Beyond Cancer Type: New Pan-Tumor Targets Emerge

Alexander Drilon, MD

The growing use of genomic profiling technologies will help promote the development of anticancer therapies based on molecular features of a tumor rather than the body site of origin. The trend began 3 years ago and continues with the development of promising new biomarkers, according to research experts.

On June 16, 2020, the FDA approved the PD-1 inhibitor pembrolizumab (Keytruda) for adult and pediatric patients with unresectable or metastatic solid cancers with a high tumor mutational burden (TMB-H) whose disease has progressed after prior therapy and who do not have satisfactory treatment alternatives.¹

The decision marked the third tumoragnostic biomarker that the agency has recognized. The trend started with the approval of pembrolizumab for patients with unresectable or metastatic microsatellite instability-high (MSI-H)/mismatch repair–deficient (dMMR) solid tumors in May 2017.² It has continued with the approvals of larotrectinib (Vitrakvi) and entrectinib (Rozlytrek) for adult and pediatric patients with NTRK gene fusions, which encode TRK proteins, in November 2018 and August 2019, respectively (Timeline).³

Timeline. FDA Tumor-Agnostic Drug Approvals3

Additionally, on May 8, 2020, the FDA approved selpercatinib (Retevmo) for 3 tumor types with RET alterations: RET fusion–positive non–small cell lung cancer (NSCLC) and thyroid cancer, and RET-mutant medullary thyroid cancer (MTC).³

Investigators are now setting their sights on the next pan-tumor molecular targets of interest, which include RET, ROS1, ALK, FGFR, BRAF, and the AXL kinase, in an effort to introduce more drugs into the pipeline.⁴ MET exon 14 and NRG1 alterations also are on the radar, experts said in interviews with OncologyLive®.

The development of therapies based on molecular characteristics is made possible by advancements in next-generation sequencing that have led to the identification of recurrent genomic alterations such as mutations, amplifications, deletions, translocations, fusions, and other structural variants across tumor types. The therapies that have flowed from such profiling techniques are credited in part to the advent of tumor-agnostic clinical trial designs and master protocols such as the NCI-MATCH trial, which was established to evaluate whether patients whose tumors harbor specific gene mutations will benefit from targeted therapies regardless of histology.⁵

The oncology community has hailed this trend as a paradigm shift in oncology drug development. Additionally, investigators who helped pioneer precision medicine strategies expect the list of pan-tumor targets to grow.

“The approval of pembrolizumab and the early-generation TRK inhibitors paved the way for subsequent drug development in a tumor-agnostic fashion, so now the question becomes ‘Are there other drivers that are found across a variety of cancers that might be amenable to targeted therapy as well?’ and the answer is yes,” Alexander Drilon, MD, whose research led to the approval of larotrectinib, said in an interview.

“Tumor-agnostic drug development is a bit of an evolving field, and for me, where it really starts is making sure that we are able to test for these drivers and that [clinicians] can run the tests on a substantial number of patients,” said Drilon, a medical oncologist and research director of Early Drug Development at Memorial Sloan Kettering Cancer Center in New York, New York.

TMB Joins the Fold

TMB, defined as the number of mutations per megabase in the DNA of cancer cells, has been recognized as a biomarker of response for patients treated with checkpoint immunotherapy. The recent pembrolizumab approval covers patients with TMB-H solid tumors with 10 or more mutations per megabase as determined by an FDA-approved test. Notably, the approval does not extend to pediatric patients with TMB-H central nervous system cancers because the safety and effectiveness of pembrolizumab in this population has not been verified yet.¹

The decision was based on findings from the ongoing, phase 2 KEYNOTE-158 basket trial (NCT02628067), which enrolled patients with anal, biliary, cervical, endometrial, salivary, thyroid, or vulvar carcinoma; mesothelioma; a neuroendocrine tumor; or small cell lung cancer. Investigators used the FoundationOne CDx assay, which is the approved companion diagnostic for this indication, to assess TMB status in formalin-fixed paraffin-embedded tumor samples.⁶

KEYNOTE-158’s efficacy population included 1050 patients who received pembrolizumab at 200 mg every 3 weeks. Of those, 755 were evaluable for TMB status and 102 (13%) were TMB-H. The overall response rate (ORR) was 29% (95% CI, 21%-39%) in the TMB-H group, which included complete responses in 4% of patients and partial responses in 25%. The median duration of response had not been reached at a median follow-up of 11.1 months, with 57% of patients having responses that lasted 12 months or longer and 50% having responses that endured for at least 24 months.⁶

Data from a subgroup analysis showed that the ORR was highest in patients with endometrial cancer (n = 15; 47%; 95% CI, 21%-73%); neuroendocrine cancer (n = 5; 40%; 95% CI, 5%-85%); and cervical cancer (n = 16; 31%; 95% CI, 11%-59%).⁶

The FDA’s decision was applauded by Roy S. Herbst, MD, PhD, Ensign Professor of Medicine (Medical Oncology), professor of pharmacology, and chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital, and associate cancer center director for translational research at Yale Cancer Center in New Haven, Connecticut. “It’s great to see the use of innovative biomarkers and immunotherapy come together with this approval and encouraging that we now have an option for patients with TMB-H tumors across cancer types, including rare cancers,” Herbst said in a press release.⁷

Brian Alexander, MD, MPH, chief medical officer at Foundation Medicine, said the TMB-associated approval is the result of “years of research into how TMB levels may influence a patient’s response to immunotherapy.”⁷

Nevertheless, the clinical utility of TMB status as a pan-tumor biomarker for immunotherapy has generated debate. In November 2019, 2 exploratory analyses of TMB in patients with NSCLC who received pembrolizumab therapy showed conflicting results.⁸

Howard A. “Skip” Burris III, MD, chief medical officer and president of clinical operations at Sarah Cannon Research Institute in Nashville, Tennessee, said he has been “intrigued” by TMB-H status: “I have seen TMB high be the only marker for a patient who has had an excellent response in my clinic.”

However, Burris, in an interview that took place before the pembrolizumab approval for TMB-H tumors, said that TMB-H status is “relative to the tumor type” and can consequently be the subject of variability. “I sit on several steering committees and it is interesting that we see TMB high being greater than 10 [mutations per megabase], greater than 20, and we just had a publication where greater than 16 was the number,” Burris said.

Andrew McKenzie, PhD, director of personalized medicine at Sarah Cannon Research Institute, is a proponent of further exploring the predictive value of TMB-H status and feels that “elevated mutational burdens are symptomatic of an underlying biological cause.” However, he cautioned that further study and subsequent refinement of this marker are necessary, largely because of its variability. For example, McKenzie has seen the definition of TMB-H differ across drug developers. “With each company, the algorithm is a little different, and there isn’t a standard or FDA-approved guideline for [defining TMB-H], so we are still figuring out what ‘high mutational burden’ means,” McKenzie said. “I think we are just beginning to understand how to analyze and interpret TMB.”

Further, McKenzie continued, a need exists to increase the knowledge base regarding TMB-H status and its relationship to immunotherapeutic response. “Skin cancers have a disproportionately high tumor mutational burden compared [with a malignancy like] ovarian cancer, which has a relatively low tumor mutational burden,” he said. “However, just a small increase in the tumor mutational burden of an ovarian cancer might have a really big difference in [a patient’s] response to therapies that we just do not understand yet.”

Variability is a complicating factor in TMB-H status because of differences in the methodologies used for assessing TMB status, Alison Schram, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center stated in an interview. “Sequencing assays have different gene content and a given TMB number probably does not mean the same thing across all assays,” she said.

MSI/dMMR Indications Expand

Although opinions may vary on the intricacies of TMB-H expression across tumor types, indications for cancers that are MSI-H or dMMR continue to expand. Overall, investigators have estimated that approximately 2% to 4% of all diagnosed cancers harbor dMMR, with higher frequencies observed in endometrial (17%-33%), gastric (9%-22%), and colorectal (6%-13%) cancers. These defects in DNA repair mechanisms can lead to mutations in the microsatellites that make up repetitive DNA sequences, resulting in MSI-H levels.⁹

The FDA used findings from patients with MSI-H or dMMR cancers who participated in 5 clinical trials to support pembrolizumab’s initial accelerated approval for patients with unresectable or metastatic MSI-H/dMMR solid tumors in 2017. The ORR rate was 39.6% (95% CI, 31.7%-47.9%) among 149 patients, which consisted of 90 patients (60%) with metastatic colorectal cancer (mCRC) and 59 (40%) with 1 of 14 other malignancy types.²

The accelerated approval also applied to adult and pediatric patients with disease progression following prior treatment and who have no satisfactory alternative treatment options, as well as patients with MSI-H or dMMR mCRC that progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.²

Since then, the FDA has approved 3 regimens based on tumors that are MSI-H or dMMR: the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) for patients with mCRC that has progressed after prior chemotherapy, nivolumab monotherapy for mCRC after prior treatment, and pembrolizumab for patients with mCRC. Additionally, the agency approved the combination of pembrolizumab plus lenvatinib (Lenvima) for patients with progressive endometrial cancer that is not MSI-H/dMMR.³

On June 29, 2020, the biomarker moved into the frontline setting with a new FDA approval for pembrolizumab in patients with MSI-H/dMMR CRC. Efficacy was demonstrated in findings from the phase 3 KEYNOTE-177 study (NCT02563002) in 307 patients with treatment-naïve MSI-H/dMMR stage IV CRC, 153 of whom were assigned to pembrolizumab monotherapy and 154 to standard-of-care chemotherapy. Control therapies under evaluation in KEYNOTE-177 include oxaliplatin, leucovorin, levoleucovorin, 5-fluorouracil (modified FOLFOX6); and irinotecan, leucovorin, or levoleucovorin (FOLFIRI), administered with or without bevacizumab (Avastin) or cetuximab (Erbitux).10

Data recently presented at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Meeting showed that treatment with frontline pembrolizumab led to a statistically significant improvement in PFS compared with chemotherapy in patients with MSI-H metastatic CRC. The median PFS was 16.5 months (95% CI, 5.4-32.4) with the immune checkpoint inhibitor and 8.2 months (95% CI, 6.1-10.2) with chemotherapy (HR, 0.60; 95% CI, 0.45-0.80; P = .0002). The 24-month PFS rates were 48.3% and 18.6%, respectively.10

Pembrolizumab also presented a less toxic up-front therapeutic option for patients compared with chemotherapy, with a lower incidence of grade 3 or higher treatmentrelated adverse events (22% vs 66%). Cumulatively, these factors indicate that pembrolizumab should be the new frontline standard-of-care in patients with MSI-H metastatic CRC, investigators said.¹⁰

Investigational Pipeline Grows

Following the seminal pan-cancer indications for pembrolizumab, larotrectinib, and entrectinib, Drilon said he has seen “many companies take more of an interest in tumor-agnostic drug development.” (Table).⁴

Expanding the existing approvals for drivers for which targeted therapy is known to be “highly active” in a particular tumor type to other cancers that the initial indication did not include is 1 avenue for developing additional tumor-agnostic agents in the future, Drilon said. Identifying new drivers for which no precision therapies have been approved, such as NRG1 fusions, is another, he added.

Schram agreed that “drugging previously undruggable targets” will be a pivotal component of tumor- agnostic drug development moving forward.

RET

RET activating fusions and mutations are oncogenic drivers that represent a tumor-agnostic predictive biomarker for RET inhibition. Whereas RET point mutations are associated with MTC, RET fusions typically present in 20% of papillary thyroid carcinoma and 1% to 2% of lung adenocarcinoma cases.¹¹

The rationale for focusing tissue-agnostic drug development on emerging targets such as RET has been validated by the recent approval of selpercatinib, according to McKenzie. “With selpercatinib, you see a common target across multiple tumor types that now has an FDA label [with indications] for several different tumor types,” he said.

Specifically, selpercatinib’s May 8, 2020, accelerated approval covered adults with metastatic RET fusion–positive NSCLC, adults and pediatric patients 12 years or older with advanced or metastatic RET-mutant MTC who require systemic therapy, and adult and pediatric patients 12 years or older with advanced or metastatic RET fusion–positive thyroid cancer who need systemic therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate). The indication was based on efficacy data from the phase 1/2 LIBRETTO-001 study (NCT03157128), whose results showed that treatment with the highly selective RET inhibitor induced high and durable responses in patients with NSCLC, MTC, and thyroid cancer.¹²

“RET fusions can be found across many different cancers at lower frequencies. Hopefully, the next push for selpercatinib will be tumor agnostic,” said Drilon, who added that the LIBRETTO-001 basket study continues to “interrogate” selpercatinib’s pan-tumor possibility in other solid tumors. Drilon is the first author of the LIBRETTO-001 trial, which is actively recruiting participants across cohorts.

Pralsetinib (BLU-667), an investigational RET inhibitor, may strengthen the case for RET-directed tumor-agnostic drug development. Findings from the RET fusion–positive NSCLC cohort of the phase 1/2 ARROW trial (NCT03037385) presented at the 2020 ASCO Virtual Scientific Program showed that pralsetinib induced rapid and durable responses in this subgroup.¹³

Table. Novel Pan-Tumor Therapies in Development4

The ORR was 65% (95% CI, 55%-73%) among the 116 total patients evaluable for response, 61% (95% CI, 50%-72%) among the 80 patients who received prior platinum therapy, and 73% (95% CI, 52%-88%) among the 26 patients with treatment-naïve disease. The disease control rate was 93% (95% CI, 87%-97%), 95% (95% CI, 88%-99%), and 88% (95% CI, 70%-98%), respectively, with 96% of the evaluable patients experiencing a reduction in tumor size. Further, the median DOR was not reached (NR; 95% CI, 11.3 months–NR).¹³

Pralsetinib also had robust intracranial activity: The intracranial ORR was 56% in the 9 patients with measurable central nervous system metastases at baseline, and 33% of patients had an intracranial complete response.¹³ The investigational agent is currently under priority review for the treatment of locally advanced or metastatic RET fusion–positive NSCLC, and the FDA is scheduled to decide on pralsetinib’s indication in this setting by November 23, 2020. Blueprint Medicines, pralsetinib’s developer, also intends to submit a new drug application for the RET inhibitor in advanced RET-mutant and RET fusion–positive thyroid cancers in June 2020.¹⁴

MET Exon 14

Like RET fusions, MET exon 14 (METex14) skipping mutations affect an array of solid tumors. The molecular alterations occur in approximately 3% to 4% of newly diagnosed cases of metastatic NSCLC¹⁵ and correlate with poor prognoses and weak responses to standard therapies, including immunotherapy. Beyond NSCLC, the genomic aberrations also surface in melanoma (6.15%), renal cell carcinoma (3.34%), and non-Hodgkin lymphoma (2.59%), among other tumor types.¹⁶

On May 6, 2020, the FDA granted an accelerated approval to capmatinib (Tabrecta) for adults with metastatic METex14-mutant NSCLC, based on ORR data from the phase 2 GEOMETRY mono-1 trial (NCT02414139).17 Notably, capmatinib is the first and only therapy currently approved for advanced NSCLC with a METex14 mutation.15

“We know from the data that we have that MET exon 14 skipping mutations are enriched in lung cancer but not unique to it, so I think that’s one target where we’re going to see clinical trials recruit patients [with] all different tumor types to see [whether capmatinib] has the same effect,” McKenzie said.

ROS1 and NRG1

As actionable driver mutations that present in 2% of NSCLC cases,¹⁸ ROS1 fusions could be a fruitful area of focus for tissue-agnostic therapeutic endeavors, according to Drilon. In 2016, the FDA approved crizotinib (Xalkori) for patients with metastatic ROS1-positive NSCLC.³

“ROS1 fusions drive non–small cell lung cancer, but are also found in other cancers and were first discovered in glioblastomas…[they] also occur in cholangiocarcinomas, gastrointestinal carcinomas, and spitzoid tumors,” Drilon said, adding that responses have also been seen with administration of the ROS1 inhibitor entrectinib across adult and pediatric patients with sarcomas and breast cancers.

“One possibility for tumor-agnostic drug development is expanding the approval of [drugs targeting] ROS1 beyond non–small cell lung cancers,” Drilon continued.

NRG1 fusions, which are enriched in pancreatic cancers and lung cancers but are also found in many other tumor types in The Cancer Genome Atlas dataset, represent another possibility, according to Drilon. “NRG1 is a driver for which we do not yet have an approved therapy, but the hope is that the first approval will be tumor agnostic,” he said.

Therapies under investigation in NRG1 fusion–positive malignancies include zenocutuzumab (MCLA-128; NCT02912949), tarloxotinib bromide (NCT03805841), and seribantumab (NCT04383210), among others. Schram agreed that NRG1 fusions, among other fusions, are actionable, cross-tumor targets for tissue-agnostic drug development that should be pursued.

“Many of the most exciting success stories in genome-directed therapy have been in targeting oncogenic fusions,” Schram said. As examples, she cited therapies directed at BCR-ABL proteins for Philadelphia chromosome–positive chronic myeloid leukemia, ALK and ROS1 fusions in lung cancer, and NTRK fusions across tumor types. She noted that ALK, RET, ROS1, and NRG1 fusions are currently being studied in basket trials, signifying that they are promising targets, regardless of the tumor type.

More Data Are Needed

The experts interviewed for this article concurred that expanded adoption of molecular profiling will be critical to this paradigm-changing approach to anticancer drug development. “We are only really able to move forward with understanding the biology of cancers and their response to tumoragnostic therapies if we can find the drivers in patients’ tumors,” Drilon said.

Although methodologies such as nextgeneration sequencing can provide necessary insights into the genomic aberrations that can guide tissue-agnostic drug development and treatment decisions, sequencing modalities “are not yet standard of care for all tumor types, which can be a barrier [to access],” Schram noted.

References:

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2. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. FDA. Updated May 30, 2017. Accessed June 25, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-first-tissuesite-agnostic-indication

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7. FDA approves second biomarker-based indication for Merck’s Keytruda (pembrolizumab), regardless of tumor type. News release. Merck; June 17, 2020. Accessed June 25, 2020. https://investors.merck.com/news/press-release-details/2020/FDA-Approves-Second-Biomarker-Based-Indication-for-Mercks-KEYTRUDA-pembrolizumab-Regardless-of-Tumor-Type/default.aspx

8. TTMB is not established as a marker for pembrolizumab efficacy in NSCLC. European Society for Medical Oncology. September 27, 2019. Accessed June 25, 2020. https://www.esmo.org/oncology-news/tTMB-Is-Not-Established-as-a-Marker-for-Pembrolizumab-Efficacy-in-NSCLC

9. Marabelle A, Le DT, Ascierto PA, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair–deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2020;38(1):1-10. doi:10.1200/JCO.19.02105

10. Andre T, Shiu KK, Kim TW, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: the phase 3 KEYNOTE-177 study. J Clin Oncol. 2020;38(suppl 18):LBA4. doi:10.1200/JCO.2020.38.18_suppl.LBA4

11. Liu X, Hu X, Shen T, Li Q, Mooers BHM, Wu J. RET kinase alterations in targeted cancer therapy. Cancer Drug Resist. Published online May 11, 2020. doi:10.20517/cdr.2020.15

12. Retevmo. Prescribing information. Lilly USA, LLC; 2020. Accessed June 25, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213246s000lbl.pdf

13. Gainor JF, Curigliano G, Kim DW, et al. Registrational dataset from the phase I/II ARROW trial of pralsetinib (BLU-667) in patients (pts) with advanced RET fusion+ non-small cell lung cancer (NSCLC). J Clin Oncol. 2020;38(suppl 15):9515. doi:10.1200/JCO.2020.38.15_suppl.9515

14. Blueprint Medicines announces data presentations at ASCO20 highlighting deep, durable clinical activity and well-tolerated safety profile of pralsetinib across broad range of RET fusion-positive tumors. News release. Blueprint Medicines Corporation; May 29, 2020. Accessed June 25, 2020. ir.blueprintmedicines.com/news-releases/news-release-details/blueprint-medicines-announces-data-presentations-asco20

15. Novartis announces FDA approval of MET inhibitor Tabrecta for metastatic non-small cell lung cancer with METex14. News release. Novartis; May 6, 2020. Accessed June 25, 2020. https://www.novartis.com/news/media-releases/novartis-announces-fda-approval-met-inhibitor-tabrecta-metastatic-non-small-cell-lung-cancer-metex14

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