Jennifer Fink


This past year, 2020, will go down as a practice-changing one for the treatment of esophageal cancer, said Yelena Y. Janjigian, MD, chief of gastrointestinal oncology at Memorial Sloan Kettering Cancer Center, in New York, New York, during an interview with Targeted Therapies in Oncology.

Though coronavirus disease 2019 dominated news headlines, oncologists made significant strides that will likely improve survival rates for patients diagnosed with cancer of the esophagus. The PD-1 checkpoint inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo) both gained new indications for use in the second-line setting, and additional research suggests they may be beneficial in the first-line setting as well.

“For decades, we had very few options available for the treatment of esophageal cancer, particularly squamous cell cancer,” said Manish A. Shah, MD, chief of the Solid Tumor Service and codirector of the Center for Advanced Digestive Disease at NewYork-Presbyterian, both in New York, New York. “That’s why the advent of PD-1 inhibitors in addition to chemotherapy is so important.”

PD-1 Checkpoint Inhibition in the Frontline Setting

Until recently, treatment options for patients with unresectable/locally advanced or metastatic esophageal cancer have been limited. Five-year survival rates are less than 5%.

 However, adding a checkpoint inhibitor to chemotherapy may bolster the effectiveness of frontline treatment for these malignancies and dramatically improve survival rates, according to results of 2 global, phase 3 clinical trials, KEYNOTE-590 (NCT03189719)

 presented at the European Society for Medical Oncology Virtual Congress 2020.

In the KEYNOTE-590 study, investigators reported a median overall survival (OS) of 12.4 months for patients treated with pembrolizumab plus chemotherapy (cisplatin and 5-fluorouracil [5-FU]) compared with 9.8 months for chemotherapy alone (HR, 0.73; 95% CI, 0.62-0.86; 

< .0001). Median progression-free survival (PFS) was 6.3 months versus 5.8 months (HR, 0.65; 95% CI, 0.55-0.76; 

The survival benefit of adding pembrolizumab to chemotherapy was also analyzed in terms of combined positive score (CPS), a measure that reflects the proportion of tumor cells positive for PD-L1 protein expression. Patients with CPS of 10 or more seemed to garner the most benefit from the combination therapy, with a median OS of 13.5 months versus 9.4 months for chemotherapy alone (HR, 0.62; 95% CI, 0.49-0.78; 

 < .0001). Median PFS was 7.5 months versus 5.5 months (HR, 0.51; 95% CI, 0.41-0.65; 

Immune-mediated adverse events (AEs) and infusion reactions were more common in patients treated with both pembrolizumab and chemotherapy. Grade 3 or higher immune-mediated AEs occurred in 7.0% of the pembrolizumab/chemotherapy group compared with 2.2% of the chemotherapy-alone group.

Notably, KEYNOTE-590 included patients with squamous cell carcinoma of the esophagus and those with esophageal adenocarcinoma. Both groups experienced benefit from the addition of immunotherapy.

Shah, one of the investigators for KEYNOTE-590, noted that he hopes the FDA will approve pembrolizumab in combination with chemotherapy for first-line treatment of esophageal cancer later this year.

Nivolumab also shows promise in the first-line setting. CheckMate649, the largest randomized, global, phase 3 study of PD-1 inhibitor–based therapies as frontline treatment for esophageal cancer, randomized patients to receive either chemotherapy or nivolumab plus chemotherapy.

 The trial included patients with advanced unresectable or metastatic esophageal adenocarcinoma, gastroesophageal junction (GEJ) cancer, and advanced gastric cancer, marking the first time patients with esophageal cancer were included in a study of gastric and GEJ cancers. The inclusion of esophageal cancer makes sense, said Janjigian, principal investigator on CheckMate649, because cancer genome research has revealed that adenocarcinoma of the stomach, GEJ, and esophagus is remarkably similar.

“Splitting them up by anatomic location is a bit artificial,” she said, “particularly because when we see adenocarcinoma of the esophagus, it’s almost always in the last third of the esophagus. Higher up, it’s almost always squamous cell cancer.”

Because patients with esophageal or gastric adenocarcinoma typically receive FOLFOX (folinic acid, 5-FU, and oxaliplatin)chemotherapy, all patients in CheckMate649 received that chemotherapy regimen. The combination arms also received nivolumab at 360 mg every 3 weeks or 240 mg every 2 weeks.

“Nivolumab lends itself well to every-2-week dosing with FOLFOX because that’s administered every 2 weeks as well,” Janjigian noted.

Median OS for patients with PD-L1 CPS of 5 or more who received the nivolumab plus chemotherapy regimen was 14.4 months compared with 11.1 months for similar patients who received chemotherapy alone (HR, 0.71; 98.4% CI, 0.59-0.86; P < .0001). For patients with CPS of 1 or more, median OS was 14.0 months and 11.3 months (HR, 0.77; 99.3% CI, 0.64-0.92; P = .0001). In patients with CPS of 5 or more, nivolumab plus chemotherapy was associated with a 32% reduction in the risk of progression or death versus chemotherapy alone (median PFS, 7.7 months vs 6.0 months; HR, 0.68; 98% CI, 0.56-0.81; P < .0001). The nivolumab combination also produced a PFS benefit in patients with CPS of 1 or more (median PFS, 7.5 months vs 6.9 months; HR, 0.74; 95% CI, 0.65-0.85) and in the overall patient cohort (median PFS, 7.7 months vs 6.9 months; HR, 0.77; 95% CI, 0.68-0.87).

Notably, the objective response rate (ORR) was 60% in the combination treatment group (n = 78) versus 45% for chemotherapy alone (n = 391; P < .0001), with 12 complete responses (CRs) and 48 partial responses (PRs) versus 7 CRs and 38 PRs, respectively.

Serious treatment-related AEs (TRAEs) were more common in the nivolumab/chemotherapy group; 17% of the combination group experienced a grade 3 or 4 AE compared with 10% of the chemotherapy group. However, there were similar rates of TRAEs in patients with CPS of 5 or more and all patients across both treatment arms.

Janjigian described the results of Check-Mate649 as “very exciting” and anticipated likely FDA approval of nivolumab in combination with chemotherapy for first-line treatment of esophageal adenocarcinoma.


“When, and for which populations? That’s to be determined,” Janjigian said, noting that the regulatory authorities may decide to approve the combination regimen for patients with a minimum CPS of 5 or 1 or for all patients regardless of PD-L1 expression.

Approval of immunotherapy/chemotherapy combination regimens for first-line treatment of esophageal cancer may have a dramatic impact on patients’ clinical outcome.

“I believe that doing immunotherapy as early as possible would be important because that’s when patients are still relatively well and functional. If we want to improve their survival outcomes, this is our chance to do it,” Janjigian said. “We also know that many patients never get treatment beyond the first line, either because they’re very ill or for other reasons. If you look at some trials, only about 30% to 40% of patients ever get immunotherapy at later lines.”

With pembrolizumab and nivolumab both showing efficacy in combination with chemotherapy in the frontline setting, clinicians will have to decide which regimen best suits individual patients. Although the combination regimens have not yet been studied head-to-head, KEYNOTE-590 and CheckMate649 offer some guidance.

“For squamous cell cancer, the only available data are from KEYNOTE-590, which used pembrolizumab, so I certainly think that’s what you would use for squamous cell carcinoma in the first-line setting,” Shah said. “For adenocarcinoma, I think it will depend a bit on the specifics of FDA approval.”

The fact that both pembrolizumab and nivolumab are commonly used drugs will likely accelerate the uptake of the new first-line regimens. “There shouldn’t be much of a learning curve,” Shah said. “Once the FDA approves new indications, clinicians should very quickly integrate these treatments into practice.”

Janjigian said some savvy patients already have requested nivolumab/chemo-therapy. “We’ve been able to get occasional insurance approvals already, based on our presented data,” she said.

PD-1 Checkpoint Inhibition in the Second Line and Beyond

Second-line use of PD-1 inhibitors is quickly becoming the standard of care, thanks to FDA approval of pembrolizumab

 and nivolumab to treat advanced esophageal cancer refractory or intolerant to previous chemotherapy based on KEYNOTE-181 (NCT02564263)1 and ATTRACTION-3 (NCT02569242).

 KEYNOTE-181 compared pembrolizumab versus chemotherapy in patients with advanced or metastatic esophageal squamous cell carcinoma or adenocarcinoma. Patients received either pembrolizumab 200 mg every 3 weeks or chemo-therapy (paclitaxel, docetaxel, or irinotecan). Results were stratified by PD-L1 CPS.

“We found that in squamous cell cancers, particularly if the CPS is 10 or higher, pembrolizumab demonstrates significant activity over chemotherapy,” said Shah, an investigator on the study.

For patients with CPS of 10 or more, median OS with pembrolizumab was 9.3 months versus 6.7 months for the chemotherapy group (HR, 0.69; 95% CI, 0.52-0.93; 

 = .0074), and the estimated 12-month OS rates were 43% (95% CI, 33.5%-52.1%) and 20% (95% CI, 13.5%-28.3%), respectively. The addition of pembrolizumab did not improve efficacy outcomes for patients with adenocarcinoma and/or CPS of less than 10.

Notably, patients treated with pembroli-zumab also experienced fewer AEs. TRAEs occurred in 86% of patients treated with chemotherapy versus 64% of patients treated with pembrolizumab. Grade 3 or higher TRAEs occurred in 40.9% of patients in the pembrolizumab group and 18% of patients in the chemotherapy group.

Durable responses were more common in the pembrolizumab group, in which 53.5% of patients experienced a response lasting at least 9 months versus 38.1% of the chemotherapy group.

On July 30, 2019, the FDA approved second-line use of pembrolizumab to treat patients with recurrent, locally advanced, or metastatic squamous cell carcinoma of the esophagus with CPS of 10 or higher.

ATTRACTION-3 investigated the effectiveness of nivolumab compared with chemotherapy (paclitaxel or docetaxel) in the second-line setting. ATTRACTION-3 focused exclusively on squamous cell carcinoma, and patients were enrolled regardless of PD-L1 expression.

At a minimum follow-up of 17.6 months, OS was significantly improved in the nivolumabgroup (median OS, 10.9 vs 8.4 months for the chemotherapy group; HR, 0.77; 95% CI, 0.62-0.96; 

 = .019). Just 18% of the patients treated with nivolumab experienced grade 3 or 4 TRAEs, compared with 63% of patients treated with chemotherapy.

On June 10, 2020, the FDA approved nivolumab for the treatment of patients with unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma who, like the participants in ATTRACTION-3, had previously received fluoropyrimidine- and platinum-based chemotherapy.

Janjigian hailed the approvals of pembrolizumab and nivolumab in the second-line setting but said that “clinically, it may not be enough,” given that most cases of esophagealcancer in the United States are adenocarcinoma, not squamous cell carcinoma. “I think that’s the place where we may need to explore chemotherapy plus immune checkpoint inhibitors,” she said.

Currently recommended third-line therapy for both squamous cell cancer of the esopha-gus and esophageal adenocarcinoma is pembrolizumab, on the basis of KEYNOTE-180 (NCT02559687), a phase 2, single-arm study that produced an ORR of 9.9% (95% CI, 5.2%-16.7%) in the overall patient population.

As this KEYNOTE-180 outcome illustrates, there is room for improvement. “As of 2020, for adenocarcinoma, we use pembrolizumab monotherapy in the third line,” Janjigian said. “However, most [patients] with relatively low PD-L1 expression have very minimal, if any, response.”

PD-1 Checkpoint Inhibition as Adjuvant Therapy

Administering nivolumab after trimodality therapy (chemotherapy, radiation, and surgery) may improve outcomes for patients with resectable locally advanced esophageal cancer or GEJ cancer.

At present, neoadjuvant chemoradiotherapy, followed by surgery, is the standard of care for this patient population. However, the risk of recurrence after treatment is high. CheckMate 577 (NCT02743494), a global, phase 3 study, investigated the effectiveness of administering adjuvant nivolumab after trimodality therapy.

Results were promising. Compared with placebo, nivolumab provided superior disease-free survival (DFS), with a 31% reduction in the risk of recurrence or death. Median DFS in the nivolumab group (22.4 months) was double that in the placebo group (11.0 months; HR, 0.69; 96.4% CI, 0.56-0.86; 

 = .0003). DFS results also favored nivolumab across multiple patient subgroups (TABLE 2).

“CheckMate 577 is practice changing,” Janjigian said. “In my mind, there’s very little downside to doing additional adjuvant therapy if the patient is motivated.”

Although nivolumab is not yet approved for use as adjuvant therapy for esophageal cancer, change is on the horizon. On January 20, the FDA accepted a supplemental biologics 

license application for this indication and granted it priority review status, based on the results of CheckMate 577.10 “I believe the regulatory authorities will be able to take action based on disease-free survival, but we will see. We may need to wait until we have overall survival data [from Check-Mate 577],” Shah said.

However, Janjigian is not sure nivolumab will have a long-term role as an adjuvant treatment. “There are several other studies right now exploring the use of immunotherapy in the neoadjuvant setting,” she said. “Certainly, in lung cancer and other diseases, preoperative immunotherapy has been shown to be very promising.”

Lingering Research Questions and Unmet Needs

Although investigators and clinicians are thrilled to have additional treatment options, the fact remains that “most patients with metastatic esophageal cancer will still, unfortunately, die of their disease,” Shah said.

Investigators continue to evaluate possible treatment regimens. KEYNOTE-811 (NCT03615326) is currently examining the effectiveness of adding pembrolizumab to trastuzumab (Herceptin) and chemotherapy (cisplatin plus 5-FU or oxaliplatin plus capecitabine) for frontline treatment of HER2-positive, unresectable, metastatic gastric, or GEJ cancer. KEYNOTE-811 initiation was based on results of an earlier phase 2 study (NCT02954536), in which a similar regimen in a similar patient population produced an ORR of 87% and a disease control rate of 100%.

Other checkpoint inhibitors may eventually be added to clinicians’ tool kit. Pembrolizumab and nivolumab were the first 2 FDA-approved PD-1–targeting checkpoint inhibitors, but many others have since been developed. Investigators continue to evaluate their effectiveness in treating many types of cancer, both alone and in combination with other therapies. “The future treatment of esophageal and gastric cancers will likely include the combination of checkpoint inhibitors with other drugs,” Shah said.

1. Noone AM, Cronin KA, Altekruse SF, et al. Cancer incidence and survival trends by subtype using data from the Surveillance Epidemiology and End Results Program, 1992-2013. 

. 2017;26(4):632-641. doi:10.1158/1055-9965.EPI-16-0520

2. Kato K, Sun JM, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced esophageal cancer: the phase 3 KEYNOTE-590 study. 

. 2020;31(suppl 4):S1192-S1193. doi:10.1016/j.annonc.2020.08.2298

3. Moehler M, Shitara K, Garrido M, et al. Nivolumab (nivo) plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC)/esophageal adenocarcinoma (EAC): first results of the CheckMate 649 study. 

. 2020;31(suppl 4):S1191. doi:10.1016/j.annonc.2020.08.2296

4. FDA approves pembrolizumab for advanced esophageal squamous cell cancer. FDA. Updated July 31, 2019. Accessed January 4, 2021. 

5. Kato K, Cho BC, Takahashi M, et al. Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial. 

. 2019;20(11):1506-1517. doi:10.1016/S1470-2045(19)30626-6

6. FDA approves nivolumab for esophageal squamous cell carcinoma. FDA. Updated June 11, 2020. Accessed January 4, 2021. 

7. Shah MA, Kojima T, Hochhauser D, et al. Efficacy and safety of pembrolizumab for heavily pretreated patients with advanced, metastatic adenocarcinoma or squamous cell carcinoma of the esophagus: the phase 2 KEYNOTE-180 study. 

. 2019;5(4):546-550. doi:10.1001/jamaoncol.2018.5441

8. Kato K, Shah MA, Enzinger P, et al. KEYNOTE-590: phase III study of first-line chemotherapy with or without pembrolizumab for advanced esophageal cancer. 

. 2019;15(10):1057-1066. doi:10.2217/fon-2018-0609

9. Kelly RJ, Ajani JA, Kuzdzal J, et al. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer (EC/GEJC) following neoadjuvant chemoradiation therapy (CRT): first results of the CheckMate 577 study. 

. 2020;31(suppl 4):S1193-S1194. doi:10.1016/j.annonc.2020.08.2299

10. US Food and Drug Administration accepts for priority review application for Opdivo (nivolumab) as adjuvant therapy for patients with resected esophageal or gastroesophageal junction cancer. News release. Bristol Myers Squibb. January 20, 2021. Accessed January 25, 2021. 

11. Chung H, Bang Y, Fuchs C, et al. KEYNOTE-811 pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction cancer: a double-blind, randomized, placebo-controlled phase 3 study. 

. 2019;30(suppl 4):IV25. doi:10.1093/annonc/mdz155.093

12. Janjigian YY, Chou JF, Simmons M, et al. First-line pembrolizumab (P), trastuzumab (T), capecitabine (C) and oxaliplatin (O) in HER2-positive metastatic esophagogastric adenocarcinoma (mEGA). Presented at: 2019 Gastrointestinal Cancers Symposium; January 16-19, 2019; San Francisco, CA. Accessed January 26, 2021. 

Articles

This past year, 2020, will go down  as a practice-changing one for the treatment of esophageal cancer, said Yelena Y. Janjigian, MD.

Checkpoint Inhibitors Gain Traction in the Frontline Setting for Cancers of the Esophagus

For metastatic pancreatic cancer, treatment options expanded in late 2018 through 2019 with FDA approvals of larotrectinib (Vitrakvi) for the treatment of solid tumors with 

 fusions; entrectinib (Rozlytrek), another pan-tumor agent for 

 fusions; and olaparib (Lynparza), a PARP inhibitor that can be used as maintenance treatment for some patients with 

The recently updated American Society of Clinical Oncology (ASCO) guidelines for the treatment of metastatic pancreatic cancer offer guidance on how to incorporate these therapies into clinical practice.

Notably, the 2020 update recommends early testing for genomic alterations.

“Pancreas cancer has lagged, compared [with] other solid tumor types, in molecular testing and transitioning from indiscriminate chemotherapy to genome immune targeted drugs,” said Gregory Botta, MD, PhD, a medical oncologist at Moores Cancer Center at UC San Diego Health in La Jolla, California. “These guidelines push oncologists across the board to start implementing next-generation sequencing into their practice, and that can change outcomes for our patients.”

Median overall survival (OS) for patients with advanced metastatic disease is about 12 months,

 and fewer than 10% of patients are alive 5 years after their initial diagnosis.

 Although targeted therapies have offered hope to patients with many other types of cancer, including lung cancer and breast cancer, there were few good treatment options for patients with metastatic pancreatic cancer until recently.

Early Germline and Somatic Testing Recommended

The ASCO guidelines recommend “early testing for actionable genomic alterations…for patients who are likely to be potential candidates for additional treatment after first-line therapy.”

 Germline and tumor (somatic) testing are recommended, and testing should look for microsatellite instability/mismatch repair deficiency, 

 Ideally, genomic testing should be conducted as part of an initial assessment so results are available in a timely fashion when clinical decisions are made.

Integrating genomic testing into clinical practice will require new systems. “There’s a whole pipeline that needs to be developed for each individual practice and clinician,” Botta said. A discussion with the patient focusing on the pros, cons, and logistics of genomic testing is recommended; the updated ASCO guidelines specifically state that this conversation should include “the frequency of actionable findings, treatment implications of testing results, and genetic counseling related to germline testing.”

Deciding which tests to order is important, as a variety of institutions and companies now offer next-generation sequencing. Oncology practices must set aside time to complete required paperwork and develop a process to ensure timely review of test results.

Targetable Genomic Alternations Affect a Minority of Patients With Pancreatic Cancer

Although the updated ASCO guidelines are a significant step forward, they “will have a modest impact on the overall care of patients with pancreatic cancer,” said Minsig Choi, MD, director of outpatient medical oncology and gastrointestinal medical oncology at Stony Brook Cancer Center in New York.

“Targeted therapies are helpful for patients with these alterations, but most patients with advanced pancreatic cancer are still left with conventional chemotherapy,” Choi said.

However, early genomic testing gets targeted therapies to patients who are likely to benefit from them, and research suggests that targeted therapy may improve clinical outcomes. According to a retrospective analysis of the Know Your Tumor registry trial, patients with pancreatic cancer who had actionable molecular alterations and received a matched therapy had a significantly longer median overall survival than patients who only received unmatched therapies (2.58 years vs 1.51 years). The overall survival for patients who received a matched therapy was also significantly longer than the OS rate for patients who did not have an actionable molecular alteration (2.58 years vs 1.32 years).

Larotrectinib or Entrectinib Recommended for Patients With NTRK Fusions

For the first time, treatment with larotrectinib or entrectinib is recommended in the second- and later line settings for patients with tumors harboring 

 fusions. Both drugs were approved by the FDA for patients with solid tumors on the basis of basket trials that included few patients with pancreas cancer.

The safety and efficacy of larotrectinib was established in a study of 3 trials involving 55 patients with TRK fusion-positive tumors; 1 of those patients had pancreatic cancer. The overall rate of response was 75%; 13% of patients experienced a complete response, and 62% (including the 1 patient with pancreatic cancer) experienced a partial response. Seventy-three percent of patients were progression free at 6 months; 55% were progression free at 1 year.

Entrectinib was tested in more than 50 patients with solid tumors with NTRK molecular alternations. The objective response rate was 57.4%, with 4 complete responses. A partial response was observed in 2 of the 3 patients with pancreatic cancer. Median progression-free survival (PFS) was 11.2 months and OS was 20.9 months.

“These were not randomized trials and only included small numbers of [patients with pancreatic cancer], but the response rates were so overwhelmingly high compared [with] standard treatment that these drugs were included in the guidelines,” Botta said. “Currently, overall survival with chemotherapy in a second-line setting is about 6 months; with best supportive care, it’s about 2.8 months. When a study shows overall survival of 21 months, as with entrectinib, that’s huge.”


To date, larotrectinib and entrectinib have not been studied head-to-head, so “the best choice remains unknown,” said Ryan W. Huey, MD, assistant professor in the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston. Future research may provide additional guidance.

At this point, Botta said, there’s “a bit more data” to support entrectinib. “Entrectinib improved both PFS as well as OS; larotrectinib improved PFS but not OS,” he said.

A Second-Line Option for Patients With BRCA Mutations

 mutation and have completed at least 16 weeks of first-line platinum-based chemotherapy without disease progression may either continue chemotherapy or switch over to olaparib maintenance, according to the guidelines.1 The recommendation to consider olaparib is based on the phase 3 POLO trial (NCT02184195), in which some patients were started on maintenance olaparib 4 to 8 weeks after chemotherapy.

 Their outcomes were compared with those of patients who received a placebo after completing chemotherapy. Median PFS was significantly longer in the olaparib group than the placebo group (7.4 months vs 3.8 months). However, an interim analysis of OS did not show a significant difference (18.9 months with olaparib vs 18.1 with placebo).

Of note, this trial compared olaparib to a treatment holiday, which is not the current standard of care, said Alok Khorana, MD, director of the Gastrointestinal Malignancies Program at the Cleveland Clinic in Ohio and a contributor to the updated ASCO guidelines. “A more appropriate control would have been continued chemotherapy,” he said.

Additional studies may provide further information and eventually help clinicians appropriately sequence treatment for patients with 

 mutations. At present, though, olaparib may be a good option for those who have plateaued on chemotherapy. “You can say, ‘We’ve exhausted the efficacy of chemotherapy. Let’s change you over to olaparib, so instead of coming into the infusion center 2 or 3 times a month, you can take olaparib on your own at home,’” Botta said.

Olaparib may also be a good option for patients who are experiencing chemotherapy-related toxicities, he said. Switching these patients to olaparib may allow them to regain quality of life.

Addressing Cost and Logistical Challenges

Scientifically, the guidelines are clear: there is significant potential benefit to genomic testing for all patients with pancreatic cancer. However, deciding to test or not is a complex decision that must be made in concert with the patient.

Cost is a major concern for many patients. “Next-generation sequencing is now widely available, and costs have dropped significantly,” Khorana said. “Some tests are covered by insurance, and some patient advocacy organizations are also arranging for expense-free testing for patients.” However, in light of uncertainty regarding insurance coverage and copayments, patients may be hesitant to agree to genomic testing. Of 1856 patients initially referred to the Know Your Tumor registry, a program of the Pancreatic Cancer Action Network that coordinates molecular testing and delivers a report of molecularly tailored treatment recommendations, 15 patients declined to move forward with the program because of the perceived risk of financial burden, even though “most patients had adequate insurance or were deemed to be eligible for financial assistance through the laboratories, and patients were reassured that [the] clinical coordination team would help to negotiate to minimize the cost of molecular testing.”

When cost is a consideration and the likelihood of discovering an actionable alteration is low, patients may decline genomic testing despite potential benefits. A frank discussion of costs and treatment alternatives is necessary, and physicians must allow time to effectively hear and address patient concerns. “It’s best to ensure patients are fully informed so there are no ‘surprise billing’ issues,” Khorana said.

Genomic testing may enable patients to enroll in targeted clinical trials. “Identification of alterations may help direct patients to specific mutation-directed trials and thereby improve access to newer drugs,” Khorana said. Already, clinical trials are studying various 

 mutations and the response of patients with these mutations to specific therapies. In the future, scientists may identify additional actionable alternations, allowing clinicians to target various subsets of pancreatic cancer more precisely.

“All pancreas cancers derive in the pancreas, but everybody’s pancreas cancer is different,” Botta said. “Genome sequencing allows us to personalize treatment, so we get the appropriate therapy with the appropriate drugs to the right patients.”

1. Sohal DPS, Kennedy EB, Cinar P, et al. Metastatic pancreatic cancer: ASCO guideline update. J Clin Oncol. 2020;38(27):3217-3230. doi:10.1200/JCO.20.01364

2. Pishvaian MJ, Blais EM, Brody JR, et al. Overall survival in patients with pancreatic cancer receiving matched therapies following molecular profiling: a retrospective analysis of the Know Your Tumor registry trial. 

. 2020;21(4):508-518. doi:10.1016/S1470-2045(20)30074-7

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

. 2019;381(4):317-327. doi:10.1056/NEJMoa1903387

4. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. 

. 2018;378(8):731-739. doi:10.1056/NEJMoa1714448

5. Doebele R, Paz-Ares L, Farago AF, et al. Entrectinib in NTRK-fusion positive (NTRK-FP) non-small cell lung cancer (NSCLC): Integrated analysis of patients enrolled in three trials (STARTRK-2, STARTRK-1 and ALKA-372-001). Presented at: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. doi:10.1158/1538-7445.AM2019-CT131

In the future, scientists may identify additional actionable alternations, allowing clinicians to target various subsets of pancreatic cancer more precisely.









Genomic Testing Makes Inroads After First-Line Therapy in Metastatic Pancreatic Cancer

Until recently, few options existed for patients with HER2-positive breast cancer who progressed on earlier lines of therapy. “We had a first-line and second-line therapy; and then, third line and beyond, there wasn’t what we would consider a standard regimen,” Rashmi K. Murthy, MD, MBE, assistant professor in the Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston, said in an interview with 

Progression-free survival (PFS) was often short, typically less than 5 months. Brain metastases, which occur in approximately 40% to 50% of patients with HER2-positive breast cancer, affected the quality of life of many who survived.

Recent approvals of 3 drug combinations—neratinib (Nerlynx) in combination with capecitabine1; tucatinib (Tukysa) plus trastuzumab (Herceptin) and capecitabine

; and Phesgo, a subcutaneous formulation containing trastuzumab, pertuzumab (Perjeta), and hyaluronidase-zzxf for injection under the skin

—offer new tools that may prolong life and control brain metastases across lines of therapy. In addition, promising research has demonstrated the potential for the second- generation antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) to treat patients who have received 2 or more lines of prior therapy.

HER2-Targeted Agents Gain Indications in Metastatic Disease 

Recent data have indicated that HER2-targeted tyrosine kinase inhibitors (TKIs) are reasonable options for therapy of patients with metastatic breast cancer in the second-line setting and beyond.

In February 2020, the FDA approved neratinib (an irreversible pan-HER TKI) in combination with capecitabine for adults with advanced or metastatic HER2- positive breast cancer who have already received 2 or more anti-HER2–based regimens.

 Approval for this indication was based on the NALA trial (NCT01808573), which compared the effectiveness of capecitabine plus neratinib versus capecitabine plus lapatinib (Tykerb), a reversible TKI targeting both EGFR and HER2. The trial demonstrated that neratinib resulted in a superior 12-month PFS rate of 28.8% versus 14.8% for the lapatinib arm. The corresponding mean PFS values were 8.8 months and 6.6 months (HR, 0.76; 95% CI, 0.630.93; 

 = .0059). Median overall survival (OS) improved numerically for the neratinib group, at 21.0 months compared with 18.7 months for the lapatinib group, but the difference was not statistically significant (HR, 0.88; 95% CI, 0.72-1.07; 

 = .2086). Median response duration was also longer for the neratinib group, at 8.5 months versus 5.6 months with lapatinib (HR, 0.50; 95% CI, 0.33-0.74;

“The NALA trial showed a modest progression-free survival benefit, but it has not yet shown a [significant] overall survival benefit,” Murthy said. Of note were results regarding the development of metastatic central nervous system (CNS) disease. There were fewer interventions for CNS disease in patients treated with neratinib (22.8%) compared with lapatinib (29.2%; 

 = .043), and time to intervention for CNS disease also improved in the neratinib arm. These results led investigators to suggest that the neratinib combination may have helped prevent or at least delayed the development of CNS disease.

Importantly, although neratinib has shown some efficacy in patients with brain metastases, the NALA trial did not include any patients with active, symptomatic brain metastases. The phase 2 TBCRC 022 trial (NCT01494662) evaluated the neratinib/capecitabine combination in 49 patients with measurable, progressive HER2-positive brain metastases. In patients without prior lapatinib therapy (n = 37), the CNS objective response rate (ORR) was 49%, with 19% of patients having stable disease (SD) for 6 or more cycles; only 3% of patients experienced progressive CNS disease only. Among those who had previously received lapatinib (n = 12), the CNS ORR was 33%, with 25% of patients having SD for 6 or more cycles; only 8% of patients experienced progressive disease in the CNS only.

In the lapatinib-naïve group, the median PFS was 5.5 months and the median OS was 13.3 months. Corresponding rates in the lapatinib group were 3.1 months and 15.1 months. These results led investigators to conclude that the combination is active against refractory, HER2-positive breast cancer brain metastases. 

Diarrhea is the primary toxicity associated with neratinib, and it was the most common AE in both the NALA and TBCRC 022 trials. The investigators recommended strategies for diarrhea prevention and management to limit the dose reductions and study discontinuation associated with this AE (TABLE

Approval for tucatinib in combination with trastuzumab and capecitabine in patients with advanced, unresectable or metastatic HER2-positive breast cancer following 1 or more prior anti-HER2–based regimens was based on the HER2CLIMB study (NCT02614794).

 The phase 2 trial compared the triplet regimen against placebo plus trastuzumab and capecitabine and included patients with active brain metastases. All patients had previously received trastuzumab, pertuzumab, and trastuzumab emtansine (T-DM1; Kadcyla) in the metastatic setting.

“To date, there had not been a randomized study for metastatic HER2-positive breast cancer that included patients with brain metastases,” Murthy said. The inclusion of these high-risk patients was a deliberate decision based on “preclinical data that suggested [tucatinib] would have efficacy across the blood-brain barrier,” she said. “There are also preclinical data 

showing that mice that had intracranial disease and were treated with tucatinib lived longer than mice that had been treated with lapatinib or neratinib.”

As expected, data from the trial showed significant benefits for patients treated with the tucatinib combination, with 1-year PFS rates of 33.1% versus 12.3% for the placebo group (HR, 0.54; 95% CI, 0.42-0.71; 

 < .001). Among patients with brain metastases, the 1-year PFS rates were 24.9% for the tucatinib group and 0% for the placebo group. In the overall cohort, 2-year OS rates were 44.9% in the tucatinib group and 26.6% in the placebo group (HR, 0.66; 95% CI, 0.50-0.88; 

“HER2CLIMB showed a survival advantage for patients with [previously] treated brain metastases, an effect that had not been seen before with such large numbers of patients in a controlled clinical trial,” said William J. Gradishar, MD, professor of medicine (hematology and oncology) and chief of hematology and oncology in the Department of Medicine at Northwestern University Feinberg School of Medicine in Chicago, Illinois. “This is probably the most compelling data set for a specific therapy that affects survival of patients who have brain metastases.”

According to an exploratory analysis of patients with CNS disease treated on HER2CLIMB, 47.3% of those with active, measurable brain lesions treated with the tucatinib triplet regimen experienced intracranial ORR compared with only 20.0% of those who were treated with the placebo regimen (

 = .03). In all patients with brain metastases, CNS PFS (time to disease progression in the brain or death) improved significantly (HR, 0.32; 95% CI, 0.22-0.48; 

 < .00001), as did OS (HR, 0.58; 95% CI, 0.400.85; 

 = .005), and these benefits were further validated in subgroups of patients whose brain metastases were classified as either active or stable.

“It’s not just that patients with brain metastases were staying alive longer but also that they saw objective shrinkage of the tumors in the brain,” said Ian E. Krop, MD, PhD, associate chief of the Division of Breast Oncology of the Susan F. Smith Center for Women’s Cancers and clinical research director of the Breast Oncology Center, both at Dana-Farber Cancer Institute in Boston, Massachusetts.

In the overall cohort, adverse effects (AEs), particularly diarrhea and elevated aminotransferase levels, occurred more frequently in the tucatinib group.7 “There was about a 13% incidence of grade 3 or higher diarrhea on tucatinib versus 9% on the placebo arm, but the diarrhea was quite manageable with short courses of antidiarrheals and wasn’t a significant problem,” said Murthy, who treated patients participating in HER2CLIMB and was the first study author. “We know that capecitabine, in and of itself, can cause diarrhea. For me, based on the adverse effect profile, it was hard to tell which patients were on tucatinib and which were on placebo.” 

Most patients in the tucatinib group experienced AEs, but less than 6% discontinued treatment with tucatinib because of them.

Based on the results of both the NALA and HER2CLIMB trials, Krop said, “I think it makes more sense to use the HER2CLIMB regimen with tucatinib than it does to use neratinib” when treating women with metastatic HER2-positive breast cancer. “To me, the question is: Does neratinib work in a patient whose cancer has progressed on tucatinib?” he said. “Neratinib is a very potent and powerful agent in the laboratory setting; it’s an irreversible inhibitor, as opposed to tucatinib, which is reversible. Based on that, it may be that even when a cancer becomes resistant to tucatinib, it could still be sensitive to neratinib. I think that’s a question that needs to be addressed.”

T-DM1 and T-DXd are HER2-directed antibody-drug conjugates. Both agents have data supporting their use in patients with HER2-positive breast cancer, with FDA-approved indications in the relapsed setting.

In the prospective phase 3b KAMILLA trial (NCT01702571), which involved T-DM1, almost 43% of patients with measurable brain metastases and HER2-positive locally advanced or metastatic breast cancer derived clinical benefit from treatment.

 Three of the 126 patients with measurable brain metastases experienced a complete response. Twenty-four had a partial response, and 27 experienced SD lasting 6 months or more. Almost half of patients (49.3%) who had not received prior radiotherapy for brain metastases experienced metastasis shrinkage of 30% or more. The median PFS and OS in these patients was 5.5 months and 18.9 months, respectively.

Patients with brain metastases experienced more nervous system toxicities from treatment, including epilepsy, seizure, and brain edema, than did those without brain involvement. Grade 5 AEs occurred in 3.5% of patients with baseline brain metastases and 1.9% of patients without brain metastases.

These data led investigators to conclude that T-DM1 is active and generally well tolerated, and patients who develop brain lesions during treatment with the agent may benefit from continued T-DM1 treatment after local therapy.

Krop detailed how T-DXd stands apart from other available agents with a similar mechanism of action. “The antibody part is essentially the same, but the payload—the chemotherapy part—is a different class of chemotherapy,” he said. “It’s from a class that’s not typically used in the treatment of breast cancer, so there’s less of a chance the cancer would have developed resistance.”

Additionally, Krop said, “once the conjugate delivers the payload to a HER2-positive cancer cell, some of the chemotherapy molecules can diffuse out of the cell and kill neighboring tumor cells.” That is important because research has shown that heterogeneous HER2 expression can decrease the effectiveness of drugs like T-DM1. “If you have a tumor that’s a mixture of cells, some with a lot of HER2 [expression] and others without, the concern is that you’ll kill the high-HER2 cancer cells but leave some behind,” he said.

The DESTINY-Breast01 trial (NCT03248492) examined the effects of T-DXd in patients with heavily pretreated HER2-positive metastatic breast cancer. All patients had previously been treated with T-DM1; most had received multiple other therapies as well. Nearly 61% of patients experienced a response to therapy. Median response duration was 14.8 months, and median PFS was 16.4 months.

“To see a 61% response rate in a very heavily pretreated population is unprecedented,” Krop said. “The response rates and duration of disease control are much better than [what] we’ve seen with any other drug in this setting.” The most common grade 3 or higher AEs were decreased neutrophil count (20.7%), anemia (8.7%), and nausea (7.6%). Patients developed interstitial lung disease at a rate of 13.6%.

“The downside to trastuzumab deruxtecan is that a fraction of patients can experience interstitial lung disease. A few on the trial died,” Gradishar said. “But for the most part, the drug is well tolerated.” Given the risk of serious lung involvement, he said that clinicians should carefully question patients about their breathing and lung health and “have a low threshold” for determining which complaints should receive more in-depth attention.

Of the 184 patients treated on the trial, 48 experienced disease progression; among them, the CNS (brain) was the site of progression in only 4 patients. Two of these patients had CNS metastases at baseline and experienced CNS progression at 78 and 85 days. Brain metastases were noted at 323 and 498 days in the other 2 patients, who had no prior history of CNS disease. Additionally, a patient experienced 55% regression of a metastatic brain lesion after 12 weeks of treatment; she had undergone 16 prior lines of treatment, wholebrain radiotherapy, and stereotactic radiosurgery.

Median PFS values were similar for patients with and without brain involvement. 

Despite these promising findings, additional research is needed to expand the examination of T-DXd’s impact beyond stable, asymptomatic brain metastases. As Murthy noted, the DESTINY-Breast01 trial “did not include patients with active brain metastases.”

According to Krop, investigators are currently conducting studies to determine whether administering T-DXd sooner might ultimately extend survival and disease-free progression. Trials are currently comparing the effectiveness of T-DM1 and T-DXd in the second-line setting.

Subcutaneous Injection Is Approved for Metastatic HER2-Positive Disease, With Potential in the Recurrent Setting 

On June 29, 2020, the FDA approved Phesgo, a fixed-dose combination of trastuzumab and pertuzumab, along with hyaluronidase-zzxf, for subcutaneous administration in combination with intravenous chemotherapy to treat adults with metastatic HER2-positive disease.

 This new formulation, which can also be used in patients with recurrent disease, combines 2 monoclonal antibodies to be administered as a single subcutaneous injection.

This approval has the potential to dramatically alter the treatment experience for patients with HER2-positive breast cancer, as the combination of trastuzumab, pertuzumab, and taxane chemotherapy, administered intravenously, is currently listed as a preferred regimen for patients with HER2-positive recurrent or metastatic breast cancer in the National Comprehensive Cancer Network Clinical Practice Guidelines.

 Intravenous infusion of trastuzumab and pertuzumab typically takes 1.0 to 2.5 hours, whereas subcutaneous injection of Phesgo takes approximately 5 to 8 minutes.

Results of the phase 2 PHranceSCa study (NCT03674112) showed that 85% of patients receiving treatment for HER2-positive breast cancer preferred subcutaneous treatment because it was more comfortable and required less time in the clinic. The results of the phase 3 FeDeriCa study (NCT03493854), which supported the Phesgo approval, demonstrated noninferiority of the subcutaneous option compared with standard intravenous delivery. Specifically, blood concentrations of trastuzumab and pertuzumab after subcutaneous treatment confirmed delivery of sufficient drug doses.

Options Will Continue to Expand Across the Continuum of Care

Based on these data, Krop said new options represent an opportunity to tailor treatment across lines of therapy depending on the patients’ needs. “I don’t think we can use a one-size-fitsall approach anymore,” he said. “You have to pay attention to the specifics of the particular patient in front of you. If you have a patient who has progressive brain metastases, then I think it clearly makes sense to use the tucatinib triplet regimen. In contrast, if you have a patient who’s never had brain metastases or had a metastasis long ago that was treated and hasn’t recurred, I think treating with T-DXd gives you a high chance of a good and durable response.”

“I think the real comparison now is between trastuzumab deruxtecan and tucatinib. Trastuzumab deruxtecan has an advantage in that it was first out and it’s a single drug, not a 3-drug regimen,” Gradishar said. “Where it’s lacking at this point is that there are more data regarding brain metastases with tucatinib than with trastuzumab deruxtecan.”

Moving forward, novel drug combinations may further expand treatment alternatives. “We saw excellent results with trastuzumab deruxtecan,” Murthy said. “We’ve seen excellent results with tucatinib. What about combining those 2 drugs and seeing [whether] we can improve outcomes even further?

1. FDA approves neratinib for metastatic HER2-positive breast cancer. FDA. Updated February 26, 2020. Accessed August 31, 2020. https://bit.ly/3jACK8P

2. FDA approves tucatinib for patients with HER2-positive metastatic breast cancer. FDA. Updated April 20, 2020. Accessed August 31, 2020. https://bit.ly/3gPhryO

3. FDA approves breast cancer treatment that can be administered at home by health care professional. FDA. June 29, 2020. Accessed August 27, 2020. https://bit.ly/3cnaPqA

4. Modi S, Saura C, Yamashita T, et al; DESTINY-Breast01 Investigators. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. 

. 2020;382(7):610-621. doi:10.1056/NEJMoa1914510

5. Saura C, Oliveira M, Feng YH, et al; NALA Investigators. Neratinib plus capecitabine versus lapatinib plus capecitabine in HER2-positive metastatic breast cancer previously treated with ≥2 HER2-directed regimens: phase III NALA trial. 2020;38(27):3138-3149. doi:10.1200/JCO.20.00147.

6. Feldman RA, Gelman RS, Anders CK, et al; Translational Breast Cancer Research Consortium. TBCRC 022: a phase II trial of neratinib and capecitabine for patients with human epidermal growth factor receptor 2–positive breast cancer and brain metastases. 

. 2019;37(13):1081-1089. doi:10.1200/JCO.18.01511

7. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. 

. 2020;382(7):597-609. doi:10.1056/NEJMoa1914609

8. Lin NU, Murthy RK, Anders CK, et al. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB). 

Until recently, few options existed for patients with HER2-positive breast cancer who progressed on earlier lines of therapy. Recent approvals of 3 drug combinations offer new tools that may prolong life and control brain metastases across lines of therapy.

Jennifer Fink | Authors

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