Gina Battaglia

Tipifarnib, a highly potent and selective nonpeptide farnesyltransferase inhibitor (FTI), has shown highly durable responses in HRAS-mutant, heavily pretreated head and neck squamous cell carcinoma (HNSCC) that has failed to respond to other approved therapies. However, the high variability in responses among different types of 

-altered cancers highlights the need to identify rational therapeutic combinations that enhance response to HRAS-directed therapies.

HRAS is 1 of 3 human RAS proteins (along with KRAS and NRAS), which play important roles in proliferation, survival, and differentiation of cells and are commonly altered in several types of cancer.

 Alterations in the HRAS gene are present in approximately 0.97% of all cancers,

 with relatively high prevalence noted in urothelial carcinoma (4.42%),1 salivary duct carcinoma (13%-27%),

 alterations has also been associated with poorer progression-free survival (PFS) in patients with HNSCC who received cetuximab (Erbitux), a targeted monoclonal antibody that inhibits EGFR, in the first-line recurrent or metastatic setting.

Despite the high prevalence of RAS mutations in cancer, therapeutic targeting of RAS has been difficult in part because RAS proteins with activating mutations do not have increased enzymatic activity that can be inhibited, said Alan L. Ho, MD, PhD, in an interview with Targeted Therapies in Oncology. Ho indicated that novel approaches for targeting RAS are needed.

“Many of the successes of targeted therapy have been [with] drugs targeting enzymatic activity of certain oncogenes, so pharmacologically developing approaches to inhibit RAS activity, even though that seems like a logical step for treatment of human cancers, has been difficult,” said Ho, who is the Geoffrey Beene Junior Faculty Chair at Memorial Sloan Kettering Cancer Center in New York.

Effective RAS signaling requires attachment of the RAS proteins to the inner surface of the plasma membrane. Farnesyltransferase, a cytosolic metalloenzyme, initiates this process by transferring a 15-carbon hydrophobic moiety to the sulfhydryl group of cysteine in the RAS protein’s C-terminal CAAX motif. This process, farnesylation, plays an important role in the cellular membrane association and activity of RAS and other signaling proteins associated with cancer progression

; therefore, inhibition of farnesyl-transferase has been of clinical interest for the treatment of 

Tipifarnib was the first selective FTI to be studied in clinical trials, beginning in 1997, but it showed only modest activity in 

-altered tumors. Results of subsequent studies revealed that KRAS and NRAS can undergo an alternative form of prenylation mediated by geranylgeranyl transferase that rescues these proteins from the membrane dis-placement caused by FTIs.

 However, HRAS is not a substrate for geranylgeranyl transferase, and FTIs were shown to suppress the membrane localization and downstream signaling of HRAS in human cancer cell lines expressing a mutant form of HRAS (FIGURE).

 These findings suggest a potential role for tipifarnib in 

“HRAS is unique in that it is solely dependent upon farnesyltransferase to localize to the membrane,” Ho said. “We have in vitro and some in vivo studies from our institution demonstrating that 

-driven cancers are particularly susceptible to FTIs.”

-driven tumors, along with the increased availability of tumor genotyping to identify tumors that may benefit from FTIs, has revived interest in tipifarnib as a possible treatment option for 

-altered cancers. The original protocol for the phase 2 KO-TIP-001 trial (NCT02383927) included a cohort of patients with 

-mutant thyroid cancer (cohort 1) and one with 

-mutant nonthyroid solid tumors (cohort 2).

Preliminary results presented at the European Society for Medical Oncology 2018 Congress showed that tipifarnib was well tolerated and induced a partial response (PR) in 5 of 6 patients (83%) with locally advanced or met-astatic HNSCC, none of whom had responded to prior lines of therapy, including platinum chemotherapy, immunotherapy, and cetuximab with or without chemotherapy.

The study also demonstrated a relationship between high mutant-

 variant allele frequency (VAF) and response to tipifarnib, which prompted amendment of the protocol to discontinue enrollment of the thyroid cancer cohort (because of low response rates), limit cohort 2 to patients with HNSCC with a mutant-

 VAF of 20% or greater, and add a third cohort of patients with squamous cell carcinomas (other than HNSCC) harboring 

Ho, the first author on the study, explained the rationale for narrowing the focus to patients with HNSCC. “Along the way, we discovered that there was a particularly good signal in [patients with] 

-mutant head and neck cancer,” he said. “Because sometimes you only get limited shots at demonstrating activity of these approaches, the decision was made to focus that second cohort of [patients with] solid tumors entirely on [patients with] head and neck cancer to fully delineate the true signal of tipifarnib in 

Ho added that the starting dose was also reduced from 900 mg to 600 mg, taken twice daily on a 1-week-on, 1-week-off schedule, to improve tolerability and help patients maintain an effective dose for as long as possible.

Interim results for the HNSCC cohort, which were presented at the 2019 American Association for Cancer Research/National Cancer Institute/European Organisation for Research and Treatment of Cancer International Conference on Molecular Targets and Cancer Therapeutics, included an objective response rate (ORR) of 56% in 18 evaluable patients, most of whom were pretreated, with a median of 2 prior therapies (range, 0-6).8 Responses were durable, and the PFS was numerically higher with tipifarnib than with the patient’s last prior therapy (6.1 vs 2.8 months). The treatment was generally considered tolerable, with the most common grade 3 or higher treatment-emergent adverse events of anemia (35%), neutropenia (20%), leukopenia (10%), thrombocytopenia (10%), and nausea (10%) adequately managed with supportive care.

“All of the treatment-emergent adverse events that we’ve seen are consistent with the known [adverse] effect profile that’s been previously delineated in past phase 2 and 3 trials,” said Ho.

An analysis of the HNSCC cohort presented at the 2020 American Society of Clinical Oncology Virtual Scientific Program showed an ORR of 50% (95% CI, 26.0%-74.0%), with a median duration of response (DOR) of 14.7 months, a PFS of 5.9 months, and an overall survival (OS) of 15.4 months. By contrast, 3 FDA-approved therapies for second-line treatment of HNSCC have ORRs of 13% to 16%, a median PFS of 2 to 3 months, and a median OS of 5 to 8 months.

“We believe a median overall survival of 15 months is unprecedented in this patient population and represents a substantial improvement compared [with] historical bench-marks with current standard of care,” said Troy Wilson, PhD, JD, president and CEO of Kura Oncology, a biopharmaceutical company in San Diego, California, in a press release.11 “Taken together, these data support our enhanced focus on patients with 

-mutant HNSCC, a population in desperate need of effective new treatments, and reinforce our confidence in the ongoing AIM-HN registration-directed trial.”

This international phase 2 trial (AIM-HN/SEQ-HN; NCT03719690) was initiated in response to the KO-TIP-001 results in patients with HNSCC. The AIM-HN cohort is evaluating the efficacy of tipifarnib in 

-mutant HNSCC, and the SEQ-HN cohort is an observational substudy evaluating the effect of 

 mutations on response to first-line HNSCC therapies. The primary outcome measure is ORR, and secondary outcome measures include DOR, time to response, OS, and PFS.

Although early results suggest promising efficacy of tipifarnib in HNSCC with a high mutant-

 VAF, reports suggest more modest efficacy in other tumor types harboring 

 alterations. A recent analysis of patients with salivary gland cancer who were in the original cohort 2 of the KO-TIP-001 trial (n = 7), or who received tipifarnib under individual patient FDA investigational new drug application or single patient expanded access requests (n = 6), showed that of 12 evaluable patients, 1 had a PR and 7 had stable disease (SD) as best response.11 The median duration of SD was 9 months, with SD continuing for at least 6 months in 6 of the 7 patients.

 The median PFS and OS were 7 months (95% CI, 5.9-10.1) and 18 months (95% CI, 9.6-22.4), respectively.

In the phase 2 IST-01 trial (NCT02535650), which included patients with refractory metastatic urothelial carcinoma harboring missense, nonsynonymous HRAS mutations (n = 14) or the rs2075606 (T>C) single-nucleotide variant (SNV) in the tumor suppressor gene STK11 (n = 7), tipifarnib produced ORRs of 24% in the intention-to-treat analysis and 42% in the subgroup of patients with 

-mutant tumors. Four patients (19%) achieved PFS at 6 months, including 3 patients with missense 

 mutations and 1 patient enrolled as an STK11 SNV carrier who also had a nonsense mutation in 

. The study authors recommended further studies evaluating the addition of agents, such as immune checkpoint inhibitors, to tipifarnib to improve outcomes in urothelial carcinoma.

“Just based on the response rates, there’s a range of activity of tipifarnib demonstrated against HRAS-mutant malignancies based on lineage, with [patients with head and neck cancer] showing the best activity,” said Ho. “The reasons for these disparities are not known and are a subject of investigation right now on the preclinical side.”

Results of one preclinical study showed that although tipifarnib led to tumor regression and improved survival in mice bearing 

-driven poorly differentiated and anaplastic thyroid tumors, early and late resistance to tipifarnib was observed. Whole-exome sequencing of several resistant tumors identified a nonsense mutation in 

 at high allele frequencies. The investigators noted that these gene alterations drive acquired resistance to tipifarnib by reactivating RAS/MAPK downstream signaling and concluded that this finding supports the drug’s on-target effects.

“The natural question becomes: [Are] the differences in responses or clinical activities related to tumor-specific differences in the biochemical responses or feedback or increased likelihood of resistance…or [is it] simply [because] HRAS plays different roles in the different tumor types?” said Ho. “These are all possibilities that are being examined preclinically. What we know from the clinical data is that there’s a range of activity that is not entirely explained based on 

According to Ho, further study of tipifarnib in larger groups of patients and development of rational therapeutic combinations are important steps to identify the role of tipifarnib in [treating] 

-driven cancers. In one study, liquid biopsies identified acquired activating 

, or NRAS mutations after cetuximab exposure in more than one-third of patients with HNSCC, whereas HRAS mutations were observed in only 4.3% of patients with cetuximab-naïve HNSCC. The study results also showed acquired 

 mutations in 46% of patients with disease progression during cetuximab treatment, whereas no RAS mutations were identified in patients without progression.

Ho said that although these observations need further study, they suggest that combining cetuximab with an agent that targets RAS activation may be an approach to prevent or delay emergence of acquired resistance or to overcome established resistance to cetuximab. He also said that sequencing tumors of patients who have progressed on cetuximab may identify patients with 

 mutations who could benefit from HRAS-directed therapy.

As for combination therapy, Ho said that although cetuximab is the most obvious addition to study with tipifarnib, the recent incorporation of immune checkpoint blockade into standard-of-care options for HNSCC raises the question of whether such agents could be combined safely and effectively with tipifarnib.

Ho concluded that increased clinical trial participation and identification of patients eligible for HRAS-directed therapy through next- generation sequencing will be essential to identify patients most likely to benefit from tipifarnib and clarify the differences among tumor lineages and 

 gene alterations that influence responsiveness to tipifarnib.

“I encourage people to get next-generation sequencing for head and neck tumors and, if [they have] 

 mutations, get them referred to clinical trials so that we can fully understand the activity and safety and, hopefully, get [tipifarnib] into standard treatment,” said Ho.

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4. Leblanc O, Vacher S, Lecerf C, et al. Biomarkers of cetuximab resistance in patients with head and neck squamous cell carcinoma. 

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6. Whyte DB, Kirschmeier P, Hockenberry TN, et al. K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. 

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7. Ho AL, Chau N, Bauman J, et al. Preliminary results from a phase 2 trial of tipifarnib in squamous cell carcinomas (SCCs) with HRAS mutations. 

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8. A farnesyltransferase inhibitor study. Kura Oncology. Accessed September 28, 2020. https://bit.ly/2Gf3MV1

9. Ho A, Brana I, Haddad R, et al. Preliminary results from a phase 2 trial of tipifarnib in head and neck squamous cell carcinomas (HNSCCs) with HRAS mutations. Abstract presented at: American Association for Cancer Research/National Cancer Institute/European Organisation for Research and Treatment of Cancer International Conference on Molecular Targets and Cancer Therapeutics; October 26-30, 2019; Boston, MA. 

10. Ho AL, Hanna GJ, Scholz CR, et al. Preliminary activity of tipifarnib in tumors of the head and neck, salivary gland and urothelial tract with HRAS mutations. 

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11. Kura Oncology reports overall survival data from phase 2 trial of tipifarnib in HRAS mutant head and neck squamous cell carcinoma. News release. Kura Oncology Inc. May 29, 2020. Accessed September 8, 2020. https://bit.ly/2FkfwoB 

12. Hanna GJ, Guenette JP, Chau NG, et al. Tipifarnib in recurrent, metastatic HRAS-mutant salivary gland cancer. 

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13. Lee HW, Sa JK, Gualberto A, et al. A phase II trial of tipifarnib for patients with previously treated, metastatic urothelial carcinoma harboring HRAS mutations. 

. Published online July 7, 2020. doi:10.1158/1078-0432.CCR-20-1246 

14. Untch BR, Dos Anjos V, Garcia-Rendueles MER, et al. Tipifarnib inhibits HRAS-driven dedifferentiated thyroid cancers. 

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15. Braig F, Voigtlaender M, Schieferdecker A, et al. Liquid biopsy monitoring uncovers acquired RAS-mediated resistance to cetuximab in a substantial proportion of patients with head and neck squamous cell carcinoma. 

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Articles

The high variability in responses among different types of HRAS-altered cancers highlights the need to identify rational therapeutic combinations that enhance response to HRAS-directed therapies.

Targeting HRAS Mutations With Investigational Tipifarnib May Hold Promise in Some Tumor Types

Targeting component of signal transduction pathways associated with KRAS may be the long-awaited solution for management of certain cancers harboring 

 mutations, once considered an undruggable target, according to promising results from early-stage clinical trials. However, the efficacy of each combination therapy will likely depend on the tumor lineage, Gordon Mills, MD, PhD, told 

 mutations are common in multiple types of cancer, including colorectal cancer (CRC), non–small cell lung cancer (NSCLC), low-grade serous ovarian cancer (LGSOC), endometrial cancer, and pancreatic cancer. Although one drug (AMG 510) has shown early promise in targeting advanced cancers with the 

efforts to directly target other KRAS mutations have been largely unsuccessful. Mills suggested that the multiple functions of the mutation likely contribute to the difficulty of directly targeting the kinase.

“KRAS is not only a proliferation inducer, it is also a potent mediator of resistance to apoptosis and other mechanisms of cell death,” Mills, who is director of precision oncology at the Knight Cancer Institute and a professor of cell, developmental, and cancer biology at the School of Medicine, both of Oregon Health & Science University in Portland, said when discussing current research. “You have cells that are primed to remain viable under therapeutic stress, [which may be] why targeting 

-mutant tumors has been harder than expected.”

Using drug combinations to target proteins that indirectly interact with KRAS has emerged as a promising alternative methodology. Mills said that these types of multitargeted approaches will likely be necessary to achieve a durable therapeutic response in most cancers harboring mutant 

“The expectation that you’re going to see marked activity of a monotherapy in a 

-mutant tumor is naive,” he said. “These are aggressive tumors [that are] difficult to treat.”

A meta-analysis showed that upregulation of Pololike kinase 1 (PLK1)—a serine/threonine kinase that regulates mitotic progression

—in CRC was associated with poorer overall survival, lymph node metastasis, and more advanced disease stages.

 In another study, a genome-wide RNA interference screen identified PLK1 as having synthetic lethal interactions with the 

-mutant CRC cells were more sensitive to PLK1 inhibition than 

–wild-type cells; the former cells arrested in prometaphase, accumulated, and subsequently died.

Onvansertib (NMS-P937) is an oral, highly selective ATP-competitive inhibitor of PLK1. Its specificity for PLK1 may improve its long-term safety profile over other PLK inhibitors that also target the PLK2 and PLK3 isoforms.

 A preclinical study showed that onvansertib had antiproliferative effects in multiple cell lines derived from hematologic and solid malignancies, including CRC, and the mechanism of action was determined to be induction of mitotic cell cycle arrest followed by apoptosis. In mice implanted with HT29 human colon adenocarcinoma xenografts, the combination of onvansertib and irinotecan led to greater tumor regression than either drug alone.

These preclinical findings supported the rationale for adding onvansertib to standard-of-care second-line therapy—chemotherapy combination folinic acid (leucovorin), fluorouracil, and irinotecan (FOLFIRI) plus bevacizumab (Avastin)—in 

-mutated metastatic CRC. Results from a phase 1b/2 trial (NCT03829410) presented at the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium in January showed that 5 of 5 evaluable patients with metastatic 

-mutant disease had tumor regression at 8 and 16 weeks after starting therapy with onvansertib plus FOLFIRI/bevacizumab, with responses observed across several 

mutations. At 16 weeks, tumor shrinkage greater than 25% was observed in 3 of the 5 patients, 1 of whom became eligible for curative surgery.

More recently, updated results presented at the 2020 American Association for Cancer Research (AACR) Virtual Annual Meeting I showed a partial response (PR) or stable disease (SD) in 7 of 8 evaluable patients. Prior research had found that a decrease in 

-mutant circulating tumor DNA (ctDNA) measured in the plasma was an early marker of therapeutic response. Consistent with this, 5 patients had a decrease in 

-mutant ctDNA to nondetectable levels in the first treatment cycle (28 days), and all of these patients had tumor regression at 8 weeks.

RAF-MEK With FAK Inhibition in Advanced Cancers

 mutations found in cancer keep KRAS in a persistently active state; this leads to deregulated MAPK pathway signaling via the downstream RAF/MEK/ERK components (FIGURE).

The MAPK pathway plays roles in cell survival, cell cycle progression, and differentiation. MEK1/2 is frequently studied as an optimal therapeutic target in this pathway because of its narrow substrate specificity; inhibiting MEK1/2 blocks ERK1/2 activity without affecting other signaling pathways.

 VS-6766 (also known as CH5126766, CKI27, and RO5126766) inhibits the MAPK signaling pathway by blocking the kinase activity of MEK and the ability of RAF to phosphorylate MEK, which prevents compensatory activation of MEK.

However, activation of focal adhesion kinase, or FAK, has been shown to be a possible mechanism of resistance to MEK inhibition. FAK is overexpressed in multiple advanced-stage cancers and promotes tumor progression and metastasis through effects on cancer cells and stromal cells in the tumor microenvironment.

 In preclinical studies, suppression of FAK induced cell death in xenograft and transgenic models of 

and concomitant inhibition of FAK and RAF/MEK in vitro provided synergistic antitumor effects.

Interim results of an ongoing phase 1 trial (FRAME; NCT03875820) presented at the 2020 AACR Virtual Annual Meeting I showed that a combination of VS-6766 and the FAK inhibitor defactinib demonstrated early signs of clinical activity in patients with advanced cancers harboring a 

 Responses were observed in 4 of 6 patients with 

-mutant LGSOC, 3 of whom had had prior exposure to a MEK inhibitor. Responses were durable, with a median time on treatment of 20.5 months. Although responses were less robust and durable in the 10 patients with

-mutant NSCLC, a PR was observed in 1 patient and disease control was observed in 8, with a median time on treatment of approximately 18 weeks.

After observing relatively high response rates among patients with the 

 G12V mutation in the above study, the investigators performed a combined analysis that included data from that trial and a previously published single-agent study of VS-6766 whose results were presented in 2017 at the ASCO Annual Meeting (NCT02407509).

 This combined analysis showed an overall response rate (ORR) of 57% in patients with 

 G12V–mutant NSCLC, including 2 of 5 patients on single-agent VS-6766 and 2 of 2 patients who received the combination of VS-6766 and defactinib.

 G12V–mutant gynecologic cancers, the ORR was 60% (1 of 2 patients on single-agent VS-6766 and 2 of 3 patients on combination therapy).

Mills noted that lineage-specific events affect the function and mechanism of action of 

 and may partly explain why the efficacy and durability of therapeutic combinations vary among different types of 

-mutant cancers, as was observed with LGSOC and NSCLC. “Co-mutations, other aberrations, and lineage-specific gene expression patterns all condition the effects of targeted therapies,” he said.

MEK Inhibition in Low-Grade Serous Ovarian Cancer 

The unique structure of MEK is advantageous for the design of ATP-noncompetitive inhibitors such as binimetinib (Mektovi); their binding site has a low degree of sequence homology, producing selectivity for MEK1/2. In contrast, ATP-competitive MEK inhibitors have a binding site, the ATP-binding pocket, that is highly homologous among multiple protein kinases; this leads to inadvertent multikinase inhibition and associated toxicity.

Despite this advantage, the phase 3 MILO/ ENGOT-ov11 trial (NCT01849874), which compared binimetinib to physician’s choice of chemotherapy in patients with LGSOC, was terminated after the interim analysis showed no difference in median progression-free survival (PFS; 9.1 months vs 10.6 months with chemotherapy; HR, 1.21; 95% CI, 0.79-1.86) or ORR (16% vs 13%).

 A post hoc molecular analysis showed that the median PFS was significantly longer for patients with KRAS mutations (17.7 months vs 10.8 months for patients with 

 mutation status may predict benefit from binimetinib.

 status alone should guide the decision to use a MEK1/2 inhibitor is unclear. A phase 2/3 study (NCT02101788) showed that the MEK inhibitor trametinib (Mekinist) was associated with longer PFS and duration of response than physician’s choice of chemotherapy in women with recurrent or progressive LGSOC or peritoneal cancer. These results led the investigators to conclude that trametinib has the potential to represent a new standard of care in the treated patient population, which was a biomarker unselected group.

RAF Family Kinase Inhibition in Solid Malignancies 

The RAF kinases (ARAF, BRAF, and CRAF) are activated by KRAS in the MAPK signaling pathway, and 

 mutations are a common therapeutic target due to their high frequency in solid malignancies such as melanoma and CRC. BRAF inhibitors vemurafenib (Zelboraf) and dabrafenib (Tafinlar) have demonstrated strong clinical activity in 

 V600E–mutated melanoma, but their relatively weak efficacy in other 

-mutant tumors, such as CRC, may be related to 

-mediated reactivation of the MAPK signaling pathway through a feedback activation mechanism.

 Combining EGFR and BRAF inhibitors led to better efficacy in preclinical models than either agent alone, suggesting that inhibiting both enzymes may improve clinical efficacy across a wider range of tumors with abnormal MAPK pathway activation.

Lifirafenib (BGB-283) is a novel, first-in-class inhibitor of wild-type ARAF, BRAF, and CRAF; BRAF V600E; and wild-type EGFR and KRAS that showed strong efficacy in xenograft models of 

A phase 1 trial (NCT02610361) was designed to evaluate the safety, pharmacokinetics, maximum tolerated dose, and preliminary antitumor activity in patients with 

 mutations, PRs were observed in 2 (1 with endometrial cancer and 1 with codon 12–mutated NSCLC) and SD was observed in 32, including 5 with endometrial cancer and 2 with NSCLC.

The authors also noted that although prolonged disease control was observed in NSCLC and endometrial cancer, the clinical activity of lifirafenib appeared to be more limited in 

-mutated CRC and pancreatic cancer, supporting the premise that oncogenic KRAS is context dependent and requires different treatment approaches based on tumor type.

In addition to drugs that target KRAS-associated proteins, multiple other types of therapeutics have been combined with MEK inhibitors to treat 

-mutant cancers, with promising results from ongoing early-stage clinical trials. A phase 1/2 trial (NCT03162627) is examining selumetinib (a MEK1/2 inhibitor) plus the PARP inhibitor olaparib (Lynparza) in solid tumors with RAS pathway alterations and ovarian tumors with PARP resistance. Additionally, pembrolizumab (Keytruda) and trametinib in 

-mutated stage IV NSCLC are being examined in a phase 1 trial (NCT03299088).

“There is a lot of excitement out there right now about 

-mutant tumors,” said Mills. “We are doing far better than we were a couple of years ago.”

However, Mills stated that applying effective strategies to treat 

-mutated pancreatic cancer remains a key challenge moving forward. 

 mutations are common in this type of cancer and the long-term efficacy of currently approved therapies is limited.

 mutations are clearly contextual in what they do, and what happens in some tumor types, such as endometrial and low-grade serous ovarian cancers, is very different from what we see in pancreatic cancer,” said Mills. “We should not immediately say that the poor outcomes in pancreatic cancer are due to 

 [mutations] in the context of it being a pancreatic cancer.”

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The efficacy of each combination therapy targeting KRAS will likely depend on the tumor lineage, said Gordon Mills, MD, PhD.

Targeting KRAS-Mutant Tumors With Indirect Targeting of Related Pathways Yields Hope in Solid Tumors

PARP  inhibitors&nbsp; following&nbsp; platinum-based chemotherapy as well as immunotherapy combinations have shown early signs of efficacy in metastatic pancreatic cancer with homologous recombination deficiency (HRD), according to data presented at the 2020 Gastrointestinal Cancers Symposium, held January 23 to 25 in San Francisco, California. Recent research also presented at the meeting showed that most patients with a germline

-related malignancies, further supporting the recent recommendation for universal germline testing in the 2020 National Comprehensive Cancer Network (NCCN) guidelines for pancreatic adenocarcinoma.

However, management of patients with early disease progression remains a challenge.

PARP Inhibitors and Germline  BRCA&nbsp; Mutations Olaparib

In December 2019, olaparib (Lynparza)  became the first PARP inhibitor approved by the FDA as maintenance&nbsp; therapy for&nbsp; patients with deleterious or suspected deleterious germline&nbsp;

-mutated metastatic pancreatic adenocarcinoma who have not had disease progression on  at least 16 weeks of first-line platinum-based chemotherapy.

This approval was largely supported by the results of the POLO study, a double-blind, placebo-controlled, multicenter phase III trial that showed an improvement in progression-free survival (PFS) with olaparib and provided important proof of principle that&nbsp;

PARP inhibitors following platinum-based chemotherapy as well as immunotherapy combinations have shown early signs of efficacy in metastatic pancreatic cancer with homologous recombination deficiency, according to data presented at the 2020 Gastrointestinal Cancers Symposium, held January 23 to 25 in San Francisco, California.

Gina Battaglia | Authors

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