.6 months), and a notable improvement in overall response rate (79.7% vs. 43.6%). Coupled with a hazard ratio for death of 0.55, Enhertu appears poised to take over from Kadcyla in second-line HER2+ metastatic breast cancer.

The waterfall chart above shows that Enhertu’s improvements in efficacy far outweigh its slightly worse side effect profile when compared to Kadcyla. The jump in efficacy, as well as its trickle-down effect on mortality and morbidity, deliver a strong clinical innovation score of 25.9%.  Drugs with clinical innovation above 10% usually dominate their segments; Enhertu’s improvement in this population is similar to Tagrisso’s advantage in second-line EGFR+ NSCLC.

We expect Enhertu to dominate treatment in this setting within two years.

Moreover, the FDA recently granted Enhertu Breakthrough Therapy Designation in patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-negative) breast cancer who received a prior systemic therapy in the metastatic setting or developed disease recurrence within six months of completing adjuvant chemotherapy. HR+ patients should additionally have received or be ineligible for endocrine therapy.

The DESTINY-Breast04[3] trial studied Enhertu versus investigator’s choice chemotherapy (e.g., eribulin) in 2L+ HER2-low metastatic breast cancer. Enhertu offers a significant increase in progression-free survival (9.9 vs. 5.1 months) and median overall survival (23.4 vs. 16.8 months) compared to chemo, and a dramatic improvement in overall response rate (52.3% vs. 16.3%). This trial could portend a paradigm shift in breast cancer classification, targeting the entirety of HER2 expression.

The waterfall chart below shows that Enhertu’s improvements in efficacy in HER2-low patients, and resultant impact on mortality and morbidity, offer strong clinical innovation of 14% compared to chemotherapy.

Enhertu is a transformative advance for HER2-low metastatic breast cancer patients, and should dominate the space in the near future.

[1] https://www.daiichisankyo.com/media/press_release/detail/index_3159.html

[2] Cortes et al. 2022

[3] Modi et al. 2022

Weighing Efficacy vs. Tolerability: Lenvima + Keytruda in Advanced ccRCC

Conclusion: Despite its toxicity, the overwhelming efficacy advantage of the Keytruda + Lenvima regimen in first-line (1L) treatment of advanced clear cell renal cell carcinoma (ccRCC) puts it in a position to lead the market in this indication. Tolerability concerns will limit its share.

Winning an FDA approval in August 2021, the combination of Lenvima (lenvatinib, Merck + Eisai) and Keytruda (pembrolizumab, Merck) is the most recently approved TKI/IO therapy with an NCCN category 1 recommendation for 1L treatment of advanced ccRCC. This is the third TKI/IO combination to secure an FDA approval and category 1 recommendation, with Inlyta (axitinib, Pfizer) + Keytruda being approved in April 2019, and Cabometyx (cabozantinib, Exelixis) + Opdivo (nivolumab, BMS) approved in January 2021. The approvals and category 1 recommendations of these regimens span all risk groups. These regimens have since bumped sunitinib (Sutent by Pfizer, which went generic in August 2021) from a category 1 recommendation to a category 2A recommendation. Our comparison of the category 1 TKI/IO regimens in this indication shows that although the Lenvima + Keytruda regimen may be more toxic than the others, this disadvantage is modest relative to its major improvement in efficacy. Our analysis is based on phase 3 clinical trial data (CLEAR, CheckMate 9ER, and KEYNOTE-426).

Historically, new regimens with clinical innovation over 10% achieve strong patient share. Lenvima + Keytruda shows 13.4% clinical innovation over Inlyta + Keytruda, driven by improved efficacy.

Lenvima + Keytruda should excel commercially in patients who are able to tolerate it. Dose reductions and interruptions will help manage the toxicity of this regimen and expand its usage to patients who may not able to tolerate it otherwise.

For the clinical benefit that Lenvima + Keytruda provides relative to Inlyta + Keytruda, its higher price is reasonable. Because of this, it falls within the “cloud” of drugs that have historically achieved good market access, and we predict that Lenvima + Keytruda will perform well commercially.

As a side note, Cabometyx + Opdivo is likely to capture share in this indication as a more tolerable alternative to Lenvima + Keytruda, with its efficacy improvement driving its 7.1% clinical innovation over Inlyta + Keytruda.

Rybrevant and Exkivity: two highly innovative new therapies to treat EGFR Exon 20 Insertion positive mNSCLC

Conclusion: Two highly innovative new therapies, Rybrevant and Exkivity, were approved by the FDA within four months of each other. We think that Janssen’s Rybrevant is likely to come out on top in this competition.

EGFR- positive NSCLC has several targeted options for treatment such as Tagrisso (osimertinib) and Tarceva (erlotinib). However, EGFR exon 20 insertion positive mNSCLC, for which existing EGFR TKIs are ineffective, is still treated with chemotherapy.  These patients have a poor prognosis and this mutation affects approximately 2% of those diagnosed with NSCLC.

Janssen’s bispecific antibody therapy, Rybrevant (amivantamab- vmjw), was launched May 2021 and Takeda’s oral tyrosine-kinase inhibitor, Exkivity (mobocertinib), was launched September 2021. Both agents are approved for EGFR Exon 20 insertion patients who have progressed on or after platinum-based chemotherapy. We reviewed data from the phase I/II approval trials for these two agents, CHRYSALIS (Rybrevant) and EXCLAIM (Exkivity). These drugs were granted accelerated approval by the FDA based on ORR and response duration.

Both Rybrevant and Exkivity show significant Clinical Innovation over the previous standard of care, docetaxel, with 19.0% and 17.4% improvement respectively. New agents with Clinical Innovation over 10% historically achieve strong patient shares. These drugs have similar efficacy (mOS, mPFS and response rates) and WAC prices. However, they differ notably in safety/tolerability, with Rybrevant having a significant advantage over Exkivity.   Rates of serious diarrhea are high in patients who took Exkivity, and it has two black box warnings for cardiovascular safety - QTc prolongation and torsades de pointes (an abnormal heart rhythm that can lead to sudden cardiac death). Rybrevant is administered as an IV infusion every two weeks, while Exkivity is taken orally once a day.

Rybrevant was approved four months ahead of Exkivity, and is vying for more approvals in all-comers (i.e., beyond the Exon 20 mutation) in 1L EGFR+ mNSCLC vs. Tagrisso with a phase III trial in progress, in addition to phase III trials in 2L EGFR+ mNSCLC. It also has phase II trials in other cancers, including esophageal and gastric.

Exkivity appears to be further behind in earlier phase trials, including a phase I/II trial in solid tumors harboring EGFR or HER2 mutations and phase I studies in renal and hepatic impairment. The Janssen strategy is to compete in the broader EGFR+ NSCLC population, whereas Takeda pursues opportunities in other malignancies and therapeutic areas. 

Prioritizing Indications: An Analytical Framework

Developing drugs with potential across multiple populations requires setting priorities. Equinox helps development teams quantify opportunity and risk by indication, to better inform prioritization decisions.

Clinical Improvement, Population Size, and Medical Need: A New Drug in 8 Indications

This graph shows how important commercial factors compare across candidate indications for a new drug: the sizes of the target populations, the level of unmet medical need in each population, and the improvement the drug would offer over the standard of care (SOC), which drives patient share.

This improvement will vary by indication. We use a rigorous technique to quantify that improvement, which we call “Clinical Innovation”. Validating using real world market performance, we have observed that these general rules hold up remarkably well:

• Drugs with 10% or greater Clinical Innovation typically dominate their segments

• Drugs with 5 to 10% Clinical Innovation achieve good patient shares

• But new drugs with less than 5% Clinical Innovation typically struggle; they impose high risk on the developer

Moreover, we have quantified how Clinical Innovation correlates with a new drug’s market access, pricing potential, and patient share.  We use those correlations to predict commercial outcomes for a drug in each of its target patient segments, providing development teams with a strategic perspective to compare opportunity and risk by indication.

In this example, the agent is highly innovative in 2L CRC (a large population), as well as in 2L TNBC and 1L ALK+ NSCLC.  It also is moderately innovative in 1L and 2L melanoma, and 2L pancreatic cancer.  In 2L prostate cancer, however, the agent’s Clinical Innovation is well below the 5% threshold, suggesting the agent will not be competitive in this population.  In 3L melanoma, it offers modest improvement, but this indication will be required to get to the more lucrative 1L and 2L melanoma populations.

Calculating patient share as a function of Clinical Innovation, we can estimate the revenue outlook for the asset in each target population. Development teams use this output (and others from our process) to inform decisions about development strategy.

Trodelvy: A New Option for Later Lines TNBC

Conclusion: Trodelvy offers moderate clinical innovation in relapsed/refractory triple-negative breast cancer (R/R TNBC), suggesting it will be prescribed to a large share of patients in this population.  We compare the results with other recent launches in breast cancers.   

In April 2020, the FDA granted accelerated approval to Trodelvy (sacituzumab govitecan-hziy, Gilead) in patients with metastatic TNBC who have failed two prior lines of therapy. Now, a year later, the FDA has granted full approval to Trodelvy for women with TNBC who have had received two or more systemic therapies, at least one for metastatic disease. Our analysis is based on phase III clinical data (NCT02574455).

TNBC makes up 15-20% of metastatic breast cancer incidence and remains an area of high unmet need. Patients at later lines have historically had few options—all of which offered short time to progression and poor survival rates.

Trodelvy boasts a significant increase in both median progression-free survival (mPFS) and median overall survival (mOS) when compared to physician’s choice chemotherapy. In the phase III ASCENT trial, Trodelvy patients without brain metastasis had an average PFS of 5.6 months, compared to 1.7 months for chemotherapy; mOS almost doubled, going from 6.7 months to 12.1. Trodelvy’s efficacy in patients with brain metastasis was only marginally less impressive. When modeled in Equinox’s framework, these results yield a Clinical Innovation score for Trodelvy of 9.3%, which is moderately differentiated (defined as 5-10% improvement), based on a large set of historical examples.

To put into context Trodelvy’s commercial outlook in R/R TNBC, we can compare it with other breast cancer therapies launched in recent years, regarding:

• Sizes of the populations (bubble size)

• Level of medical need (Y-axis)

• Clinical improvement over the previous standard of care (Equinox Group’s “Clinical Innovation” metric, on the X-axis)

Green bubbles represent drugs with a clinical innovation score greater than 10% (highly innovative drugs)

Yellow bubbles represent drugs with a clinical innovation score of 5-10% (moderately innovative drugs)

Orange bubbles represent drugs with a clinical innovation score of less than 5% (low innovation drugs)

The level of unmet medical need in R/R TNBC treated with chemotherapy is extraordinarily high at 4.22 on Equinox Group’s 0-5 unmet need scoring system.  Need is driven by the excess risk of mortality: 50 times higher than in an age-matched population. 

Our analysis suggests Trodelvy will achieve good patient share in this small population.  Its Clinical Innovation is only slightly lower than that achieved by Perjeta (in combination with trastuzumab + docetaxel) in 1st line HER2+ metastatic breast cancer – a regimen that dominates treatment in its population.

Enhertu in 3rd line HER2+ mBC addresses the second highest level of medical need among the indications here; it offers strong clinical innovation of 26%, suggesting it has strong patient share potential.

Trodelvy’s modest revenue of $72 million in Q1 2021 reflects its initial launches in small patient populations.  In contrast, Ibrance is targeted to a much larger, lower-need population, offers high clinical innovation (15.7%) and has achieved a substantial patient share and sales ($5.4 billion in 2020).  Kisqali’s more modest sales of $687 million in 2020 are explained by its lack of meaningful improvement vs. Ibrance and a launch that was two years later.

Trodelvy is in development in larger populations, including early lines of TNBC, HR+/HER 2- metastatic breast cancer and metastatic non-small-cell lung cancer. Its commercial outlook in those indications, including patient share and pricing potential, will depend on the level of Clinical Innovation it delivers.

Monjuvi: Newest Blockbuster in Relapsed/Refractory DLBCL

Conclusion: Monjuvi achieves an impressive clinical benefit for its substantial efficacy improvements over Polivy (polatuzumab vedotin) + bendamustine + rituximab for adults with R/R DLBCL who have failed one or more prior lines of treatment, but favorable market access may be linked to the availability of generic lenalidomide, which remains a question

Monjuvi (tafasitamab-cxix, MorphoSys and Incyte) was approved in August 2020 in combination with Revlimid (lenalidomide) for relapsed or refractory diffuse large B-cell lymphoma (DLBCL) patients. Though the populations enrolled in the Monjuvi and Polivy trials were similar, having received between one to three or more prior lines of therapy, Monjuvi was approved with a differentiated second-line label for R/R DLBCL, while Polivy was approved for third-line.

Monjuvi + lenalidomide boasts a significant increase in progression-free survival compared to Polivy + bendamustine + rituximab (12.1 vs.7.5 months), as well as a notable improvement in overall response rate (55% vs. 42%). While survival data is not yet mature, even the most conservative modeled estimate (22.8 vs. 12.4 months) sees Monjuvi offering significant clinical benefit for R/R DLBCL patients eligible for a second or later line of treatment.

The waterfall chart below shows that Monjuvi offers a significant improvement in efficacy, which produces further benefits in mortality and morbidity, delivering a strong clinical benefit score of 19%.

While offering substantial clinical benefit, this regimen is expensive, exceeding $360,000 annually, assuming Revlimid’s branded price (WAC).  

Analysts expect Monjuvi to be a blockbuster, projecting $1 billion sales at peak. We believe Monjuvi’s commercial success hinges on the availability of cost-effective generic lenalidomide (expected to be rolled out in 2022 on a limited volume basis), in the absence of which payer pushback is a near certainty.

Comparing Opportunity Across Subpopulations: Rozlytrek as a Case Study

Medical need and the opportunity to reduce it can vary widely across patient segments within a tumor type.  Analyzing those differences can help development teams gain meaningful insights into the range of commercial opportunities across segments.   

Roche’s targeted cancer drug Rozlytrek was approved in August 2019 for metastatic non-small-cell lung cancer (NSCLC) patients whose tumors are ROS1-positive. ROS1 rearrangements present in just 1-2% of NSCLC patients, and a little over one third of these patients develop brain metastases. By analyzing the published clinical data in Equinox Group’s modeling framework, we conclude that:

1. The level of medical need in patients with brain metastases is considerably higher than it is in the writ-large ROS1-positive population, and more importantly

2. Rozlytrek’s clinical improvement in ROS1-positive patients with brain metastases is substantial, while among the writ-large population the improvement is modest

Comparing the Level of Medical Need in Two Populations

The chart below compares unmet medical need (as measured in Equinox’s model) for the two populations when treated with Xalkori, which was the standard of care for ROS1-positive patients before the approval of Rozlytrek. Patients with brain metastases have 24% higher medical need than the writ-large population.  As the chart shows, higher need in the brain metastases population is driven by inferior efficacy and worse mortality outcomes.

Comparing Rozlytrek’s Clinical Improvement over Xalkori in Each Population

When we model Rozlytrek against Xalkori in the writ-large ROS1-positive population, we find little difference in efficacy between the two agents. Rozlytrek’s overall clinical innovation (mostly attributable to safety/tolerability) is only 1.3% in this broader group; historically, drugs with less than 5% clinical innovation are seen as undifferentiated.

However, when we restrict the analysis to patients who have brain metastases, Xalkori is less effective and Rozlytrek achieves an impressive clinical innovation score of 12.8% (drugs with clinical innovation above 10% usually dominate their branded segments).  The far greater overall improvement in patients with brain metastases is attributable primarily to over 3 months greater mPFS (we assume mOS changes are proportional, as those data were not mature at publication).

Rozlytrek’s efficacy in cancer that has spread to the brain is an important advantage over Xalkori that is clearly illustrated only when we model the appropriate subset of ROS1-positive NSCLC patients. And while both the writ-large and brain metastases population analyses provide useful information on their own, examining them side-by-side sheds further light on the sources of advantage for the asset in this tumor.

Pfizer Combo Gains an Edge in BRAF+ Melanoma

Conclusion: The Braftovi + Mektovi regimen has bolstered the role of BRAF + MEK inhibitor combinations in BRAF-mutated melanoma.

The Braftovi + Mektovi combination (Pfizer via Array BioPharma) gained approval in 2018 for patients with unresectable or metastatic melanoma with a BRAF mutation. It is the most recent combination of a BRAF and MEK inhibitor to be approved for this indication, following Novartis’s Tafinlar/Mekinist combination and Genentech’s Zelboraf/Cotellic.

The new combination offers moderate clinical benefit over the previous BRAF/MEK inhibitor combinations, showing an incremental benefit in PFS, but a strong survival benefit that underlies the improved mortality score in the Equinox unmet need framework. Although the new combination faces two well-established competitors and was relatively late to the party, its moderate level of clinical innovation (drugs with improvements of 5 – 10% typically compete reasonably well) suggests that it will capture a meaningful share of this market.

The Braftovi + Mektovi also combination appears to be priced appropriately, relative to the incremental clinical benefit it confers over Zelboraf + Cotellic.  The figure below shows that, compared to our exemplar set of oncology drugs that have achieved good market access, it is in the cloud, suggesting the incremental price and benefit are in good balance; early sales reports confirm that the combination is achieving good access.

New Treatments on the Horizon

The pipeline for new melanoma treatments is robust, with many new combinations for both BRAF mutated and wild-type patients, including triplet regimens targeted to BRAF patients.  Whether those triplets offer sufficient clinical benefit to justify their incremental costs remains to be seen.

Current major melanoma players (BMS, Merck, Novartis, and Roche) and other companies are investigating novel agents and combinations targeted to melanoma sub-populations. Analyzing those new agents and combinations through our lens can help development teams anticipate the commercial outlook of their programs under a range of plausible clinical outcomes.

A Reliable Predictor of NICE Recommendation

The United Kingdom’s National Institute for Health and Care Excellence (NICE) began publishing recommendations on cancer drugs in 2000. Nearly three-quarters of these recommendations are positive: either recommended, optimized or recommended for use in the Cancer Drugs Fund (CDF).

We looked at the 31 instances of drugs/indications that Equinox had assessed and that received or could have received NICE appraisals (in two instances, companies declined to seek appraisal). As the table below shows, we find a strong correspondence between Equinox’s evaluation of innovation for an agent in an indication and the result of the NICE appraisal, whether positive (recommended, optimized or recommended for use in the CDF) or negative (not recommended or no appraisal).

Note: “Innovative” means 5% or higher on Equinox Group’s Clinical Innovation metric

As with NICE’s evaluation of cost-effectiveness, Equinox employs a robust method to calculate the magnitude of value delivered, which depends on the clinical benefit a drug offers as well as the seriousness of the disease that it treats. In the figure below, the value delivered for the same 31 instances of drug/indications is color-coded based on NICE recommendation status.

Overall, we see that Equinox’s measures of clinical innovation and of value delivered are compelling predictors of the recommendations NICE will ultimately make.