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 

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. 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 

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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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15. Grisham R. MILO/ENGOT-ov11: phase-3 study of binimetinib versus physician's choice chemotherapy in recurrent or persistent low-grade serous carcinomas of the ovary, fallopian tube, or primary peritoneum. Presented at: 2020 Society for Gynecologic Oncology Annual Meeting on Women’s Cancer; March 28-31, 2020. Accessed June 26, 2020. https://bit.ly/2ATeCxs 

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Articles

Clinical 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

When administered with carboplatin and paclitaxel,the PARP inhibitor veliparib increased progression-free survival (PFS) in patients with hormone receptor–positive breast cancer and triple-negative breast cancer (TNBC) who were positive for germline 

1/2 mutations. These findings from the phase 3 BROCADE3 trial (NCT02163694) were reported at the 2020 European Society for Medical Oncology Breast Cancer Virtual Meeting. In the hormone receptor–positive subset of patients treated with veliparib, carboplatin, and paclitaxel (n =174),the 2-year and 3-year PFS rates by investigator assessment were 27.5% and 17.5%, respectively. Among the 92 patients with hormonereceptor–positive disease randomized to carboplatin/paclitaxel, the 2-year rate of PFS was 15.3% and the 3-year rate of PFS was 8.6%. The median PFS was 13.0 months with the 3-drug approach versus 12.5 months with carboplatin and paclitaxel alone (HR, 0.69; 95% CI, 0.52-0.93; 2-sided 

“In both subgroups, the benefit of veliparib was durable, with an increased probability of remaining progression free at 2 and 3 years compared with placebo,” saidJean-Pierre Ayoub, MD,lead author of the study and an assistant clinical professor in the Department of Medicine at the Université de Montréal in Quebec, Canada.

The trimodality also led to a superior survival benefit in patients with TNBC. The 2-year investigator- assessed PFS rate was 40.4% compared with 25.0% with carboplatin and paclitaxel. The 3-year rate of PFS also favored veliparib plus carboplatin/paclitaxel. “It’s impressive to see [that] at 3 years in the veliparib arm, 35.3% of patients in this poor prognostic, triple- negative subgroup are progression free compared [with] 13.0% in the placebo arm,” Ayoub said.

In this subgroup, the median PFS was 16.6 months (95% CI, 12.3-22.7) in the veliparib, carboplatin, and paclitaxel arm and 14.1 months (95% CI, 11.0-15.8) with chemotherapy (HR, 0.72; 95% CI, 0.52-1.00; 2-sided 

These subgroup-specific findings build on the survival benefit observed in the intention-to-treat (ITT) population, in which the investigator-assessed median PFS was 14.5 months with the veliparib regimen and 12.6 months with chemotherapy (HR, 0.705; 95% CI, 0.566-0.877; 

Overall survival (OS) in the study, which enrolled 509 patients, was similar across subgroups, Ayoub said. The median OS was 32.4 months on the veliparib arm and 27.1 months with chemotherapy in the hormone receptor–positive subgroup (HR, 0.96; 95% CI, 0.681.36; 2-sided

 = .829). Among patients with TNBC, the median OS was 35.0 months with the 3-drug regimen versus 30.0 months with carboplatin and paclitaxel (HR, 0.92; 95% CI, 0.62-1.36; 2-sided 

Neither P value was significant, according to Ayoub, who also noted that adding veliparib did not improve the objective response rate or clinical benefit rate in either subgroup. However, he noted that responses appeared more durable in the veliparib arms. “This may account for the difference that you see in median PFS to a likely carryover effect of the veliparib-treated patients, where we see improvement in PFS to 20.3 months in hormone receptor–positive versus 16.6 months in the placebo arm,” he said.

The overall toxicity profile “was not substantially different between the treatment arms and was generally comparable in the subgroups of patients with hormone receptor–positive disease and triple-negative breast cancer,” Ayoub said. Additionally, safety in the hormone receptor–positive and TNBC subgroups was similar in the ITT population.

In both subgroups, the incidence of any-grade anemia, neutropenia, nausea, and diarrhea was increased by more than 5% in the veliparib arm versus the chemotherapy arm. Although there were some differences between the subgroups, they were not directionally consistent. Neutropenia (78.2%), anemia (40.8%), thrombocytopenia (35.6%), leukopenia (32.2%), and fatigue (6.3%) were the 5 most common grade 3 or higher adverse effects observed in veliparib-receiving patients with hormone receptor–positive disease. This f inding was consistent in the veliparib-treated TNBC group, in which these toxicities affected 84.0%, 44.4%, 43.8%, 25.9%, and 8.0% of patients, respectively.

Ayoub J-P, Friedlander ML, Dieras VC, et al. Veliparib plus carboplatin-paclitaxel in patients with HER2-negative advanced/metastatic gBRCA-associated breast cancer: results in hormone receptor-positive and triple-negative breast cancer subgroups from the phase III BROCADE3 trial. 

. 2020;31(suppl 2):140O. doi:10.1016/j.annonc.2020.03.241

“In both subgroups, the benefit of veliparib was durable, with an increased probability of remaining progression free at 2 and 3 years compared with placebo,” 

Veliparib Leads to PFS Boost in Certain Breast Cancer Subsets

A recent FDA action for the FGFR1/2/3 inhibitor pemigatinib (Pemazyre) marked the first approval of a targeted agent for cholangiocarcinoma, and the oncology field is likely to see additional systemic therapy approvals for bile duct cancers. The incidence of biliary tract cancers, which are typically broken down into subgroups of intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer, are rising, which experts associate with obesity and other etiologic risk factors. These cancers are aggressive, and few treatment options, aside from a handful of chemotherapy regimens, including gemcitabine/cisplatin in the frontline setting and FOLFOX (folinic acid, fluorouracil, and oxaliplatin) in the second line, are available.

Like never before, presentations related to systemic therapies for biliary tract cancers are taking center stage at medical and oncology conferences, generating hope that treating physicians will have multiple options in the near future.

Targeted Therapies for Intrahepatic Cholangiocarcinoma 

In April of this year, the FDA granted accelerated approval to pemigatinib for the treatment of patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma that harbors an 

 aberration as detected by an FDA-approved test.

 fusions and rearrangements are found almost exclusively in intrahepatic cholangiocarcinoma, and the presence of this aberration has motivated investigators to explore the use of FGFR inhibitors in this disease.

The trial that led to the approval, the single-arm phase 2 FIGHT-202 study (NCT02924376), comprised 3 cohorts: patients with 

 fusions or rearrangements (n = 107), those with other 

 alterations (n = 20), and those with no 

 alterations (n = 18). At the median follow-up of 17.8 months, the cohort with 

 fusions or rearrangements achieved an objective response rate (ORR) of 35.5%, made up of 3 complete responses (CRs; 2.8%) and 35 partial responses (PRs; 32.7%). The median time to first response was 2.7 months, and the median duration of response was 7.5 months. No patients in the other cohorts achieved responses.

In line with previously reported data for the agent, hyperphosphatemia was the most common adverse effect (AE), occurring in 60% of patients overall. Grade 3 or greater AEs affected 64% of patients, including hyperphosphatemia in 12% and arthralgia, stomatitis, hyponatremia, abdominal pain, and fatigue in 5% each.

Although the trial investigators urged against cross-trial comparisons, these data compare favorably against historical controls of patients with cholangiocarcinoma treated in the second-line setting and beyond.

“The antitumor activity of pemigatinib in patients with 

 fusions or rearrangements compares favorably with that reported for other second-line chemotherapy and targeted therapies,” the study investigators, who were led by Ghassan K. Abou-Alfa, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, wrote. “The observed proportion of patients with an objective response and the progression-free survival in this study suggests that pemigatinib has encouraging clinical activity in patients with 

Futibatinib (TAS-120), another highly selective drug, inhibits FGFRs 1 through 4. The agent was investigated in a phase 1 trial of patients with advanced solid tumors and showed an ORR of 25% in patients with advanced refractory cholangiocarcinomas that harbor 

Phase 2 FOENIX-CCA2 trial (NCT02052778) data reported as part of the American Society of Clinical Oncology 2020 Virtual Scientific Program further supported these findings, with an ORR of 37.3% observed in 67 patients treated with a continuous dose of 20 mg daily of futibatinib. The investigators noted 1 CR and 24 PRs; 30 patients (44.8%) had stable disease, leading to a disease control rate (DCR) of 82.1%. Reponses were durable, with an average duration of response of 8.3 months. At the analysis, 25 were still receiving therapy.

At a follow-up of 11.4 months, the median progression-free survival (PFS) was 7.2 months, with rates of PFS at 6 and 12 months of 61.0% and 39.4%, respectively.

Serious treatment-related AEs occurred in 10.4% of patients. Investigators reported drug interruptions and dose reductions in 55.2% and 50.7% of patients, respectively. Similar to pemigatinib, a high rate of all-grade hyperphosphatemia was observed, at 88.1%.

The study results led to the phase 3 FOENIX- CCA3 trial (NCT04093362) of futibatinib versus gemcitabine/cisplatin as frontline therapy for patients with advanced cholangiocarcinoma with 

IDH1 as a Viable Target in Intrahepatic Disease 

, around 13% of intrahepatic cholangioarcinomas will harbor a mutation in 

. Phase 1 study data previously demonstrated rationale for the use of IDH1 inhibition in patients with cholangiocarcinoma from a clinical trial cohort of patients with advanced solid tumors.

The small molecule inhibitor ivosidenib (Tibsovo) demonstrated statistically significant improvement in PFS compared with placebo when administered to patients with previously treated 

-mutant cholangiocarcinoma in the randomized phase 3 ClarIDHy trial (NCT02989857). The IDH1 inhibitor already has an FDA indication for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) who are 75 years or older or in patients with AML that is relapsed or refractory and harbors a susceptible 

The reduction in the risk of disease progression or death with ivosidenib was 63% compared with placebo, with median PFS in months of 2.7 versus 1.4 (HR, 0.37; 95% CI, 0.25-0.54; 

<.0001). There was also substantial improvement in the proportion of patients remaining progression free at 6 months (32% vs 0%) and 12 months (22% vs 0%) with ivosidenib following the start of therapy. These benefits were observed regardless of the number of prior therapies and were consistent across subgroups, according to the study investigators, who were led by Abou-Alfa.

Median overall survival (OS) was 10.8 months with ivosidenib and 9.7 months for placebo (HR, 0.69; 95% CI, 0.44-1.10; 

 = .060). Rates of survival at 6 months (67% vs 59%) and 12 months (48% vs 38%) also favored ivosidenib. At data cutoff, 57% of patients treated with placebo had crossed over to the experimental arm, and the investigators observed a favorable OS result for ivosidenib versus placebo in the overall population. In an analysis that accounted for crossover, the adjusted median OS was 6.0 months for patients in the placebo group (HR, 0.46; 95% CI, 0.28-0.75; 

Serious AEs occurred at rates of 30% and 22% in the ivosidenib and placebo groups, respectively, and were deemed treatment related in 2% of patients on ivosidenib. None of the serious AEs in the placebo group were identified as treatment related.

“Although the findings reported here are specific to patients with 

-mutant, advanced cholangiocarcinoma, representing a relatively small subset of the disease population, the incidence of intrahepatic cholangiocarcinoma is increasing internationally and represents an area of growing unmet need,” Abou-Alfa et al wrote in the paper.

Immunotherapy Agents in Biliary Tract Cancer

Recent data also demonstrated the validity of immunotherapies in the treatment of advanced biliary tract cancers, and these systemic therapies are gaining a foothold in the space.

PD-1 and PD-L1 inhibitors such as nivolumab (Opdivo) and durvalumab (Imfinzi), respectively, have shown promise as either single agents or in combination with standard-of-care chemotherapy in both the treatment-naïve and relapsed settings.

In a phase 2 study (NCT02829918) of patients (n = 54) with histologically confirmed, advanced relapsed biliary tract cancer, nivolumab monotherapy induced an investigator-assessed ORR of 22% that included all PRs and a DCR of 59%. Four responders demonstrated durable objective responses lasting at least 1 year. Median PFS and OS were 3.7 months (95% CI, 2.3-5.7) and 14.2 (95% CI, 6.0-NR), respectively.

All patients with responses were determined to have mismatch repair–proficient tumors. Because mismatch repair deficiency is associated with responses to PD-1/L1 inhibitors, the f indings led the investigators to conclude that further investigation on biomarkers of therapy for this agent is warranted. In addition, PD-L1 expression was strongly associated with longer PFS (HR, 0.23; 95% CI, 0.10-0.51; 

 < .001). They concluded that further studies of nivolumab as monotherapy in this patient population are warranted to support the findings and evaluate for tumor biomarkers that may indicate benefit with this treatment strategy.

Atezolizumab (Tecentriq) with the MEK inhibitor cobimetinib (Cotellic) has the potential to prolong PFS versus atezolizumab monotherapy in biliary tract cancer following prior therapies, according to results of a phase 2 trial presented at the 2020 American Association for Cancer Research Virtual Annual Meeting I.

MEK inhibition has shown immunomodulatory effects in preclinical models of biliary tract cancer but not enough to pursue monotherapy indications, so 1 of the 2 arms in the randomized trial added daily cobimetinib to the administration of the PD-L1 inhibitor atezolizumab in patients with pretreated disease. The trial met its primary end point of statistically significant improvement in PFS with the combination versus atezolizumab monotherapy, at 111 days versus 57 days, respectively (

Disease control rates for the combination (n = 38) and single-agent (n = 39) arms were 45.2% and 32.4%, respectively. Each arm had 1 PR and no CRs. One patient with a microsatellite instability–high tumor was included in each arm, but neither patient had an objective response. Mark Yarchoan, MD, of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland, who presented the f indings, said the ORR of 2.9% observed with single-agent atezolizumab is low compared with the response rates seen in other immunotherapy trials and supports the notion that PD-L1 inhibitor therapy alone has limited activity in biliary tract cancer, historically considered an immunolgically cold tumor.

AEs were manageable and consistent with the known toxicities of both study drugs. Treatment-related grade 3 events occurred in 38.5% of patients receiving the single agent and 44.7% of those in the combination group. The manageable safety profile coupled with the potential for PFS benefit led the trial investigators to call for further investigation into the combination.

The efficacy and tolerability of durvalumab (Imfinzi) plus tremelimumab added to standard-of-care cisplatin/gemcitabine was evaluated in a phase 2 trial (NCT03046862) with 3 treatment arms: a biomarker cohort of patients treated with chemotherapy alone (n = 30), patients treated with cisplatin/ gemcitabine plus durvalumab (n = 45), and those receiving cisplatin/gemcitabine plus durvalumab and tremelimumab (n = 46).

ORRs for the durvalumab and the durvalumab plus tremelimumab arms were 73.4% and 73.3%, respectively; this compared favorably with the control arm, which had a response rate of 50.0%. In addition, promising OS was observed with both immunotherapy arms, with medians of 18.1 months for durvalumab and 20.7 months for durvalumab and tremelimumab.

Although the investigators warned against drawing conclusions from these data, the promising efficacy seen here warrants further exploration. The durvalumab plus cisplatin/ gemcitabine is being explored in the phase 3 TOPAZ-1 trial (NCT03875235).

1. Yarchoan M, Cope L, Anders RA, et al. A multicenter randomized phase 2 trial of atezolizumab as monotherapy or in combination with cobimetinib in biliary tract cancers (BTCs): a NCI Experimental Therapeutics Clinical Trials Network (ETCTN) study. Presented at: 2020 American Association for Cancer Research Virtual Annual Meeting I; April 27-28, 2020. Abstract CT043. bit.ly/2BCTMCw 

2. FDA grants accelerated approval to pemigatinib for cholangiocarcinoma with an FGFR2 rearrangement or fusion. FDA. April 17, 2020. Updated April 20, 2020. Accessed June 23, 2020. bit.ly/2zWlvxF 

3. Abou-Alfa GK, Sahai V, Hollebecque A, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. 

. 2020;21(5):671-684. doi:10.1016/S1470-2045(20)30109-1 

4. Goyal L, Meric-Bernstam F, Hollebacque A, et al. FOENIX-CCA2: a phase II, open-label, multicenter study of futibatinib in patients (pts) with intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 gene fusions or other rearrangements. 

. 38(suppl 15):108. doi:10.1200/ JCO.2020.38.15_suppl.108

5. Lowery MA, Burris HA 3rd, Janku F, et al. Safety and activity of ivosidenib in patients with IDH1-mutant advanced cholangiocarcinoma: a phase 1 study. 

. 2019;4(9):711-720. doi:10.1016/ S2468-1253(19)30189-X 

6. Tibsovo. Prescribing information. Agios Pharamceuticals, Inc; 2018. Accessed June 23, 2020. bit.ly/2Yt73XG 

7. Kim RD, Chung V, Alese OB, et al. A phase 2 multi-institutional study of nivolumab for patients with advanced refractory biliary tract cancer. 

. 2020;6(6):1-8. doi:10.1001/jamaoncol.2020.0930 

8. Oh DY, Lee KH, Lee DW, et al. Phase II study assessing tolerability, efficacy, and biomarkers for durvalumab (D) ± tremelimumab (T) and gemcitabine/cisplatin (GemCis) in chemo-naïve advanced biliary tract cancer (aBTC). 

. 38(suppl 15):4520. doi:10.1200/JCO.2020.38.15_ suppl.4520

Promising Data Follow on First Targeted Therapy Approval in Biliary Tract Cancer

In the face of canceled medical meetings this spring, continuing medical education (CME) offerings from Physicians’ Education Resource, LLC® (PER®) were quickly transitioned from an in-person format to virtual presentations that have the ability to reach more medical specialists nationwide (

take our POLL on the impact of a virtual meeting format at the end of this article

). Additionally, the organization made a concerted effort to add new programs to its roaster specifically on the treatment of patients during the coronavirus disease 2019 (COVID-19) pandemic.

Early on in the pandemic, PER® and its parent company MJH Life Sciences™, the largest privately held, independent, full-service medical media company in North America, moved quickly to bring oncologists the most up-to-date information on treating patients with cancer through these challenging times. PER®started hosting webinars focused on COVID-19 and has now launched a series, “

COVID-19 and Cancer Care: What Oncologists Need to Know Today

.” The first live CME-certified COVID-19 webinar that aired on March 23 drew a virtual audience of more than 1200 attendees, who tuned in to hear oncology experts discuss the risk and potential impact of COVID-19 for patients with hematologic and solid tumor malignancies, optimal preventive protocols for how oncologists could protect themselves and their staffand across inpatient and outpatient settings, and therapeutic strategies.

The “COVID-19 and Cancer Care” program has evolved into an ongoing live meeting series, occurring every Monday, and features insights from eminent practicing oncologists.

Beyond COVID-19–focused online CME activities and webinars, the transition of various live events and conferences from an in-person to a digital format has been a driving force at PER®. One innovation is the ASCO Direct Highlights™ series featuring expert analysis of clinical findings presented during the 2020 American Society of Clinical Oncology (ASCO) Virtual Annual Meeting. These sessions aired live in June on PER®’s website to registered participants.

PER® also quickly transformed its multiday in-person conferences to a virtual format. Just 1 day before the 

 Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies conference was scheduled to take place on March 13, New York Gov. Andrew M. Cuomo formally banned all public gatherings of more than 500 people. MJH Life Sciences™, however, had already made the decision days before to pivot and present the conference as a virtual meeting.

According to meeting organizers, it’s difficult to mirror an in-person program. Clinicians come to events not only to stay up-to-date on the content, but also to interact with the experts and ask them questions.

“The biggest opportunity we had, which was also the biggest challenge, was how to create highly interactive programs where there can be Q&A, where attendees can interact with the faculty in real-time, and where faculty can poll the audience and comment on what their results are in real-time. These are the components that really foster that interaction with a capital ‘I,’” Phil Talamo, CHCP, president of PER®, said regarding the changes to the meeting format. “And it is something that attendees have come to expect from a first-class PER® educational session.”

Talamo and his team at PER® rose to meet the challenge, converting 100% of programing that was scheduled from in-person events to virtual events. Additionally, the company has seen a low opt-out rate, and many repeat attendees. Feedback from the events has been that the programing is engaging and interactive, and attendees like the ability to be able to ask questions.

Participation in the virtual meetings mirrors that of the in-person events. Attendees come for the content and the faculty, Talamo said. “The programs that do well live and in person also do well online. For virtual programming, we have been designing them to be content-relevant based on timeliness. Depending on the data cycle, the format may change. We’ve done a number of post-ASCO webcasts and depending on the ASCO data [that we are presenting], we’re going to have varying methods of disseminating data, with both traditional lectures that provide detailed analyses of new studies, and also panel discussions such as Medical Crossfire to address diverse perspectives of data interpretation.”

Despite the disruption caused by the COVID-19 pandemic, PER® has continued its mission to keep community oncology care providers informed and connected with experts in the field.

“We fulfilled our commitment to the community to make sure that education was available. We have proven that we can continue to be the trusted provider and resource in education through both virtual and on-demand activities. So even if this [pandemic] continues into next year, our incredible team has done a very nice job of keeping the community armed with the data they need and the expertise to care for their patients,” he said.

Although Talamo is unsure when live events will resume, he expects that when they do, there will likely be a virtual component to all events. Clinicians may still be unable to attend because of institution restrictions on travel. These clinicians, however, depend on the data that are provided through these events to treat their patients. There is so much uncertainty about COVID-19, and no one knows what is going to happen next, he said.

“The one thing we do know is people are still going to get cancer, and they are still going to need state-of-the-art treatment. Things are going to continue to change and evolve. We want to make sure we are doing all we can as a trusted provider of education to support clinicians. The impact of COVID is real, and the spirit of the oncology community is going to lead to a positive path forward,” Talamo said.

Fewer interactions with individuals in the pharmaceutical industry

More time to learn about practice-changing breakthroughs 

In the face of canceled medical meetings this spring, continuing medical education offerings from Physicians’ Education Resource, LLC®  were quickly transitioned from an in-person format to virtual presentations that have the ability to reach more medical specialists nationwide.

July 2 2020

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

Veliparib Leads to PFS Boost in Certain Breast Cancer Subsets

Promising Data Follow on First Targeted Therapy Approval in Biliary Tract Cancer

Live, Virtual Events Take Center Stage for PER

Breast, Ovarian Screening Questionnaire Reveals Just 1 in 5 Women Meet NCCN Criteria for Genetic Testing

Investigational Targeted Agents for Myelopreservation Hold Potential to Improve Care

Educational Interactions Among Oncologists Remain a Subtle Loss During COVID-19 Pandemic

Coping With Physician Depression in the Era of COVID-19

Survey Finds Changes to Physician–Patient Communication During COVID-19