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

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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.

Trikafta: A Major Step Forward for Cystic Fibrosis Patients

Cystic fibrosis (CF) affects more than 30,000 patients in the US. Recent treatments for CF focus on modulating the CFTR gene, with Vertex Pharmaceuticals’ Kalydeco (ivacaftor), Orkambi (lumacaftor/ivacaftor), and Symdeko (tezacaftor/ivacaftor) as the only approved therapies that provide more than symptomatic relief. Those agents, however, either are indicated for small segments of the CF population or offer modest clinical improvements as measured in Equinox Group’s model. 

Enter Vertex’s newest treatment, Trikafta (elexacaftor/tezacaftor/ivacaftor), approved in October 2019, which expands the number of CF patients who can benefit from CFTR modulators and offers significant improvement in clinical outcomes.  Trikafta has a broad label for all CF patients aged 12 years and older with at least one F508del mutation (approximately 85% of CF patients in the US carry a copy of the F508del mutation). Trikafta’s approval allows Vertex to treat both the underserved heterozygous F508del population and the homozygous F508del population, where both Orkambi and Symdeko are options.

Trikafta offers very high clinical innovation in patients with the heterozygous F508del mutation, delivering a 15% improvement over Pulmozyme (dornase alfa, Genentech) — with clear gains in efficacy, mortality, and morbidity:

For these heterozygous patients, Equinox’s Rare Disease Normative Price Calculator finds Trikafta to be reasonably priced at annual US WAC of $311,500, given its level of clinical benefit.

Equinox Group’s research and predictive model for pricing agents targeted to rare diseases has found that three factors drive pricing potential:

• Size of the patient population

• Level of disease seriousness (mortality and morbidity), and

• Clinical improvement as measured in the Equinox unmet need model

Trikafta’s published data in the homozygous population is not sufficient to allow Equinox to accurately characterize the clinical benefit for those patients, so we cannot comment on the appropriateness of its price in that population. 

In Q1 of 2020, Trikafta achieved $900 million in sales.  That substantial and rapid commercial success is attributable both to a much larger target population than Vertex’s older CF treatments and to its very high clinical innovation in the heterozygous F508del group. 

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.

Brukinsa: Shooting behind the duck in R/R mantle cell lymphoma

Conclusion: Brukinsa will have a hard time differentiating itself as the third BTK inhibitor to reach market in relapsed/refractory mantle cell lymphoma (R/R MCL).

Brukinsa, developed by the Chinese biotech Beigene, is the most recent BTK inhibitor to earn an indication in R/R MCL. Approved in November of 2019, Brukinsa follows Imbruvica and Calquence to market, with those two enjoying a 6- and 2-year head start, respectively.

As shown in the clinical characteristics table above, Brukinsa has a marginally better response rate, but an inferior mPFS when compared to up-and-coming Calquence. Equinox’s Unmet Need framework allows us to numerically compare the net clinical advantage/disadvantages these agents offer in this indication.

The figure below illustrates the level of remaining unmet medical need in R/R MCL with each therapeutic option. As shown, Imbruvica was a truly transformative medicine when it was approved in 2013— 22.6% better than Velcade (historically, 10% or more represents strong differentiation).  Calquence offered a further 8% improvement over Imbruvica as measured in our framework (between 5% and 10% is considered medium improvement).  Brukinsa, however, is 6.1% worse than Calquence.  Keep in mind when viewing the graphic below that lower values represent improvement.

We expect Brukinsa to struggle to differentiate itself from the other two BTK inhibitors that beat it to market in this indication, and we believe its weak initial revenue figures are an early indicator of the trying path to success that lies ahead.