Posted by Naval Shanware, Ph.D. on February 4th, 2022.

We recently shared a look back on key trends that we had identified in 2021.  Based on January alone, 2022 appears to be heading towards being another very busy year for the oncology market, full of more innovation, competitive disruption, and regulatory intrigue!

Our team has identified five key trends that we look forward to tracking closely in 2022.  Those trends are:

1. Significant broadening of the checkpoint inhibitor market
2. Continued growth of radiopharmaceuticals
3. Time in the spotlight for allogeneic therapies (in particular, natural-killer (NK)-cell directed therapies)
4. Emergence of bi-specific antibodies as competitors to CAR-T therapies
5. Growing regulatory scrutiny for oncology medicines

Below, let’s explore each of those trends in some detail and perhaps make some predictions about how things will develop as the year moves forward.

Significant broadening of the checkpoint inhibitor market

The checkpoint inhibitor (CPI) market is substantial.  Today, it’s greater than $25 billion per year.  The vast majority of that market is made up of the PD-1/L1 class of antibodies, with Jemperli (dostarlimab, a PD-1 antibody) being the seventh and most recent entrant, gaining FDA approval last year.

The rest of the CPI market is represented by the anti-CTLA4 antibody class.  Yervoy (ipilimumab) is the only FDA-approved therapy in that class.  For 2022, we expect new entrants to broaden the CPI market considerably.

PD-1/L1 Antibody Class

Within the PD-1/L1 antibodies, there should be a few newcomers during the year.  At least three of those entrants have already been approved in the Chinese market and are expected to make a price / discount-based play in an effort to wrest share from the PD-1/L1 market leaders.  These therapies include:

1. Sintilimab (Tyvyt; Lilly / Innovent)
2. Toripalimab (Tuoyi; Coherus / Shanghai Junshi)
3. Sugemalimab (Cejemly; EQRx / CStone)

Due to the way the US market is designed, we do not expect them to make a significant impact on the market leaders Keytruda and Opdivo.[1]

CTLA4 Antibody Class…and Others

In the CTLA4 class, we expect the FDA to approve a second therapy, AstraZeneca’s tremelimumab. This agent has been highly successful in two Phase 3 trials, so there is a high likelihood that it gets filed and approved this year.[2] [3]

We also expect approval of at least one new CPI class, the anti-LAG3 antibody.  Relatlimab (Bristol Myers Squibb) has a priority review.[4]  There are other potential CPI classes moving forward, as well.  During 2022, we should see pivotal readouts for

1. Magrolimab (CD47 class, Gilead)*
2. Sabatolimab (TIM3 class, Novartis)
3. Tiragolumab (TIGIT class, Roche)

*Illustrating the uncertainty of clinical development in the oncology space: magrolimab and azacitidine recently received a clinical hold, tossing some uncertainty into the space.[5]

Success in one or more of the agents mentioned above could drive a further “gold rush” in these mechanistic classes.  Several large pharmaceutical companies with approved PD-1/L1 therapies could seek to develop proprietary offerings and/or combinations.

Continued growth of radiopharmaceuticals

Radiopharmaceuticals have been emerging as a promising new weapon against cancer, offering the benefits of radiation therapy, but in a highly targeted manner and without the “collateral damage” typically associated with traditional approaches.  Unsurprisingly, interest is burgeoning in the space.

Clinical and commercial data from 2021 appear to support further evaluation.  One of the highlights was the clinical trial success for 177Lu-PSMA-617.  In the phase 3 VISION study presented at ASCO last year,  “men who received 177Lu-PSMA-617 plus best standard of care had a 38% reduction in risk of death (median overall survival benefit of 4 months) and a 60% reduction in the risk of radiographic disease progression or death (median rPFS benefit of 5 months) compared to best standard of care alone.”[6]  The FDA has granted 177Lu a priority review with a PDUFA date in the first half of 2022.[7]  If and when it’s approved, it will likely represent Big Pharma’s third blockbuster radiopharmaceutical, after Xofigo (Bayer) and Lutathera (Novartis).

Last year saw a number of business development deals that underscore the interest in radiopharmaceuticals.  Novartis and Bayer continued to grow their lead as the companies with the strongest footprints in the sector:

• “Novartis obtained exclusive worldwide rights to develop and commercialize therapeutic applications for a library of Fibroblast Activation Protein (FAP) targeting agents including FAPI-46 and FAPI-74, through an assignment agreement with iTheranostics, Inc., an affiliate of SOFIE Biosciences, Inc.”[8]
• Bayer acquired Noria and PSMA Therapeutics to expand its portfolio in prostate cancer, gaining a preclinical small molecule directed to PSMA paired with actinium-225.[9]

Though Novartis and Bayer are leaders, other biotech companies are making a play for the space.  For example:

• Clovis Oncology is developing a pipeline of novel targeted radionuclides. Their lead candidate, FAP-2286, is a peptide-targeted radionuclide therapy that binds to the fibroblast activation protein and has the potential to treat multiple tumor types in a “pan-cancer” approach.
• Fusion Pharmaceuticals is also focused on developing next-generation radiopharmaceuticals. The company has a portfolio of early pipeline candidates including FPI-1434.  Fusion also acquired Ipsen’s intellectual property and assets related to IPN-1087,  a small molecule targeting neurotensin receptor 1 (NTSR1).  Fusion intends to use IPN-1087 to create an alpha-emitting radiopharmaceutical, FPI-2059, targeting solid tumors expressing NTSR1.[10]

2021 will be an important year in clarifying the potential of radiopharmaceuticals. If 177Lu-PSMA-617 is approved as we expect, then we’ll excitedly monitor its early commercial performance.  From a clinical perspective, we should also get early looks at data from both FAP-2286 (Clovis) and FPI-1434 (Fusion).

Time in the spotlight for allogeneic therapies (in particular, NK-cell directed therapies)

Allogeneic cell therapies had rightfully attracted a lot of attention with the promise of efficacy comparable to autologous CAR-Ts but with significantly lower cost of goods sold (COGS) and increased convenience.  However, data from allogeneic CAR-Ts in 2021 was relatively weak and appeared to show challenges with durability.[11]

Despite the challenges, though, there is still significant interest in next-generation allogeneic CAR-T therapies.  During 2022, interest in the space will most likely be focused on a different kind of allogeneic cell therapy: those using Natural Killer (NK) cells.

Fate Therapeutics provided a first look at its data in 2021 and will be closely watched as the flag bearer for this new class of cell therapies. 2022 will reveal if CAR-NK therapies will have similar challenges to the other allogeneic CAR-T therapies or will meaningfully compete and potentially replace autologous CAR-Ts.[12]

Another NK cell player, Nkarta, also expects initial data from its CAR-NK platform in 2022.  Yet another player, Affimed, is trying a different approach, leveraging NK cells derived from cord blood, pre-complexed with innate cell engager antibodies.  In November 2021, Affimed shared some promising initial data from a Phase 1/2 study in CD30+ lymphomas.  In the study, AFM13 complexed with cord blood-derived NK cells demonstrated a 100% objective response rate with a 42% complete response rate in 12 patients.[13]

From our perspective, 2022 will help determine the future of allogeneic therapies and their potential to displace autologous CAR-Ts. If durability issues persist, or if the data suggest that re-dosing is needed (versus “one-and-done” efficacy), then we predict the market will migrate towards bi-specific antibodies instead of allogeneic CAR-T therapies.

Emergence of bi-specifics as a competitor to CAR-T therapies

We expect competition between CAR-T therapies and bi-specific antibodies to intensify in 2022.  There is already competition in acute lymphocytic leukemia (ALL) between the bi-specific Blincyto® and autologous CAR-Ts.  Now, we expect competition to emerge in both multiple myeloma (MM) and follicular lymphoma (FL) in the near term, and then in diffuse large B-cell lymphoma (DLBCL).

Multiple Myeloma

In MM, Janssen has already filed for approval for teclistamab (BCMA bispecific).[14] In fact, MM could be the first indication with approvals against the same antigen for a CAR-T, a bi-specific, and an antibody drug conjugate (ADC), and could help clarify how the market might position these competing platforms.

Teclistamab, which received an FDA breakthrough designation in 2021, is also an interesting case study from a commercial perspective. The developer, Janssen, faces an intriguing commercial strategy situation.  It already promotes Darzalex® a $5 billion+ product in the same indication, and is also preparing to launch its CAR-T therapy, cilta-cel in the same market.[15]

Follicular Lymphoma

In FL, Roche/Genentech has filed for approval for mosunetuzumab[16]  This is a CD20xCD3 T-cell engaging bispecific antibody that has demonstrated compelling data in heavily pretreated patients with relapsed/refractory (R/R) FL who have received two or more prior therapies.  It showed a 60% complete response (CR) rate and a median progression-free survival of 17.9 months.[17]

CAR-T therapies are already approved (or pending) in R/R FL, including:

• Yescarta (axi-cel) is approved in adult patients with R/R FL after two or more lines of systemic therapy.[18]
• Breyanzi is approved in a subset of R/R FL patients.[19]
• In late October of last year, Novartis announced that it had received priority review by the FDA and filing acceptance by the EMA for Kymriah® to treat patients with R/R FL.[20]

Diffuse Large B-Cell Lymphoma

In DLBCL, we await data from a slew of bi-specific antibodies including epcoritamab, glofitamab and odronextamab.  If successful, these will almost certainly further intensify competition between bi-specifics and CAR-Ts.

Based on the fact that head-to-head data are generally lacking, and that bi-specific antibodies have comparatively more limited data packages, we don’t think that the market will move decisively one way or the other from a commercial standpoint in in 2022.  However, the clinical data that will be released during the year will help set the commercial path for 2023 and beyond.

Growing regulatory scrutiny for oncology medicines

After a long period of what can only be described as a ‘highly accommodative’ FDA posture toward oncology medicines, the FDA appears to be now moving towards heightened regulatory oversight in oncology.  Several companies received complete response letters (CRLs) in 2021 and already in 2022, often related to chemistry, manufacturing, and controls (CMC) issues.

In our 2021 retrospective, we had highlighted the examples of Iovance’s lifileucel and Legend Biotech / Johnson & Johnson’s cilta-cel:

• CMC issues delayed Iovance’s planned filing for lifileucel to the first half of 2022, from the originally planned 2020 submissions.[21]
• The FDA requested more time (an additional 3 months) to review information regarding an updated analytical method to measure cilta-cel’s potency.[22]

Additionally in 2021, the FDA “got tough” on drugs approved through the accelerated approval pathway that had failed confirmatory studies.  This was part of an “industry-wide evaluation” that contributed to at least four “voluntary” withdrawals of PD-1/L1s from the market.[23]

We expect the FDA to continue pursuing its policy of heightened scrutiny for companies seeking approvals in 2022.  Already this year, the FDA has handed out two CRLs, one for gefapixant (Merck), and one for somatrogon (Pfizer / OPKO).[24]  Several therapies have also received clinical holds including Gilead’s magrolimab (in combination with azacitidine), which was highlighted above.

The FDA’s leadership has also been increasingly vocal on issues that they have previously avoided. For example, FDA leadership has expressed continued displeasure at what they see as redundant efforts of large pharmaceutical companies, particularly in the realm of PD-1/L1 agents.  The even wrote a perspective on it in the New England Journal of Medicine, published December 15, 2021.

In addition, the FDA’s Richard Pazdur expressed concern regarding the recent trend of companies attempting to use China-only data to pursue FDA approvals.  For example, Innovent (with its US partner Lilly) has filed a BLA with the FDA for its PD-1 in first-line non-squamous non-small cell lung cancer (in combination with pemetrexed and platinum chemo) based on data from a China-only study. The PDUFA data is March 22 and we expect the FDA to refrain from providing a straightforward approval.  They may require new data to demonstrate “generalizability to the US population.”[25] [26]

From a cell therapy perspective, we expect continued scrutiny on cell therapy trials and their eventual approval applications.   In late 2021, there were two clinical holds placed on allogeneic cell therapies:

• In October, Allogene got hit with a clinical hold for its ALLO-501A therapy based on a “chromosomal abnormality” in their CAR-T cells.[27]
• Also in October, Gamida Cell shared that they had received a clinical hold on the Investigational New Drug (IND) application for GDA-201, their NK cell therapy.[28]

Companies should proactively work with the FDA to minimize the disruptions these clinical holds can cause. Fortunately for Allogene, its hold was removed after a 3 month delay.[29]

Closing Thoughts

This year is setting up to be another impactful one in oncology, with more innovation on tap and the likely market entry of innovative medicines.  While this is undoubtedly fantastic from a patient perspective, we are beginning to be concerned whether some segments within oncology may be getting too competitive.

Historically, approvability of a cancer medicine was the greatest barrier to commercial success. Today, in several markets including hem-onc markets like multiple myeloma and non-hodgkins lymphoma (NHL), approvability may no longer guarantee commercial viability owing to over-competition and a proliferation of me-too or undifferentiated assets.

There are some signs that we may be approaching a breaking point of sorts. In fact, already this year, we have seen two BLA/NDA applications “voluntarily” withdrawn by pharma sponsors:  cemiplimab (Regeneron) in cervical cancer[30], and parsaclisib (Incyte) in NHL.[31]  In each case, the decision was made after the company and the U.S. Food and Drug Administration (FDA) were unable to align on required post-marketing studies, which were plausibly viewed as unviable by the sponsor companies.

Similar discussions are likely taking place in the meeting rooms of several prospective market entrants, and we would not be surprised to see more “approvable” therapies choosing to not submit BLA/NDA applications.  Companies need to be more clear-eyed about understanding that approvability may not guarantee commercial success in the oncology market of 2022 and beyond.

End Notes

[1] Plieth, Jacob, Days of reckoning for immune checkpoint blockers, Evaluate Vantage, Jan. 4, 2022, https://www.evaluate.com/vantage/articles/events/company-events/days-reckoning-immune-checkpoint-blockers

[2] AstraZeneca Press Release, Imfinzi and tremelimumab with chemotherapy demonstrated overall survival benefit in POSEIDON trial for 1st-line Stage IV non-small cell lung cancer, May 7, 2021, https://www.astrazeneca.com/media-centre/press-releases/2021/imfinzi-and-tremelimumab-showed-survival-in-poseidon.html

[3] Terry, Mark, New Hope in Liver Cancer as AstraZeneca Combo Improves Survival, BioSpace, October 15, 2022, https://www.biospace.com/article/astrazeneca-s-imfinzi-and-tremelimumab-improves-survival-in-liver-cancer

[4] BMS Press Release, U.S. Food and Drug Administration Accepts for Priority Review Bristol Myers Squibb’s Application for LAG-3-Blocking Antibody Relatlimab and Nivolumab Fixed-Dose Combination as Treatment for Patients with Unresectable or Metastatic Melanoma, 9/20/21. https://news.bms.com/news/corporate-financial/2021/U.S.-Food-and-Drug-Administration-Accepts-for-Priority-Review-Bristol-Myers-Squibbs-Application-for-LAG-3-Blocking-Antibody-Relatlimab-and-Nivolumab-Fixed-Dose-Combination-as-Treatment-for-Patients-with-Unresectable-or-Metastatic-Melanoma/default.aspx

[5] Rosa, Kristi, FDA Places Partial Clinical Hold on Trials Examining Magrolimab Plus Azacitidine in MDS, AML, and Myeloid Malignancies, OneLive, Jan. 27, 2022, https://www.onclive.com/view/fda-places-partial-clinical-hold-on-trials-examining-magrolimab-plus-azacitidine-in-mds-aml-and-myeloid-malignancies

[6] Novartis Press Release, Novartis 177Lu-PSMA-617 significantly improves overall survival and radiographic progression-free survival for men with metastatic castration-resistant prostate cancer in Phase III VISION study June 3, 2021, https://www.globenewswire.com/news-release/2021/06/03/2241602/0/en/Novartis-177Lu-PSMA-617-significantly-improves-overall-survival-and-radiographic-progression-free-survival-for-men-with-metastatic-castration-resistant-prostate-cancer-in-Phase-III.html

[7] Novartis Press Release, FDA grants Priority Review for investigational targeted radioligand therapy 177Lu-PSMA-617 for patients with metastatic castration-resistant prostate cancer (mCRPC), Sep. 28, 2021, https://www.novartis.com/news/fda-grants-priority-review-investigational-targeted-radioligand-therapy-177lu-psma-617-patients-metastatic-castration-resistant-prostate-cancer-mcrpc

[8] Novartis Press Release, Novartis expands targeted radioligand therapy pipeline with in-license for compounds targeting Fibroblast Activation Protein (FAP), Mar. 30, 2021, https://www.novartis.com/news/media-releases/novartis-expands-targeted-radioligand-therapy-pipeline-license-compounds-targeting-fibroblast-activation-protein-fap

[9] Bayer Press Release, Bayer acquires Noria and PSMA Therapeutics to expand portfolio in prostate cancer, Jun. 3, 2021, https://media.bayer.com/baynews/baynews.nsf/id/F8567E357F5239D0C12586E8004A148B?open&ref=irrefndcd

[10] Fusion Pharmaceuticals Press Release, Fusion Pharmaceuticals Announces Closing of Acquisition of IPN-1087, a Small Molecule Targeting NTSR1, from Ipsen, Apr. 1, 2021. https://www.prnewswire.com/news-releases/fusion-pharmaceuticals-announces-closing-of-acquisition-of-ipn-1087-a-small-molecule-targeting-ntsr1-from-ipsen-301260820.html

[11] Plieth, Jacob, Asco 2021 – off-the-shelf cell therapy inches towards reality, Evaluate Vantage, May 20, 2021, https://www.evaluate.com/vantage/articles/events/conferences/asco-2021-shelf-cell-therapy-inches-towards-reality

[12] Plieth Jacob, Fate delivers, up to a point, Evaluate Vantage, Aug. 20, 2021, https://www.evaluate.com/vantage/articles/news/trial-results/fate-delivers-point

[13] Affimed Press Release, Affimed Announces 100% Objective Response Rate at Highest Dose in Phase 1-2 Study of Cord Blood-derived Natural Killer Cells Pre-complexed with Innate Cell Engager AFM13 for CD30-positive Lymphomas, Nov. 22, 2021, Yahoo Finance, https://finance.yahoo.com/news/affimed-announces-100-objective-response-121100566.html

[14] Taylor, Phil, J&J goes after another FDA approval for a cancer bispecific, PharmaPhorum, Dec. 30, 2021, https://pharmaphorum.com/news/jj-guns-for-another-fda-approval-for-a-cancer-bispecific/

[15] Johnson & Johnson Press Release, Janssen Announces U.S. FDA Breakthrough Therapy Designation Granted for Teclistamab for the Treatment of Relapsed or Refractory Multiple Myeloma, June 1, 2021, https://www.jnj.com/janssen-announces-u-s-fda-breakthrough-therapy-designation-granted-for-teclistamab-for-the-treatment-of-relapsed-or-refractory-multiple-myeloma

[16] Roche Press Release, Roche presents pivotal data at ASH 2021 for novel cancer immunotherapy mosunetuzumab, Dec. 11, 2021, https://www.roche.com/media/releases/med-cor-2021-12-11.htm

[17] Ibid.

[18] Lymphoma.org, https://lymphoma.org/news/u-s-food-and-drug-administration-approves-car-t-cell-therapy-for-follicular-lymphoma/, accessed Feb. 1, 2022

[19] US FDA, https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lisocabtagene-maraleucel-relapsed-or-refractory-large-b-cell-lymphoma, accessed Feb. 1, 2022

[20] Novartis Press Release, Novartis receives priority review by US FDA and filing acceptance by EMA for Kymriah® to treat patients with relapsed or refractory follicular lymphoma, Oct. 27, 2021, https://www.novartis.com/news/media-releases/novartis-receives-priority-review-us-fda-and-filing-acceptance-ema-kymriah-treat-patients-relapsed-or-refractory-follicular-lymphoma

[21] Tong, Amber, CMC holdup delays Iovance filing again — to 2022 — as FDA seeks more assay data for TIL therapy, Endpoints News, May 19, 2021, https://endpts.com/cmc-holdup-delays-iovance-filing-again-to-2022-as-fda-seeks-more-assay-data-for-til-therapy/

[22] Legend Biotech Press Release, Legend Biotech Announces Extension of PDUFA Date for Cilta-Cel, Nov. 1, 2021, https://investors.legendbiotech.com/news-releases/news-release-details/legend-biotech-announces-extension-pdufa-date-cilta-cel

[23] Plieth, Jacob, The US FDA gets tough, Evaluate Vantage, Mar 8, 2021, https://www.evaluate.com/vantage/articles/news/policy-and-regulation/us-fda-gets-tough

[24] Bratulic, Anna, FDA issues CRL for Pfizer, OPKO’s once-weekly growth hormone treatment, FirstWord Pharma, Jan. 21, 2022, https://firstwordpharma.com/story/5485151

[25] Rawson, Kate, China-Only Studies Are ‘Problematic,’ US FDA’s Pazdur Says Ahead Of Lilly/Innovent PD-1 Inhibitor Review, Pink Sheet, Dec. 16, 2021, https://pink.pharmaintelligence.informa.com/PS145411/ChinaOnly-Studies-Are-Problematic-US-FDAs-Pazdur-Says-Ahead-Of-LillyInnovent-PD1-Inhibitor-Review

[26] Plieth Jacob, Days of reckoning for immune checkpoint blockers, Evaluate Vantage, Jan. 4, 2022, https://www.evaluate.com/vantage/articles/events/company-events/days-reckoning-immune-checkpoint-blockers

[27] Carroll, John, Allogene hit with FDA clinical hold after a patient experiences ‘abnormality’ in CAR-T cells — shares hammered, Endpoints News, Oct. 7, 2021, https://endpts.com/allogene-hit-with-fda-clinical-hold-after-a-patient-experiences-abnormality-in-car-t-cells/

[28] Gamida Cell Press Release, Gamida Cell to Present NAM-Enabled, Genetically Modified NK Cell Therapy Pipeline and Update on GDA-201 at Today’s Virtual R&D Day, Oct. 26, 2021, https://investors.gamida-cell.com/news-events/press-releases/news-release-details/gamida-cell-present-nam-enabled-genetically

[29] Allogene Press Release, Allogene Therapeutics Announces Removal of FDA Clinical Hold Across All AlloCAR T™ Clinical Trials, Jan. 10, 2021, https://ir.allogene.com/news-releases/news-release-details/allogene-therapeutics-announces-removal-fda-clinical-hold-across

[30] Regeneron Press Release, Regeneron and Sanofi Provide Regulatory Update on Libtayo® (cemiplimab-rwlc) in Advanced Cervical Cancer, Jan. 28, 2022, https://www.prnewswire.com/news-releases/regeneron-and-sanofi-provide-regulatory-update-on-libtayo-cemiplimab-rwlc-in-advanced-cervical-cancer-301470298.html

[31] Incyte Press Release, Incyte Provides Update on Parsaclisib and MCLA-145, Jan. 25, 2022, https://investor.incyte.com/press-releases/press-releases/2022/Incyte-Provides-Update-on-Parsaclisib-and-MCLA-145/default.aspx