Gina Battaglia

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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. 2019;30(suppl 5):v159-v193. doi:10.1093/annonc/mdz244 

2. Valsasina B, Beria I, Alli C, et al. NMS-P937, an orally available, specific small-molecule polo-like kinase 1 inhibitor with antitumor activity in solid and hematologic malignancies. 

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. 2019;721:144097. doi:10.1016/j. gene.2019.144097 

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5. Lenz HJ, Ahn DH, Ridinger M, Erlander MG, Barzi A. A phase Ib/II study of onvansertib (PCM-075) in combination with FOLFIRI and bevacizumab for second-line treatment of metastatic colorectal cancer (mCRC) in patients with a KRAS mutation. 

. 2020;38(suppl 4). doi:10.1200/ JCO.2020.38.4_suppl.TPS265 

6. Barzi A, Lenz HJ, Samuëlsz E, et al. A phase 1b/2 study of onvansertib in combination with FOLFIRI and bevacizumab for second-line treatment of metastatic colorectal cancer in patients with a KRAS mutation. Presented at: 2020 AACR Virtual Annual Meeting I; April 27-28, 2020. https://bit. ly/3eyajGH 

7. Liu P, Wang Y, Li X. Targeting the untargetable KRAS in cancer therapy. A

. 2019;9(5):871-879. doi:10.1016/j.apsb.2019.03.002 

8. Ohren JF, Chen H, Pavlovsky A, et al. Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. 

. 2004;11(12):1192-1197. doi:10.1038/nsmb859

9. Verastem Oncology announces preliminary data from investigator-initiated study highlighting clinical activity of RAF/MEK and FAK combination in KRAS mutant tumors presented at the American Association for Cancer Research 2020 Virtual Annual Meeting I. News release. Business Wire; April 27, 2020. Accessed June 26, 2020. bwnews.pr/35gGVRh 

10. Sulzmaier FJ, Jean C, Schlaepfer DD. FAK in cancer: mechanistic f indings and clinical applications. Nat Rev Cancer. 2014;14(9):598-610. doi:10.1038/nrc3792 

11. Konstantinidou G, Ramadori G, Torti F, et al. RHOA-FAK is a required signaling axis for the maintenance of KRAS-driven lung adenocarcinomas. 

. 2013;3(4):444-457. doi:10.1158/2159-8290.CD-12-0388 

12. Shinde R, Terbuch A, Little M, et al. Phase I study of the combination of a RAF-MEK inhibitor CH5126766 and FAK inhibitor defactinib in an intermittent dosing schedule with expansions in KRAS mutant cancers. Presented at: 2020 AACR Virtual Annual Meeting I; April 27-28, 2020. Abstract CT143 

13. Chenard-Poirier M, Kaiser M, Boyd K, et al. Results from the biomarker-driven basket trial of RO5126766 (CH5127566), a potent RAF/MEK inhibitor, in RAS- or RAF-mutated malignancies including multiple myeloma. 

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Articles

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;

mutations&nbsp; in pancreatic cancer predict benefit from PARP inhibitors,

O&rsquo;Reilly, codirector of medical initiatives at the David M. Rubenstein  Center for Pancreatic Cancer&nbsp; Research and section&nbsp; head of hepatopancreatic biliary and neuroendocrine cancers at Memorial Sloan Kettering Cancer Center (MSK) in New York, New York, also noted that by providing an intravenous-free&nbsp; option&nbsp; for&nbsp; maintenance therapy, olaparib may help patients maintain a better quality of life compared with chemotherapy. &ldquo;A person can take tablets as opposed to needing to come into the clinic to receive infusions,&rdquo; she said. &ldquo;It&rsquo;s a nice quality-of-life consideration for patients in many ways. These responses in select patients can be durable, which means a lot of time away from intravenous treatment.&rdquo;

The encouraging outcomes observed with PARP inhibition and platinum-based chemotherapy underscore the importance of identifying patients with pancreatic cancer harboring a

mutation prior to treatment. A retrospective  analysis of an institutional&nbsp; database at MSK evaluated genomic profiling, clinicopathologic characteristics, and outcomes &nbsp;in patients&nbsp; with pancreatic ductal adenocarcinoma with a germline or somatic mutation in the

The analysis identified 126 patients from the MSK database between 2011 and 2018. Of these, 78 patients (62%) had a germline mutation in&nbsp;

. Among all 126 patients, just 43% and 28% had a family or personal history of

According to O&rsquo;Reilly, restriction of germline testing to patients with factors such as personal or family history of cancer, younger age, or ethnicity that is thought to be associated with

-associated malignancies may mean clinicians are  missing a large minority of patients with a pathogenic germline alteration, indicating the importance of germline testing for all individuals with pancreatic cancer. The 2020 update of the NCCN guidelines for pancreatic adenocarcinoma recommends that all patients with a diagnosis of pancreatic cancer receive germline testing using comprehensive gene panels for hereditary cancer syndromes.

&ldquo;For these patients, [there are] important findings in terms of the treatment and the information that&rsquo;s pertinent  to their family,&rdquo;&nbsp; O&rsquo;Reilly said. "That&rsquo;s a&nbsp; big message that is getting traction now.&rdquo;

The study authors also reported a relatively long median overall survival (OS; 32.1 months) compared with historical data from unselect-ed patients with pancreatic cancer. Although they noted that

mutations may indicate favorable disease biology in pancreatic cancer, the authors also suggested that platinum-based chemotherapy and PARP inhibitors may have contributed to the relatively prolonged survival observed in this subset of patients. Of the 66 patients with stage IV cancer, 43 received first-line platinum-based chemotherapy, including, 36 with a partial response (PR) or complete response (CR). Of the total 126 patients,  44 received a PARP inhibitor (in any treatment line); of these, 15 had a PR and 16 had stable disease (SD). In the 43 patients receiving&nbsp; frontline platinum therapy, 35 had a PR, 1 had a CR, and 4 had SD.

Although the retrospective analysis showed no difference in OS between patients with somatic and germline

mutations, O&rsquo;Reilly noted that more data are needed to determine whether patients with somatic

mutations or alterations in other genes involved in homologous DNA repair, such as

, can benefit from PARP inhibitors. &ldquo;We think that the somatic BRCA mutations that are pathogenic offer the same predictive benefit for olaparib,&rdquo; she said. &ldquo;We need more data in that space, and we need better understanding of what the frequency of somatic

mutations [is] in pancreas cancer.&rdquo;

Veliparib During or After Platinum Chemotherapy

PARP inhibition&rsquo;s success in the maintenance setting prompted the idea of combining platinum-based chemotherapy with a PARP inhibitor to improve tumor response and prolong PFS and OS. A multicenter, open-label, phase II trial evaluated cisplatin plus gemcitabine with ductal adenocarcinoma harboring a germline

mutation. O&rsquo;Reilly was the lead author on a report of the results published in January, which noted that the activity of both regimens exceeded prespecified efficacy thresholds, but neither PFS (10.1 vs 9.7 months;

= .60) was improved by the addition of veliparib compared with cisplatin and gemcitabine alone. Furthermore, adding veliparib led to more than double the number of grade 3 or 4 hematologic toxicities, and O&rsquo;Reilly noted that the anemia and thrombocytopenia associated with PARP inhibitors often become dose limiting over time, particularly when combined with platinum-based chemotherapy.

The study results, which were also present-ed at the symposium, showed 2- and 3-year OS rates of 30.6% and 17.8%, respectively.

An exploratory analysis examined a subset of 10 patients from both study arms (with and without veliparib) who continued with next-line therapy after official study treatment completion. These patients received &ge;4 months of platinum-based chemotherapy followed by PARP inhibition and had a median OS of  23.4 months.

According to O&rsquo;Reilly, these findings support the outcomes from POLO. The results indicate that PARP inhibitors will likely have a role as maintenance therapy following platinum-based chemotherapy and that the combination of cisplatin and gemcitabine is an effective chemotherapy regimen for patients with pancreatic cancer associated with HRD.

Immunotherapy Combinations: Ipilimumab and Nivolumab

Although immune checkpoint inhibitors (ICIs) have led to promising outcomes in many types of cancer, they have not shown strong efficacy in unselected patients with pancreatic tumors. This was observed in a recent phase II randomized clinical trial, which demonstrated an objective response rate of 3.1% in the arm that received the antiPD-L1/CTLA4 combination of durvalumab (Imfinzi) plus tremelimumab and no responses in the arm that received durvalumab monotherapy.

However, tumors with mutations in DNA dam-age repair genes, such as

, have features that have been associated with response to ICI therapy. One sequencing-based retrospective cohort study examined mutational signatures in resected pancreatic ductal adeno-carcinoma cases. Of several identified subtypes, the double-strand break repair and mismatch repair deficiency subtypes were associated with increased expression of genes implicated in antitumor immunity, including activation of CD8-positive T lymphocytes and overexpression of CTLA4, PD-L1, and IDO1, which corresponded to increases in the frequency of somatic mutations and levels of tumor-specific neoantigens.

In a similar study, 450 pancreatic adenocarcinomas were analyzed at the molecular level. Compared with the overall set of tumors, those with mutations in

had an elevated incidence of PD-1positive tumor-infiltrating lymphocytes and PD-L1 overexpression, respectively.

However, clinical trials of ICI therapy in patients with HRD cancers have shown mixed results.

Investigators at the University of Miami Sylvester Comprehensive Cancer Center retrospectively evaluated whether patients with relapsed/refractory pancreatic or biliary cancers who harbored pathogenic germline mutations in

responded to immune check-point inhibition. Using their institutional review boardapproved database, the investigators identified patients who had received ipilimumab (Yervoy) plus nivolumab (Opdivo) and performed a retrospective chart review of survival outcomes. The analysis showed that 5 of 7 patients with microsatellite-stable,

-mutated pancreaticobiliary tumors received a clinical benefit from ipilimumab plus nivolumab, with 2 CRs, 1 PR, and 2 cases of SD observed.

Although  the number of patients&nbsp; analyzed was small, O&rsquo;Reilly said, these results suggest that using ICIs in pancreatic cancer should be further explored in selected patients, perhaps as an adjunct to PARP inhibitors or platinum-based chemotherapy in the setting of HRD.

&ldquo;We do know that patients who have DNA damage repair gene mutations probably are more likely to respond to immunotherapy agents,&rdquo; she said. &ldquo;That piece of evidence is drawn from other malignancies, but there&rsquo;s some work in the pancreas cancer field that speaks to that,  so it&rsquo;s not out of left field in terms of the observation.&nbsp; Looking at this combination [ipilimumab and nivolumab] or perhaps combining [it] with other things, such as a PARP inhibitor or platinum&nbsp; chemotherapy,&nbsp; would be strategies of particular&nbsp; interest in patients with DNA damage repair gene mutations.&rdquo;

Factors Associated With Early Progression or Death

Early progression or death (within 4 months of starting therapy) is commonly observed in clinical trials of unselected patients  with pancreatic cancer, with approximately half of patients progressing or dying during the first 6 months of treatment with FOLFIRINOX (folinic acid [leucovorin], fluorouracil, irinotecan, and oxaliplatin)12&nbsp; or nab-paclitaxel (Abraxane) plus gemcitabine.

In the POLO trial (NCT02184195) of patients with

-mutated pancreatic cancer, the authors noted that 43 (21.7%) of the 198 patients with germline

mutations screened for entry had  experienced disease progression during&nbsp; first-line platinum-based&nbsp; chemotherapy prior to randomization.

O&rsquo;Reilly said that she and&nbsp; her colleagues observed similar early progression in a small number of patients in their study of cisplatin and gemcitabine with or without veliparib, and she stated that understanding how to &ldquo;get ahead of the disease for these rapidly progressing patients&rdquo; will be an important step forward in treatment.

However, studies have not decisively established factors associated  with early progression during maintenance therapy. Therefore, investigators involved in the POLO trial aimed to identify such factors in patients receiving maintenance therapy with olaparib.

An analysis of 154 patients randomized in the POLO trial showed that 33 of 92 patients in the olaparib maintenance arm and 29 of 62 in the placebo arm were identified as early progressors (defined as disease progression or death within 4 months of randomization). Multivariate  logistic regression analysis using a stepwise selection method&nbsp; was&nbsp; employed&nbsp; to search&nbsp; for baseline factors associated with early progression. The results showed that a lower score on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item module physical functioning domain, when included as a continuous variable, was the only factor associated with significantly increased risk of early progression. The odds ratio for this association was 0.973; according to the authors, this equated to a 25% change in the odds of early progression for a 10-point&nbsp; difference in the baseline physical functioning score. According to O&rsquo;Reilly, a poor baseline physical functioning score is likely a proxy for aggressive disease biology and extensive disease burden.

&ldquo;They have challenging [disease] biology, usually large disease burden, [and] often liver dysfunction because of the large disease  burden,&rdquo; she said.

The authors noted some limitations of the analysis, including the small sample size, which limited its power; the possibility that  some patients classified as early progressors already had disease progression at the initiation of study treatment; and exclusion of some patients from the multivariate analysis because of missing baseline covariate data. Additionally, some baseline variablesnamely, neutrophil count, lymphocyte count, and neutrophil-to-lymphocyte ratio&mdash;were excluded from the multivariate analysis because of high levels of missing data.

These recent data further support a role for PARP inhibitors in the maintenance setting and introduce checkpoint inhibition as a possible treatment modality for patients with pancreatic cancer harboring a germline

According&nbsp; to O&rsquo;Reilly, identifying a broader&nbsp; population of&nbsp; patients who may benefit from&nbsp; PARP&nbsp; inhibitors,&nbsp; such as those with somatic

and other homologous repair genes, and finding ways to combine PARP inhibitors with therapies such as ICIs and VEGF inhibitors will be important moving forward. She added that investigations of PARP inhibitors in other settings of pancreatic cancer, such as locally advanced disease and following standard adjuvant therapy in resectable disease, will likely start soon and represent important new directions for the field.

National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Pancreatic Adenocarcinoma (version 2020). bit.ly/2TI83n8. Accessed February 26, 2020.

FDA approves olaparib for gBRCAm metastatic pancreatic adenocarcinoma. FDA website. bit.ly/2Ts7jUe. Updated December 30, 2019.  Accessed February 26, 2020.

Golan T, Hammel P, Reni M, et al. Maintenance olaparib for germline  BRCA-mutated metastatic pancreatic cancer.&nbsp;

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Momtaz P, O&rsquo;Connor CA, Chou JF, et al. Pancreatic ductal adenocarcinoma (PDAC),  BRCA: analysis and outcomes of cohort from Memorial Sloan Kettering Cancer Center&nbsp; (MSK).&nbsp;

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O&rsquo;Reilly  EM, Lee JW, Zalupski M, et al. Randomized, multicenter, phase II trial of gemcitabine and cisplatin with or without veliparib in patients with pancreas adenocarcinoma and a germline&nbsp; BRCA/PALB2&nbsp; mutation [published online January 24, 2020].&nbsp;

O&rsquo;Reilly EM, Lee JW, Zalupski M, et al. A randomized, multicenter, phase II trial of gemcitabine (G), cisplatin (C) +/- veliparib (V) in patients with  pancreas&nbsp; adenocarcinoma&nbsp; (PDAC)&nbsp; and&nbsp; a&nbsp; known&nbsp; germline&nbsp; (g)BRCA/ PALB2 mutation.&nbsp;

. 2020;38(suppl 4; abstr 639). doi: 10.1200/ JCO.2020.38.4_suppl.639.

O&rsquo;Reilly  EM,&nbsp; Oh DY, Dhani N, et al. Durvalumab&nbsp; with&nbsp; or&nbsp; without&nbsp; tremelimumab for patients with metastatic pancreatic ductal adenocarcinoma: a phase 2 randomized clinical trial.&nbsp;

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Connor AA, Denroche RE, Jang GH, et al. Association of distinct mutational signatures with correlates of increased immune activity in pancreatic ductal adenocarcinoma.

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Millis SZ,  Abbott&nbsp; BL,&nbsp; Baker&nbsp; EH,&nbsp; et&nbsp; al. Multiplatform molecular&nbsp; profiling of pancreatic adenocarcinomas to identify BRCA1/2 mutations and PD-1/ PD-L1 status with therapeutic implications.&nbsp; J

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Terrero G, Pollack T, Sussman DA, et al. Exceptional responses to ipilimumab/nivolumab in patients with advanced pancreaticobiliary cancer and germline BRCA or RAD51 mutations.

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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.

New Homologous Recombination Deficiency Findings in Pancreatic Cancer Alter Treatment Focus

Recent randomized clinical trials that have combined immunotherapy with chemotherapy, molecular therapy, or anti-angiogenic therapy for the treatment of patients with lung cancer have shown promising results for these combinations. None of the combinations have yet risen to the top though, said Paul A. Bunn Jr, MD in his presentation at the 2016 International Lung Cancer Congress.

Bunn, Distinguished Professor and chair of Lung Cancer Research at the University of Colorado Cancer Center, summarized results from the CheckMate-012 trial (NCT01454102), in which treatment-naïve patients with advanced nonsmall cell lung cancer (NSCLC) received nivolumab (Opdivo) alone or in combination with other therapies. Similar to previous studies in melanoma, the combination of ipilimumab (Yervoy) plus nivolumab tended to yield a better response than nivolumab monotherapy, particularly in patients with high PD-L1 expression.

The addition of platinum-based doublet chemotherapy led to variable response rates (33%-47%) that were slightly higher than chemotherapy alone, along with overall survival (OS) rates ranging from 50% to 87%. Although this study is still ongoing, Bunn predicted that the results will be instrumental for prescribing therapies in the near future based on PD-L1 expression and the histologic type of the tumor.

The CheckMate-227 trial (NCT02477826) tested tumor PD-L1 status for treatment-naïve patients with stage IV or recurrent NSCLC. Patients with PD-L1positive tumors were stratifed to receive nivolumab monotherapy, nivolumab plus ipilimumab, or platinum-based doublet chemotherapy, whereas the PD-L1&ndash;negative group received nivolumab plus chemotherapy, nivolumab plus ipilimumab, or chemotherapy alone.

Bunn noted that the trial could be &ldquo;potentially game-changing,&rdquo; and noted that even the PD-L1negative group appeared to benefit substantially from combination therapy. Other ongoing trials of combination therapy in the first-line setting include the MYSTIC and NEPTUNE trials, which compare the ef cacy of durvalumab plus tremelimumab with standard of care and, in the MYSTIC trial, durvalumab monotherapy.

Although adding chemotherapy to antiPD-1 therapy may intuitively yield a superior response over nivolumab alone, Bunn indicated that some studieswhile small&mdash;do not readily confirm this. Bunn compared 2 separate studies and showed that for advanced NSCLC, nivolumab combined with platinum-based doublet chemotherapies did not produce an &ldquo;obvious&rdquo; bene t in OS over nivolumab alone. Other studies investi- gated atezolizumab (Tecentriq) in combination with various platinum-based doublet chemotherapies and showed that the majority of patients with NSCLC had a partial or complete response, although the number of patients on each regimen was small, from 8 to 16.

Bunn noted that early data on combination therapy for small cell lung cancer (SCLC) might be particularly noteworthy because this form of lung cancer tends to have a notably short response duration to chemotherapy alone. The Check- Mate-0321 trial of patients with SCLC showed the objective response rate was 31% in the group receiving nivolumab plus ipilimumab and approximately 13% in the group receiving nivolumab monotherapy, and the group with the combined therapy tended to have improved OS rates.

Additionally, Bunn noted that the response rate to combined therapy in CheckMate-032, which included patients regardless of PD-L1 status, was similar to the response rate (35%) to pembrolizumab (Keytruda) in the phase Ib KEYNOTE-028 trial of patients with SCLC and &ge;1% PD-L1 expression in tumor or tumor-infiltrating immune cells and that, unlike the short duration of response to chemotherapy, responses to the combination immunotherapy appeared durable.

&ldquo;Even though these response rates of 30% to 31% are not overwhelming, these responses really do last a long time,&rdquo; said Bunn.

Antiangiogenic agents may be synergistic with immunotherapies, Bunn stated, because of their immunomodulatory properties, including increases in T-cell trafficking into tumors and reducing suppressive cytokines, in lnfiltrating regulatory T cells, and myeloid-derived suppressor cells. Pre-clinical data in mice models suggested that a combination of anti-angiogenic agents with immunotherapy may be beneficial, and ongoing clinical trials in humans are investigating combinations of antiPD-1 agents with bevacizumab (Avastin) or ranibizumab (Lucentis).

In his experience, Bunn noted that PD-L1 expression and response rates to PD-1/PD-L1 inhibitors tend to be lower in patients with molecular driver mutations. Nevertheless, several ongoing phase I trials are showing promising responses to combination therapy, although he cautioned that tumor shrinkage is expected in patients with driver mutations receiving the appropriate molecular therapy and that early response may not predict long-term outcome.

Combination therapy with multiple immune checkpoint inhibitors or immune stimulants is undergoing investigation in early phase I/II trials. However, Bunn stated that the current data are insuficient to predict which of these combinations will prove effective or whether one particular combination is superior to another. Moreover, he predicted that the combina- tion of PD-1/PD-L1 inhibitors with CTLA-4 antibodies would be among the most effective and least toxic, whereas the combinations involving chemotherapy or molecular therapy will be more toxic and not provide additional benefit over sequential administration of the 2 agents.

Recent randomized clinical trials that have combined immunotherapy with chemotherapy, molecular therapy, or anti-angiogenic therapy for the treatment of patients with&nbsp;lung cancer have shown promising results for these combinations.&nbsp;

Author | Gina Battaglia

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