Milind Javle, MD

Milind Javle, MD, professor in the department of gastrointestinal medical oncology, division of cancer medicine at The University of Texas MD Anderson Cancer Center, discusses the phase 3 HIMALAYA study (NCT03298451) of durvalumab (Imfinzi) and tremelimumab (Imjudo) in patients with locally advanced or metastatic hepatocellular cancer (HCC).

The open-label, multicenter, global phase 3 HIMALAYA trial randomly assigned 1171 patients on a 1:1:1 basis to receive durvalumab plus tremelimumab (STRIDE), durvalumab alone, or sorafenib (Nexavar). The primary end point was overall survival (OS) improvement of STRIDE over sorafenib, and a secondary end point was noninferiority of OS of durvalumab versus sorafenib.

At a median follow-up of approximately 32 months, the median OS was 16.43 months for STRIDE, 16.56 months for durvalumab, and 13.77 months for sorafenib. The HR for superiority of STRIDE versus sorafenib was 0.78 [96.02% CI, 0.65-0.93; 

 = .0035] and the HR for noninferiority of durvalumab versus sorafenib was 0.86 [95.67% CI, 0.73-1.03; noninferiority margin, 1.08]. The objective response rate (ORR) was 20.1% for STRIDE, 17.0% for durvalumab, and 5.1% for sorafenib. According to Javle, the improvement in OS appeared to increase with time.

Javle says this trial was significant because it showed efficacy for an immune checkpoint inhibitor combination without VEGF-targeted agents, as patients with portal vein thrombosis or portal hypertension cannot receive the VEGF inhibitor bevacizumab (Avastin).

 The [HIMALAYA] study very remarkably achieved its aim with an improvement in OS demonstrable in the study arm, that is durvalumab and tremelimumab versus sorafenib. The survival improvement was around 13 months in the sorafenib arm as compared with 16 months in the STRIDE arm with a hazard ratio of 0.78. In the other 2 arms, that is the other arm durvalumab single-agent versus sorafenib, it was a noninferiority study design and that goal was achieved with the hazard ratio 0.86. Also interestingly, the response rate was higher with the STRIDE regimen over 20% versus 5% with sorafenib. The improvement in survival...appeared to increase with time. So, when you look at survival results at, say, 30 months, this difference was even greater.

So, I think this was a very important trial because it included a unique regimen of a combination of checkpoint inhibitors and did not include VEGF inhibitor–targeted therapy, because this is often a problem with systemic therapy for HCC as patients have portal vein thrombosis or portal hypertension and viruses and cannot get VEGF-directed therapies like bevacizumab. So [this is] certainly a very remarkable advance in HCC management. And I'm happy now that we have another tool in our toolbox for this cancer.

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Milind Javle, MD, discusses the phase 3 HIMALAYA study of durvalumab and tremelimumab in patients with locally advanced or metastatic hepatocellular cancer. 

Phase 3 HIMALAYA Trial Shows OS Benefit of Durvalumab in HCC

Milind Javle, MD, professor in the department of gastrointestinal medical oncology, division of cancer medicine at The University of Texas MD Anderson Cancer Center, discusses the use of durvalumab (Imfinzi) for locally advanced or metastatic biliary tract cancer (BTC).

According to Javle, no regimen in BTC has been shown to improve patient outcomes since the introduction of gemcitabine plus cisplatin. The global phase 3 TOPAZ-1 trial (NCT03875235) randomly assigned patients 1:1 to receive the combination of durvalumab, gemcitabine, and cisplatin versus gemcitabine and cisplatin plus placebo. After 6 months, patients received maintenance therapy with durvalumab or placebo.

The primary end point was overall survival (OS). At a median follow-up of 13.7 months for the durvalumab arm and 12.6 months for the placebo arm, median OS was 12.8 months with durvalumab and 11.5 months with placebo. Additionally, Javle says the OS improvement deepened over time. At 18 months, the OS rate was 35.1% for durvalumab versus 25.6% for placebo, whereas at 24 months, it was 24.9% versus 10.4%, respectively.

Additionally, there was no significant added toxicity, with the rate of grade 3 or 4 adverse events being 75.7% for the durvalumab arm versus 77.8% with the placebo arm. This was a significant trial that led to the FDA approval of durvalumab for previously untreated advanced BTC.

 The TOPAZ-1 trial was also a very remarkable study because it's been over a decade since gemcitabine and cisplatin were shown to be superior to single-agent gemcitabine. And therefore, the doublet was listed—it was basically Compendia-listed. All subsequent trials, which are combination trials, since then have been negative except this one. This trial included gemcitabine, cisplatin, and durvalumab versus gemcitabine and cisplatin plus placebo given for 6 months, followed by durvalumab maintenance versus placebo maintenance.

OS was the primary end point of the trial. There was an OS improvement between gemcitabine, cisplatin, and durvalumab, as compared with gemcitabine and cisplatin, and this difference in survival appeared to increase with time. So, for instance, at 2 years and 3 years, the [Kaplan-Meier] curves split even further, where 10% survived at the end of 2 years versus 24% in the durvalumab arm. So clearly, this was another advance, and it was achieved without additive toxicity. Patients tolerated the addition of durvalumab very well, without significant toxicities noted with the combination. So this was a significant improvement in the armamentarium that we have currently for treating BTC.

Milind Javle, MD, discusses the use of durvalumab for locally advanced or metastatic biliary tract cancer. 

Addition of Durvalumab Improves OS for Advanced BTC

 A key takeaway point for my colleagues in community oncology is, cholangiocarcinoma is a diagnosis of exclusion; it requires careful pathology, and it requires multidisciplinary care. It does not necessarily need a lot of aggressive investigations to narrow down the diagnosis. Molecular profiling has been transformative in this disease, and it’s important to consider molecular profiling as early as possible during the disease course. The access to targeted therapies, such as with infigratinib with 

 fusions, has truly changed the course of this disease. I would encourage my colleagues in the community to consider these types of treatments that I’ve described, targeting 

, and others. However, the key would be to get a good biopsy specimen for molecular profiling or perhaps with ctDNA [circulating tumor DNA] so we can help our patients beyond the standard systemic chemotherapy.

One of the reasons that I’ve advocated early molecular diagnosis was from our own experience with the infigratinib study. Patients who received infigratinib in the second line had a higher response rate than those who received infigratinib in subsequent lines of therapy. We are expecting now that when these targeted drugs are used in the first line during the investigational trial, perhaps we’ll see an even stronger signal. I hope the time will come when we don’t have to use chemotherapy anymore for these patients and spare these unnecessary toxicities. That time is not here yet, but I think we will get there with appropriate and early use of molecular profiling.

Case: A 61-Year-Old Woman with Metastatic Cholangiocarcinoma

A 61-year-old woman presents with jaundice and changes in stool and urine color.

Enlarged liver is palpable on physical examination

Blood work reveals serum levels of CA 19-9 (1400 U/ml), bilirubin 2 mg/dL, ALT 550 U/L, AST 120U/L

Patient undergoes CT imaging and is found to have multiple liver masses, consistent with metastatic disease or intrahepatic cholangiocarcinoma (iCCA)

Histopathological examination identifies adenocarcinoma, CK7+, CK20-, HepPAR-, TTF- consistent with cholangiocarcinoma or upper GI Primary

Patient is diabetic and somewhat non-compliant with her diabetes medication

Patient is treated with chemotherapy (gemcitabine + cisplatin) for 24 weeks.

Patient is monitored for disease progression every 2-3 months by CT imaging.

Patient does well for 1 year after initiation of treatment but now has elevated CA 19-9 levels.

MRI scans show several liver and bone lesions but no signs of brain metastases.

Lab results are normal (absolute neutrophil count 4,000/mm3, platelets 150,000/ml, hemoglobin 12.1 g/dL

Patient undergoes NGS testing (Foundation Medicine, Inc.) and is found to have FGFR2-BICC1 gene fusion

Patient meets eligibility criteria for infigratinib phase 2 study and is enrolled in the trial and being treated with infigratinib

Patient does not show any signs of disease progression on MRI scans for six months, suggestive of stable disease and CA19-9 levels stay within normal limits.

Concluding his reflection on novel therapies in patients with cholangiocarcinoma, Milind Javle, MD, provides closing thoughts and practical advice for his community colleagues.

Key Takeaways for the Treatment of Cholangiocarcinoma

The past year-and-a-half has been truly remarkable for cholangiocarcinoma for the patients and for the providers. We have now 3 drugs that are approved. In the 

 field, we have infigratinib, like I described, as well pemigatinib. For those with 

 mutation R132, ivosidenib is an approved drug in that situation. Clearly patients have options with targeted therapy, which I feel are much more tolerable and superior to systemic chemotherapy, and these options didn’t exist just over a year ago. It’s an exciting time for us.

Pemigatinib was the first drug to be FDA approved for the treatment of 

 fusion cholangiocarcinoma, and the results are very remarkable. The response rate in the pivotal study called FIGHT with pemigatinib for 

 fusion cholangiocarcinoma, indicated a response rate of about 35%, duration of response about 8 months, progression-free survival about 6 months, and overall survival of about 21 months. These are very encouraging results. Most of the people treated with pemigatinib had received this drug in the second line of therapy, so they were less treated. Regardless, there were several patients treated in the third and subsequent line, and they also seemed to do very well. Toxicities with pemigatinib are similar to that of infigratinib and include hypophosphatemia, some of the mucositis, and also patients can develop diarrhea, ocular toxicities. Several of these effects are class effects related to FGFR inhibition because these drugs are very specific inhibitors, therefore they have this class effect of toxicities.

There have been several other exciting developments that have not yet necessarily met the FDA bar for approval, but have become a part of the NCCN [National Comprehensive Cancer Network] guidelines now, such as the treatment of cholangiocarcinoma with 

 V600E mutation. This mutation occurs commonly in melanoma and in about 5% of cholangiocarcinoma. Dabrafenib and trametinib, which is a combination of BRAF plus MEK inhibition, appears to be very effective with almost a 40% response rate, and is now in the NCCN guidelines. Our group performed a study with trastuzumab and pertuzumab, a combination that’s widely used in breast cancer. We investigated 

-amplified biliary tract cancer, again a very promising signal, that was published recently in 

 and we hope will meet the bar for NCCN guidelines.

Immunotherapy has been an amazing development over the past decade, and there have certainly been immunotherapy trials in cholangiocarcinoma as well. MSI [microsatellite instability]-high status in cholangiocarcinoma occurs in only about 1% of patients; for them, checkpoint inhibitors like pembrolizumab and nivolumab are very promising. In terms of patients with cholangiocarcinoma who are not MSI high, immunotherapy shows a signal that is quite modest. There was a KEYNOTE trial with pembrolizumab that enrolled over 100 patients, and the response rate seen was about 5.6%. There may be a tendency toward a somewhat higher response with PD-L1, but this is not proven. Nivolumab shows a similar response rate in a smaller study, about 10%.

There are now studies being conducted with immunotherapy in combination with targeted therapies, and we hope that with those types of combinations we will get a better signal. In the first-line setting, there are 2 important phase 3 trials. One is with gemcitabine and cisplatin plus or minus pembrolizumab. This trial has completed its accrual, and we hope that it will advance the cause of immunotherapy in the first-line setting. Similarly, there’s another trial called TOPAZ being conducted with durvalumab in combination with gemcitabine and cisplatin in Asia as well as in the Western world. The results of that trial are eagerly awaited.

Dr Milind Javle discusses novel therapies recently approved or under investigation across multiple lines of therapy in patients with cholangiocarcinoma. 

Recent Changes in the Cholangiocarcinoma Treatment Landscape

 In this pivotal trial of infigratinib, enrolled patients were extensively treated. In fact, only about one-third had received 1 prior line of therapy, and the rest had received 2 or more lines of therapy. This was a heavily pretreated population. They were treated with infigratinib, 125 mg daily on a 3 weeks on, 1 week off schedule. The overall response rate in the trial was 23%. Interestingly, we noted that patients who had received fewer lines of therapy had a better response rate compared with those who had received 2 or more lines of therapy. The progression-free survival in this trial was 7 months, the duration of response was 5 months, and overall survival extended to beyond 12 months; this was a pivotal and positive trial. I’ve just described the results of FOLFOX [folinic acid, fluorouracil, oxaliplatin] standard chemotherapy, which are relatively poor in comparison. Therefore, this drug got an accelerated approval from the FDA. The accelerated approval mechanism is a conditional approval that requires a subsequent phase 3 trial, which is being conducted at this time. This is called the PROOF trial. The patients who have not received any prior chemotherapy, treatment-naïve patients, are treated with infigratinib vs gemcitabine and cisplatin in the first-line setting. We are still waiting on the results of this trial, but it’s very exciting that patients like the one described now have an FDA-approved option for the treatment of cholangiocarcinoma with infigratinib. This is now known as Truseltiq, which was only the second drug to be approved by the FDA for cholangiocarcinoma. It is certainly a historic event for treating this disease.

At our institute, we were one of the leading sites for the CBGJ398X2204 trial that included infigratinib. We have treated several patients with this therapy. Most of these patients have done quite well with progressive disease or partial responses. There are some toxicities that are encountered with this drug, but in general these are manageable. The most common toxicities include hyperphosphatemia, or elevation of levels of phosphate, which must be carefully followed and sometimes treated with dietary restriction of phosphate, and chelating agents. Other toxicities include anorexia, alteration in taste, mucositis. There is a very low incidence of diarrhea, alopecia. The 2 important toxicities to watch out for are ocular. The most common ocular toxicity is dry eyes, however there are serious ocular toxicities, including retinal pigment epithelial detachment and central serous retinopathy. These are again rare and mostly grade 1 or 2, but must be carefully followed and watched for.

Milind Javle, MD, shares his personal experience and insights on the approval and use of infigratinib, an FGFR2 fusion–targeted therapy, in patients with previously treated advanced cholangiocarcinoma. 

Metastatic Cholangiocarcinoma: Phase 2 Infigratinib Study and Personal Experience With Infigratinib

For patients who do not have actionable mutations, the first-line chemotherapy is still based on the ABC-02 trial, which is gemcitabine and cisplatin. While this is the standard of care, it’s relatively suboptimal. The response rate is in the 20% to 30% range, progression-free survival of 6 to 8 months, and overall survival of 11 months. Therefore, although it is a standard, this is a standard that we hope we can change with therapy. There have been many promising trials, including one recently conducted in the United States with gemcitabine, cisplatin, and Abraxane [paclitaxel] that we hope will change this paradigm.

In the second-line setting, the ABC-06 trial investigated the use of FOLFOX [folinic acid, fluorouracil, oxaliplatin], which is the standard chemotherapy used in colon cancer, and also used in cholangiocarcinoma. Again, it is very modest in terms of how effective it is, with a 5% response rate, progression-free survival of 4 months, and overall survival of only 6 months. Clearly, this is an area that needs further investigation, and cholangiocarcinoma represents an area of great unmet need.

Going back to our patient, she received appropriate first-line treatment, gemcitabine and cisplatin. She had a good ECOG [The Eastern Cooperative Oncology Group] performance status of 1. She handled the treatment, however not surprisingly, she experienced disease progression and the tumor stopped responding after a few months of therapy.

Oncologist Dr. Milind Javel provides an overview of first- and subsequent-line treatments for patients with cholangiocarcinoma. 

Milind Javle, MD | Authors

Articles

Phase 3 HIMALAYA Trial Shows OS Benefit of Durvalumab in HCC

Addition of Durvalumab Improves OS for Advanced BTC

Key Takeaways for the Treatment of Cholangiocarcinoma

Recent Changes in the Cholangiocarcinoma Treatment Landscape

Metastatic Cholangiocarcinoma: Phase 2 Infigratinib Study and Personal Experience With Infigratinib

Treatment Options for Metastatic Cholangiocarcinoma