“Long-term survival in non-small cell lung cancer (NSCLC) exceeded historical standards among patients treated with the immune checkpoint inhibitor nivolumab (Opdivo), according to a study reported here.
“The 129 patients in the study had an estimated 5-year overall survival of 16%. Among those with measurable levels of PD-L1 expression, 5-year survival ranged as high as 43%.”
“Bristol-Myers Squibb Company (NYSE:BMY) today announced that CheckMate -143, a randomized Phase 3 clinical trial evaluating the efficacy and safety of Opdivo in patients with first recurrence of glioblastoma multiforme (GBM), did not meet its primary endpoint of improved overall survival over bevacizumab monotherapy. These data will be presented on May 7, 2017 at the World Federation of Neuro-Oncology Societies (WFNOS) meeting in Zurich, Switzerland.
” ‘GBM is a historically difficult disease to treat and conventional treatment options have demonstrated limited responses,’ said Fouad Namouni, M.D., head of Oncology Development and head of Medical, Bristol-Myers Squibb. ‘We remain steadfast in our pursuit of treatments for diseases with the highest unmet need and continue our work to determine how our Immuno-Oncology agents can potentially improve outcomes for these patients.’ ”
“Treatment with the immune checkpoint inhibitor nivolumab (Opdivo) yielded durable responses in some patients with advanced non-small cell lung cancer (NSCLC), with a five-year survival rate of 16 percent, according to data from a phase I clincal trial presented here at the AACR Annual Meeting 2017, April 1-5.
“According to the National Cancer Institute’s SEER data, five-year survival rate for patients with advanced lung and bronchus cancer is 4.3 percent, and for those with advanced NSCLC, it is 4.9 percent.
” ‘This is the first report of the long-term survival rate in patients with metastatic NSCLC treated with an immune checkpoint inhibitor. Our study results show that for a small subset of patients, immunotherapy can work for a very long time,’ said Julie Brahmer, MD, associate professor of oncology at the Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins.”
“Bristol-Myers Squibb Company (NYSE:BMY) today announced the first overall survival (OS) data from the Phase 3 CheckMate -067 clinical trial. With a minimum follow-up of 28 months, the median OS had not yet been reached in either of the two Opdivo treatment groups and was 20 months for the Yervoy monotherapy group (95% CI: 17.1-24.6). Opdivo in combination with Yervoy and as a monotherapy reduced the risk of death 45% [hazard ratio (HR) 0.55; 95% CI: 0.42-0.72; P<0.0001] and 37% (HR 0.63; 95% CI: 0.48-0.81; P<0.0001), respectively, compared with Yervoy alone. The two-year OS rates were 64% for the Opdivo plus Yervoy combination, 59% for Opdivo alone and 45% for Yervoy alone. Results will be presented today in the press program and an oral presentation during the Update, Novel Indication, and New Immuno-oncology Clinical Trials session from 3:35 to 3:50 p.m. ET (Late-Breaking Abstract CT075) at the American Association for Cancer Research Meeting 2017 in Washington, D.C.”
By 2050, the number of deaths due to malignant melanoma in the U.S. could be three times lower than peak levels reached before 1960. Researchers presented the data behind this prediction at the 2017 European Cancer Congress in January.
It is unclear how much of this anticipated decline in deaths can be attributed to the availability of new, effective treatments. However, it is obvious that much-increased awareness of sunlight exposure as the single factor most responsible for the development of skin melanoma has contributed to lower incidence of the disease.
In any case, the armament of treatments available for metastatic melanoma is currently such that this diagnosis has transformed from being almost universally fatal (even just a few years ago) into a being largely treatable. Since 2011, the U.S. Food and Drug Administration (FDA) has approved eight new drugs for melanoma.
Now, the pressing questions are: Why do these drugs not work for all patients? How can doctors select which patients should be treated with different types of drugs (targeted versus immune checkpoint versus intralesional)? And how can doctors identify patients who may benefit from a combination of different drugs?
BRAF-mutant melanoma: targeted drugs
Getting a positive test for the BRAF V600 tumor mutation is certainly good news for a newly diagnosed melanoma patient. This is because some targeted drugs work very well against such tumors, which account for about 50% of melanomas.
The drugs vemurafenib or dabrafenib, which attack tumors by inhibiting mutant BRAF proteins, are no longer used on their own because combining them with MEK inhibitors (cobimetinib and trametinib, respectively) works so much better. The percentage of patients who respond to combined BRAF/MEK inhibition is about 70% or higher, and durable complete responses were observed in about 19% patients with stage IV or unresectable stage III melanoma in three large clinical trials that tested these combinations. The results of treatment with dabrafenib and trametinib in patients with resectable stage III melanoma were particularly impressive. One hundred percent of these patients had no relapse within the first six months after treatment, compared to just 28% of those treated with standard chemotherapy. All patients had fewer than three metastatic sites.
That last point brings us to an important question: Which stage IV patients with BRAF-mutant (BRAF+) melanoma may need a combined treatment with targeted and immunotherapy (immune checkpoint) drugs?
It is becoming clear that stage IV patients who have fewer, less bulky metastases (lower tumor burden) do much better on BRAF/MEK-targeting drugs. High blood levels of a protein called LDH has long been recognized as a poor prognostic factor in melanoma, and it has not lost its grim significance in the era of targeted and immunotherapy drugs. Patients with high LDH and many metastatic tumors may need a combined treatment with BRAF/MEK inhibitors and immune checkpoint drugs.
So far, combination treatments have proven to be efficacious in patients with high tumor burden. The problem is that combining BRAF/MEK inhibitors with immune checkpoint drugs of the type known as anti-PD-1 increases side effects (toxicity) in quite a dramatic way. The Keynote 022 clinical trial—which combined the anti-PD-1 drug pembrolizumab with dabrafenib and trametinib in a small group of patients—reported that 40% experienced serious side effects (grade 3–4), and close to 30% discontinued treatment. A response rate of 60% was observed but remains to be confirmed.
A very similar rate of side effects was observed in a trial that combined atezolizumab (another immune checkpoint drug of the type known as anti-PD-L1) with vemurafenib and cobimetinib. On a highly positive note, 83% of the patients in this trial responded to the treatment, with 10% going into complete remission. An earlier study of durvalumab (also anti-PD-L1) with dabrafenib and trametinib saw responses in 69% of patients.
Several trials have also addressed the possibility of sequential treatment with two different types of drugs in order to address the problem of toxicity.
Immune checkpoint drugs across the molecular subtypes
Immune checkpoint drugs may also be effective in tumors with mutations other than BRAF, including a mutation in the NRAS gene (NRAS+). Data are being accumulated for patients receiving the FDA-approved immunotherapy drugs nivolumab or pembrolizumab (both anti-PD-1 drugs). It appears that 47% of patients receiving nivolumab survive for three years, and 48–49% of those receiving pembrolizumab survive for 2 years (pembrolizumab data have not yet reached the 3-year point). Combination of nivolumab and ipilimumab (a type of immune checkpoint drug known as an anti-CTLA4 antibody) could eventually produce better results, but at the cost of a much higher toxicity. It is a bit difficult to say if these data are similar for BRAF+ and BRAF-/NRAS+ melanoma patients receiving immune checkpoint drugs, because most patients with BRAF+ cancers receive targeted drugs.
Patients whose tumors test positive for an NRAS mutation (NRAS+) but not for a BRAF mutation (BRAF-) certainly have fewer treatment options than those whose tumors are BRAF-positive. NRAS mutations are encountered in about 20% of melanomas, and there are no effective targeted drugs for this subgroup. The only targeted drug that has shown promise in NRAS+ melanoma is binimetinib, a MEK inhibitor. In a trial for patients who were either untreated or had not responded to immune checkpoint drugs, binimetinib produced responses in 45% of patients; of those receiving only dacarbazine, a standard chemotherapy, just 9% responded. However, binimetinib prolonged overall survival by just 1.3 months compared to dacarbazine—not exactly an impressive improvement, which is apparently why the manufacturer of binimetinib withdrew its application for FDA approval of the drug.
Other trials are testing immune checkpoint drugs combined with MEK inhibitors for patients whose melanomas have no BRAF mutations (of which a substantial proportion have mutated NRAS). No results of these trials have yet been reported. Meanwhile, a very small study reported a response rate of 45% to combination of atezolizumab (anti-PD-L1) and cobimetinib in BRAF- melanoma patients. Additional trials testing durvalumab or pembrolizumab with trametinib have not posted results yet.
Regardless of specific tumor mutations, much hope lies in the clinical exploration of combinations of drugs that activate the immune system in different ways. Numerous immune checkpoint drugs work by activating the immune system. However, unlike the anti-PD-1 and anti-CTLA4 drugs discussed above, which remove inhibitory signals from the immune system’s T cells so they can attack cancer cells, newer drugs actually activate T cells by binding to positive regulatory proteins on these cells. Other new drugs aim to eliminate inhibitory signals created in the tumor microenvironment, such as those produced by different types of inflammatory cells or regulatory T cells. I would refer the interested reader to this excellent overview of these new drugs, which are now being tested against metastatic melanoma in numerous phase I trials.
With a few exceptions, glioblastoma (GBM) remains largely incurable, and the U.S. Food and Drug Administration (FDA) has approved few treatments for the disease. Surgery (when feasible), radiation, and temozolomide are used in most patients. But even if a newly diagnosed tumor can be surgically excised, recurrences are too common.
In this blog post, I simply list some of the new treatments available in clinical trials for GBM and other high-grade brain tumors. Only drugs that have at least some preliminary results of activity are included, and the list is not meant to be fully comprehensive. The interested reader can judge for herself what might be of interest, keeping in mind that no single treatment is suitable or will work for all GBM patients. Continue reading…
“The FDA granted fast track designation to ImmunoPulse IL-12 for the treatment of metastatic melanoma that progressed during therapy with pembrolizumab or nivolumab.
“ImmunoPulse IL-12 (OncoSec Medical) is an intratumoral anticancer gene therapy that expresses interleukin-12 (IL-12).
“ ‘With the number of melanoma patients now being treated with either pembrolizumab (Keytruda, Merck) or nivolumab (Opdivo, Bristol Myers Squibb) in either the first- or second-line settings, there will be an increasing number of patients who will not respond to therapy,’ Punit Dhillon, president and CEO of OncoSec, said in a company-issued press release. ‘Thus, there is a clear need for treatments that can rescue these patients and help them benefit from these immunotherapies.’ ”
In spring of 2014, Peter Fortenbaugh noticed what appeared to be a tick that had bitten his lower calf. “It turned out not to be a tick, but it didn’t really go away,” he says.
The spot began to grow and bulge, and in October, Peter showed it to his primary care doctor, who referred him to a dermatologist to remove it. At the time, Peter recalls, it did not occur to him that the growth could be serious.
“I was actually very concerned about skin cancer because I spent a lot of time out in the sun sailing,” Peter says. “I put on a tremendous amount of sunscreen and protection, but never on my legs…I never connected the dots.”
However, a biopsy of the growth came back positive for melanoma. Peter, who lives in Palo Alto, California, with his wife and three children, immediately reached out to several doctors in the San Francisco Bay Area, and all had the same advice: “Take it out, take a biopsy.” Continue reading…
“A few weeks ago, I was watching veg-out TV, quietly wondering to myself how a show called ‘Pure Genius’ could be so darned dumb.
“Then a commercial break added a new sort of mystification: A long, vivid ad touted the cancer drug Opdivo, a form of immunotherapy — an exciting new type of treatment that harnesses the body’s own immune system — for lung cancer.
“Lung cancer is the biggest cancer killer, so, in this anomalous country that allows direct-to-consumer drug ads, it was no surprise to see a lung cancer ad on network TV.”